Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors

An Open-Label, Phase Ib Dose Escalation Trial of Oral Combination Therapy With MSC1936369B and SAR245409 in Subjects With Locally Advanced or Metastatic Solid Tumors

Status

Completed

Phases

Phase 1

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01390818

Enrollment

146

Registered

2011-07-11

Start date

2011-05-31

Completion date

2015-04-30

Last updated

2017-03-07

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Breast Cancer, Colorectal Cancer, Locally Advanced Solid Tumor, Melanoma, Metastatic Solid Tumor, Non Small Cell Lung Cancer

Keywords

MEK inhibitor (Pimasertib), PI3K/mTOR Inhibitor, Solid Tumor, Phase I

Brief summary

This research trial is testing a combination of two experimental drugs, MSC1936369B (Mitogen-activated protein extracellular signal-regulated kinase (MEK) Inhibitor) and SAR245409 (Phosphatidylinositol 3-kinase (Pi3K)/Mammalian Target of Rapamycin (mTOR) inhibitor), in the treatment of locally advanced or metastatic solid tumors. The primary purpose of the study is to determine the maximum tolerated dose of the drug combination.

Interventions

DRUGMSC1936369B (pimasertib)

MSC1936369B (pimasertib) single dose capsule was administered at dose of 15 milligram (mg), 30 mg, 60 mg, 90 mg orally in successive 21-day cycles.Dose escalation was proceeded until Maximum Tolerated Dose (MTD) was reached. Once the MTD was reached, enrollment began in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohorts enrolled subjects with Breast Cancer, Non-Small Cell Lung Cancer (NSCLC), Melanoma, and Colorectal Cancer.

DRUGSAR245409 (PI3K and mTOR inhibitor)

SAR245409 (PI3K and mTOR inhibitor) capsule was administered orally at a dose of 30 mg, 50 mg, 70 mg and 90 mg in successive 21-day cycles. Dose escalation was proceeded until MTD was reached. Once the MTD was reached, enrollment began in four disease-specific expansion cohorts at either the MTD or a lower dose recommended by the Safety Monitoring Committee. The four expansion cohort enrolled subjects with Breast Cancer, NSCLC, Melanoma, and Colorectal Cancer.

Study design

Allocation

NON_RANDOMIZED

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to 82 Years

Healthy volunteers

Inclusion criteria

* Subject with advanced solid tumors for which there is no approved therapy: * Advanced solid tumor with diagnosed alteration in one or more of the following genes (PTEN, BRAF, KRAS, NRAS, PI3KCA, ErbB1, ErbB2, MET, RET, c-KIT, GNAQ, GNA11 and/or * A histologically or cytologically confirmed diagnosis of one of the following solid tumors: pancreatic, thyroid, colorectal, non-small cell lung, endometrial, renal, breast, ovarian carcinoma and melanoma * Subject with archived tumor tissue available for transfer to the Sponsor * Subject enrolled at lower dose level cohorts and MTD expansion cohorts must have tumor available for biopsy and agree to pre-treatment and on-treatment tumor biopsies * Subject has measurable or evaluable disease by response evaluation criteria in solid tumors (RECIST) v1.1 * Subject is aged greater than or equal to (\>=) 18 years * Subjects enrolled in disease specific expansion cohorts must fulfill all the inclusion/

Exclusion criteria

listed above with the following restriction to the Inclusion Criterion number 1: * Relapsed or refractory Kirsten rat sarcoma viral oncogene homolog (KRAS) or neuroblastoma RAS viral oncogene homolog (NRAS) mutated metastatic non-small cell lung cancer (NSCLC) with no approved therapies, or * Relapsed or refractory metastatic triple negative breast cancer defined as estrogen, progesterone and HER2 negative carcinoma of the breast with no approved therapies, or * Relapsed or refractory metastatic colorectal cancer (CRC) with dual KRAS and PIK3CA mutation with no approved therapies, or * BRAF V600E/K mutated unresectable or metastatic melanoma after progression on B-Raf proto-oncogene, serine/threonine kinase (BRAF) inhibitors * Other protocol-defined inclusion criteria could apply

Design outcomes

Primary

Measure	Time frame	Description
Number of Subjects With Dose Limiting Toxicities (DLT)	Day 1 up to Day 16 in cycle 1	DLT was defined as any of the following toxicities experienced during the first cycle of treatment at any dose level (DL) and judged not to be related to the underlying disease or any concomitant medication by the Investigator and/or the Sponsor: A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation (DE) would have exposed subjects to unacceptable risk. Any Grade greater than or equal to (\>=) 3 non-hematological toxicity, except for: Grade 3 diarrhea, nausea and vomiting with a duration less than or equal to (\<=) 48 hours despite adequate supportive care and Alopecia. Grade 4 neutropenia of \> 5 days duration or febrile neutropenia. Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia. Any treatment interruption \> 2 weeks due to AEs not related to the underlying disease or concomitant medication at any dose level and any severe, life-threatening impairing daily functions complication or abnormality.

Secondary

Measure	Time frame	Description
Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Area under the concentration-time curve from time 0 to the last quantifiable concentration.
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts	Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz).
Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Half-Life (t1/2) of MSC1936369B (Pimasertib)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf.
Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.Data was not available for 'Pimasertib (MSC1936369B) 60mg Twice Daily' arm as no subjects were considered evaluable because of limited number of samples collected to characterize the terminal phase rate constant needed for the calculation of Vz/f.
Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau per Day 1 dosing interval AUCtau.
Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax/Day 1 Cmax.
Maximum Observed Plasma Concentration (Cmax) for SAR245409	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	Baseline up to 30 Days after last dose; assessed up to 4 years	An adverse event (AE) was defined as any untoward medical occurrence in a subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 30 days after last dose.
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time (0-24 hours) at which the concentration is at or above the lower limit of quantification. Unit of assessment was hour\nanogram per milliliter (hr\ng/mL).
Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts	Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.
Apparent Terminal Half-Life (t1/2) of SAR245409	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	—
Total Body Clearance (CL/f) of SAR245409	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the dose with area under the plasma concentration time curve from time zero to infinity (AUC 0-inf)=Dose/AUC 0-inf.
Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.
Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau divided by Day 1 dosing interval AUCtau.
Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax divided by Day 1 Cmax.
pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); Cycle 1 Day 1 (C1D1) and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose)	pS6 Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily, Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily, Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily and Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily reporting arms.
pERK Concentrations in PBMCs	DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); C1D1 and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose)	pERK Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily, Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily, Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily and Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily reporting arms.
Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	From the date of randomisation every 6 weeks up to assessed up to 4 years	CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD= At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.
Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts	The time to reach maximum plasma concentration (Tmax) of SAR245409 was calculated.

Countries

Italy, Spain, United States

Participant flow

Recruitment details

First subject (informed consent): May 2011. Study completion date: Apr 2015. A total of 192 subjects were screened and 146 subjects entered the trial and received the investigational medicinal product (IMP).

Pre-assignment details

Study had a 4-day Drug-Drug Interaction (DDI) period, within 1 week prior to Day 1 Cycle 1, to assess possible interaction only in selected subjects where in SAR245409 and Pimasertib were administered alone on Day 1 and Day 3, respectively.

Participants by arm

Arm	Count
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 15 milligram (mg) along with single oral dose of 30 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	3
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 30 mg along with single oral dose of 30 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	3
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 15 mg along with single oral dose of 50 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	3
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 30 mg along with single oral dose of 50 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	4
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 60 mg along with single oral dose of 50 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	4
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 30 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	3
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 60 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	19
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 90 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	14
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily Pimasertib (MSC1936369B) capsule was administered at a single oral dose of 60 mg along with single oral dose of 90 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	3
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily Pimasertib (MSC1936369B) capsule was administered twice orally at a dose of 60 mg along with twice oral dose of 30 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	3
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily Pimasertib (MSC1936369B) capsule was administered twice orally at a dose of 45 mg along with twice oral dose of 50 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject (DE cohort).	4
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily Subjects with relapsed or refractory metastatic triple negative breast cancer (TNBC) defined as estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2) negative carcinoma of the breast with no approved therapies in disease specific expansion (DSE) cohort received Pimasertib (MSC1936369B) capsule at a single oral dose of 60 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of each 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject.	26
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily Subjects with a histologically confirmed diagnosis of relapsed or refractory metastatic non-small cell lung cancer (NSCLC) in disease specific expansion (DSE) cohort received Pimasertib (MSC1936369B) capsule at a single oral dose of 60 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject.	24
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily Subjects with relapsed or refractory metastatic colorectal carcinoma/cancer (CRC) in DSE cohort received Pimasertib (MSC1936369B) capsule at a single oral dose of 60 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject.	18
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily Subjects with relapsed or refractory metastatic melanoma (MEL) in DSE cohort received Pimasertib (MSC1936369B) capsule at a single oral dose of 60 mg along with single oral dose of 70 mg SAR245409 capsule on Day 1 of 21 days cycle until disease progression, intolerable toxicity, Investigator's decision to discontinue treatment, or withdrawal of consent by the subject.	15
Total	146

Baseline characteristics

Characteristic	CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Total	Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	MEL: Pimasertib 60mg and SAR245409 70mg Once Daily
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	6 Participants	39 Participants	1 Participants	2 Participants	2 Participants	2 Participants	3 Participants	1 Participants	3 Participants	2 Participants	0 Participants	1 Participants	2 Participants	4 Participants	8 Participants	2 Participants
Age, Categorical Between 18 and 65 years	12 Participants	107 Participants	2 Participants	1 Participants	1 Participants	2 Participants	1 Participants	2 Participants	16 Participants	12 Participants	3 Participants	2 Participants	2 Participants	22 Participants	16 Participants	13 Participants
Gender Female	11 Participants	87 Participants	3 Participants	1 Participants	2 Participants	1 Participants	1 Participants	1 Participants	6 Participants	13 Participants	1 Participants	2 Participants	0 Participants	26 Participants	15 Participants	4 Participants
Gender Male	7 Participants	59 Participants	0 Participants	2 Participants	1 Participants	3 Participants	3 Participants	2 Participants	13 Participants	1 Participants	2 Participants	1 Participants	4 Participants	0 Participants	9 Participants	11 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk	EG004 affected / at risk	EG005 affected / at risk	EG006 affected / at risk	EG007 affected / at risk	EG008 affected / at risk	EG009 affected / at risk	EG010 affected / at risk	EG011 affected / at risk	EG012 affected / at risk	EG013 affected / at risk	EG014 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —	— / —
other Total, other adverse events	3 / 3	3 / 3	3 / 3	4 / 4	4 / 4	3 / 3	19 / 19	14 / 14	3 / 3	3 / 3	4 / 4	26 / 26	24 / 24	18 / 18	15 / 15
serious Total, serious adverse events	1 / 3	0 / 3	2 / 3	1 / 4	1 / 4	1 / 3	14 / 19	10 / 14	1 / 3	2 / 3	3 / 4	16 / 26	13 / 24	10 / 18	8 / 15

Outcome results

Primary

Number of Subjects With Dose Limiting Toxicities (DLT)

DLT was defined as any of the following toxicities experienced during the first cycle of treatment at any dose level (DL) and judged not to be related to the underlying disease or any concomitant medication by the Investigator and/or the Sponsor: A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation (DE) would have exposed subjects to unacceptable risk. Any Grade greater than or equal to (\>=) 3 non-hematological toxicity, except for: Grade 3 diarrhea, nausea and vomiting with a duration less than or equal to (\<=) 48 hours despite adequate supportive care and Alopecia. Grade 4 neutropenia of \> 5 days duration or febrile neutropenia. Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia. Any treatment interruption \> 2 weeks due to AEs not related to the underlying disease or concomitant medication at any dose level and any severe, life-threatening impairing daily functions complication or abnormality.

Time frame: Day 1 up to Day 16 in cycle 1

Population: The dose escalation (DE) analysis set included all subjects treated in DE cohorts who received at least 80 percent (%) of pimasertib and 80% of SAR245409 full planned doses in the first cycle (ie, 21-day period from Day 1) of treatment or who experienced a DLT during the first cycle of treatment regardless of the received amount of each drug.

Arm	Measure	Value (NUMBER)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	0 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	2 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	1 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	2 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects With Dose Limiting Toxicities (DLT)	1 subjects

Secondary

Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15

Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau per Day 1 dosing interval AUCtau.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here N signifies number of subjects evaluable for this outcome measure and n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.523 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.269 ratio
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.174 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.364 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	2.176 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	NA ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.368 ratio
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.155 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.245 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15	1.283 ratio

Secondary

Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15

Accumulation ratio (Racc) for AUCtau, calculated as Day 15 dosing interval AUCtau divided by Day 1 dosing interval AUCtau.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here N signifies number of participant analyzed for this outcome measure and n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	1.189 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	1.004 ratio
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	0.9450 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	NA ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	NA ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	1.800 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	1.256 ratio
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	0.9887 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	1.187 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15	1.022 ratio

Secondary

Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15

Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax/Day 1 Cmax.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here N signifies number of subjects evaluable for this outcome measure and n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.525 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.066 ratio
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.106 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.308 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.467 ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	NA ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.203 ratio
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.059 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.247 ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15	1.393 ratio

Secondary

Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15

Accumulation ratio (Racc) for Cmax, calculated as Day 15 Cmax divided by Day 1 Cmax.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here N signifies number of participant analyzed for this outcome measure and n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	1.041 Ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	0.8133 Ratio
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	0.8962 Ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	NA Ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	NA Ratio
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	1.336 Ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	1.070 Ratio
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	0.8950 Ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	0.9611 Ratio
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15	0.9942 Ratio

Secondary

Apparent Terminal Half-Life (t1/2) of SAR245409

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (MEDIAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.055 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	3.700 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.300 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	4.570 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.390 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	4.560 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	NA hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	NA hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	NA hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	NA hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	NA hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.310 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	2.840 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.755 hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.300 hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	4.050 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	4.070 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	6.170 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 1 (n=6, 9, 31, 2, 2, 3, 20, 19, 13, 14)	3.120 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Apparent Terminal Half-Life (t1/2) of SAR245409	Day 15 (n=6, 8, 22, 1, 1, 2, 10, 15, 8, 10)	3.065 hour

Secondary

Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib

Volume of distribution was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Apparent volume of distribution after oral dose (Vz/f) was influenced by the fraction absorbed. Apparent volume of distribution during the terminal phase, calculated by CL/f/λz. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.Data was not available for 'Pimasertib (MSC1936369B) 60mg Twice Daily' arm as no subjects were considered evaluable because of limited number of samples collected to characterize the terminal phase rate constant needed for the calculation of Vz/f.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here N signifies number of subjects evaluable for this outcome measure and n signifies the number of subjects evaluable at specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	294.3 liter
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	188.7 liter
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	261.8 liter
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	240.2 liter
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	396.4 liter
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	282.8 liter
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	283.0 liter
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	302.4 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	394.1 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	NA liter
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	226.3 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	223.8 liter
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	226.9 liter
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	250.9 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	216.2 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	230.6 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 15 (n=6, 9, 13, 9, 0, 0, 16, 16, 9, 12)	273.8 liter
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib	Day 1 (n=6, 9, 23, 13, 3, 0, 22, 22, 14, 13)	322.0 liter

Secondary

Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	174.8 litre
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	165.7 litre
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	257.2 litre
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	223.4 litre
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	355.9 litre
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	238.5 litre
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	NA litre
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	NA litre
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	NA litre
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	NA litre
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	NA litre
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	658.0 litre
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	175.2 litre
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	132.8 litre
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	251.4 litre
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	247.1 litre
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	353.6 litre
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	475.9 litre
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 15 (n=6, 8, 25, 1, 1, 2, 17, 17, 10, 13 )	293.4 litre
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	270.3 litre

Secondary

Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	426.8 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	650.4 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	742.1 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	902.0 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	1547 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	1617 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	2116 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	2552 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	773.1 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	354.9 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	NA hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	1252 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	2136 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	1882 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	1754 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	1889 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	1772 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	1988 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 26, 13, 3, 3, 24, 23, 17,13)	1093 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 0, 16, 17, 10, 13)	1506 hr*ng/mL

Secondary

Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	887.9 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	746.9 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	1265 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1168 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1362 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	1601 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	3032 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	634.0 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	298.6 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	537.5 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	2115 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	2390 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1437 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	1480 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	1542 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1365 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1074 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 3, 24, 23, 17, 15)	948.4 hr*ng/mL

Secondary

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1

Area under the concentration-time curve from time 0 extrapolated to infinity, calculated as AUC0-t + last observed concentration (Clast)/terminal rate constant (λz), using the Linear up/Log down method. Terminal rate constant (λz). The regression analysis (determination of λz) was to contain as many data points as possible (but excluding Cmax) and had to include concentration data from at least 3 different time points, consistent with the assessment of a straight line (the terminal elimination phase) on the log-transformed scale.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts

Population: The PK analysis set. Here N signifies number of subjects evaluable for this outcome measure and n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	716.5 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	1165 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	1504 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	NA hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	NA hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	331.2 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	1974 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	1445 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	1261 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1	1142 hr*ng/mL

Secondary

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)

Area under the concentration-time curve from time 0 to the last quantifiable concentration.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set . Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	625.3 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	426.8 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	902.0 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	734.4 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	1547 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	1617 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	2116 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	2552 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	773.1 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	326.1 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	1252 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	NA hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	2136 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	1781 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	1754 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	1889 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	1709 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	1988 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 10, 13)	1506 hournanogram per millilitre (hrng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 25, 13, 4, 3, 25, 23, 18, 15)	1093 hournanogram per millilitre (hrng/mL)

Secondary

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409

Area under the plasma concentration-time curve (AUC) from time zero to the last sampling time (0-24 hours) at which the concentration is at or above the lower limit of quantification. Unit of assessment was hour\*nanogram per milliliter (hr\*ng/mL).

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	683.6 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	861.0 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1248 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1125 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1566 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1334 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	3032 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	634.0 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	537.5 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	226.2 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	2232 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1976 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1408 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1437 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1479 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1365 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	854.9 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	968.8 hr*ng/mL

Secondary

Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1 for DE cohorts

Population: The PK analysis set. Here N signifies the number of subjects evaluable for this outcome measure. Data was not available for 'Pimasertib (MSC1936369B) 60mg Twice Daily' arm as no subjects were considered evaluable because of limited number of samples collected to characterize the terminal phase rate constant needed for the calculation of AUCinf.

Arm	Measure	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	451.6 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	770.9 hr*ng/mL
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	1607 hr*ng/mL
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	2202 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	503.1 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	1869 hr*ng/mL
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	1830 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	1857 hr*ng/mL
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1	1113 hr*ng/mL

Secondary

Half-Life (t1/2) of MSC1936369B (Pimasertib)

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (MEDIAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	5.855 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	6.250 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	5.410 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.670 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.840 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	6.755 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	5.590 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.800 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	3.320 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	NA hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.640 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	NA hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.840 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	5.210 hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.370 hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	5.250 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.770 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	5.210 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 15 (n=6, 9, 14, 9, 2, 1, 16, 16, 9, 12)	4.325 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Half-Life (t1/2) of MSC1936369B (Pimasertib)	Day 1 (n=6, 9, 23, 13, 4, 3, 22, 22, 15, 13)	4.240 hour

Secondary

Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The pharmacokinetic (PK) analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	131.3 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	86.06 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	212.8 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	188.2 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	234.2 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	246.1 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	406.9 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	516.4 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	143.1 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	83.72 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	232.5 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	NA nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	320.5 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	323.1 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	295.4 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	327.6 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	245.6 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	307.7 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 4, 3, 25, 23, 18, 15)	234.0 nanogram/millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)	Day 15 (n=6, 9,15,9, 3, 1, 16, 17, 13, 10)	338.9 nanogram/millilitre (ng/mL)

Secondary

Maximum Observed Plasma Concentration (Cmax) for SAR245409

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	199.8 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	192.0 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	224.1 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	295.7 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	256.9 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	222.9 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	NA nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	224.5 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	NA nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	130.2 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	117.2 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	64.22 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	323.6 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	326.0 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	235.5 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	240.6 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	239.6 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	178.9 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 15 (n=6, 6, 25, 1, 1, 3, 17, 17, 10, 13)	226.6 nanogram per millilitre (ng/mL)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Maximum Observed Plasma Concentration (Cmax) for SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	212.5 nanogram per millilitre (ng/mL)

Secondary

Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)

An adverse event (AE) was defined as any untoward medical occurrence in a subject administered a pharmaceutical product, which did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs were defined as those AEs that started between first dose of study drug and up to 30 days after last dose.

Time frame: Baseline up to 30 Days after last dose; assessed up to 4 years

Population: The safety analysis set (SAF) analysis set was to include all subjects who had received at least 1 (non-zero) administration of the trial investigational medicinal products (IMPs) MSC1936369B (pimasertib) and/or SAR245409.

Arm	Measure	Value (NUMBER)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	3 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	3 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	3 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	4 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	4 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	3 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	19 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	14 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	3 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	3 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	4 subjects
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	26 subjects
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	24 subjects
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	18 subjects
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)	15 subjects

Secondary

Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)

CR=Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than (\<) 10 millimeter (mm). PR=At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD=Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. PD= At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Time frame: From the date of randomisation every 6 weeks up to assessed up to 4 years

Population: The Efficacy Analysis Set (EEF) included all subjects who received at least 1 trial treatment dose (Pimasertib or SAR245409) and had radiographic baseline and at least one evaluable post baseline tumor assessment.

Arm	Measure	Group	Value (NUMBER)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	3 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	1 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	2 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	2 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	1 subjects
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	1 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	3 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	2 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	1 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	1 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	2 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	0 subjects
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	4 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	9 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	6 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	3 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	2 subjects
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	2 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	0 subjects
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	1 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	0 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	1 subjects
Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	2 subjects
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	8 subjects
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	7 subjects
TNBC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	1 subjects
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	3 subjects
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	1 subjects
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	10 subjects
NSCLC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	6 subjects
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	0 subjects
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	0 subjects
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	9 subjects
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	1 subjects
CRC: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	1 subjects
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Partial Response	1 subjects
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Stable disease	7 subjects
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Not Evaluable	1 subjects
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Complete Response	1 subjects
MEL: Pimasertib 60mg and SAR245409 70mg Once Daily	Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)	Progressive disease	4 subjects

Secondary

pERK Concentrations in PBMCs

pERK Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily, Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily, Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily and Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily reporting arms.

Time frame: DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); C1D1 and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose)

Population: Biomarker Analysis Set for pharmacodynamics marker analysis in PBMC included all subjects who received at least first dose of both drugs and had provided at least one pre-dose sample and one post-dose sample. Here N signifies number of subject analysed for this outcome measure and n signifies number of subject analysed at specific time point.

Arm	Measure	Group	Value (MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	1.92 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	0.67 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	3.79 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	2.85 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	2.37 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	6.10 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	4.97 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	5.56 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	6.54 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	7.42 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	6.77 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	6.74 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	3.12 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	1.60 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	6.23 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	10.84 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	2.16 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	8.74 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	6.18 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	9.46 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	0.81 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	1.87 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	1.34 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	2.15 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	2.26 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	0.94 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	1.34 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	1.37 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	3.45 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	2.61 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	0.94 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	1.33 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	2.08 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	4.47 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	2.78 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	6.96 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	2.91 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	3.40 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	4.59 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	5.29 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	2.83 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	2.50 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	3.38 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	5.33 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	1.96 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	1.24 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	1.10 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	1.54 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	3.25 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	1.60 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	4.70 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	0.94 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	1.41 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	6.26 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	5.44 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	2.36 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	2.07 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	3.35 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	1.40 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	1.96 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	1.74 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	1.27 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	3.45 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	1.20 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	1.93 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	1.55 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	1.12 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	0.95 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	1.97 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	1.26 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	1.11 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: Predose (n= 1, 0, 0, 0, 0, 0, 1)	10.55 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 4 hr post-dose (n-1,0,0,0,0,0,1)	0.68 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 8hr postdose(n= 1,1,1,1,1,1,1)	0.82 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	0.81 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	0.99 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 2 hr post-dose (n=1,0,0,0,0,0,1)	15.82 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 4 hr post-dose ((n=1,0,0,0,0,0,1)	6.50 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 2: 24 hr post-dose ((n= 0,0,0,0,0,0,1)	8.32 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D2: 24hr postdose(n= 0,0,0,0,1,1,1)	1.05 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	0.94 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D15: pre-dose(n= 1,1,1,1,1,0,1)	2.03 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	9.36 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 24 hr post-dose (n=1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	8.94 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: Pre dose (n=1,1,1,1,1,1,1)	7.42 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 1: 2 hr post-dose (n=1,0,0,0,0.0,1)	10.17 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	15.68 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 2hr postdose(n= 1,1,1,1,1,1,1)	1.04 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	DDI Day 4: 24 hr post-dose (n=0,0,0,0,0,0,1)	1.06 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D1: 4hr postdose(n= 1,1,1,1,1,1,1)	1.01 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	5.72 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pERK Concentrations in PBMCs	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	0.99 fluorescence intensity

Secondary

pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)

pS6 Concentrations in PBMCs was measured during DDI Evaluation period and Cycle 1 for DE cohorts. DDI evaluation period is a 4-day period that was performed within 1 week prior to Day 1 Cycle 1. In DDI evaluation period, On Day 1, SAR245409 was be administered alone, and on Day 3, Pimasertib was administered alone. No data were planned to be collected for Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily, Pimasertib (MSC1936369B) 45mg and SAR245409 50mg Twice Daily, Pimasertib (MSC1936369) 30mg and SAR245409 70mg Once Daily and Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily reporting arms.

Time frame: DDI Evaluation: Day 1 and 3 (predose, 2, 4, 8 and 24 hours (hr) postdose); Day 2 and 4 (24 hr postdose); Cycle 1 Day 1 (C1D1) and C1D15 (predose, 2, 4, 8, 24 hr postdose); C1D2 and C1D16 (24 hr postdose); C1D19 (predose, 2 hr postdose)

Population: The Biomarker Analysis Set for pharmacodynamics (PD) marker analysis in PBMC included all subjects who received at least the first dose of both drugs and had provided at least one pre-dose sample and one post-dose sample. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	36.15 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	36.76 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	46.16 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	0.53 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	3.02 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	68.48 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	1.08 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	41.34 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	89.14 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	87.60 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	31.08 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	69.93 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	43.48 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	26.41 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	57.51 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	55.93 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	4.34 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	51.32 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	54.54 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	88.80 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	61.02 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	25.71 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	72.14 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	90.02 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	53.37 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	81.29 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	46.95 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	45.97 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	0.76 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	24.48 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	43.70 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	83.52 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	1.28 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	114.39 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	96.98 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	56.41 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	77.62 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	50.11 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	84.57 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	67.69 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	125.77 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	48.23 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	74.15 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	92.67 fluorescence intensity
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	36.06 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	0.96 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	82.06 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	47.09 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	23.89 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	29.85 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	19.75 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	70.46 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	53.47 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	1.20 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	15.02 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	50.17 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	30.08 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	24.36 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	21.11 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	30.58 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	33.43 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	24.66 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	18.21 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	5.72 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	19.68 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	6.21 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	4.18 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	0.92 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	0.72 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	1.18 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	1.61 fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	NA fluorescence intensity
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: pre-dose (n= 1,1,1,1,1,0,1)	0.98 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D2: 24hr postdose (n= 0,0,0,0,1,1,1)	1.00 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 24hr postdose(n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 8hr postdose (n= 1,1,1,1,1,1,1)	0.96 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 4hr postdose (n= 1,1,1,1,1,1,1)	0.94 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 2: 24hr post-dose (n= 0,0,0,0,0,0,1)	28.86 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 24hr postdose (n= 1,1,1,1,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: 2hr postdose (n= 1,1,1,1,1,1,1)	1.04 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D1: Pre dose (n= 1,1,1,1,1,1,1)	36.03 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 4: 24hr post-dose (n= 0,0,0,0,0,0,1)	1.04 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI:Day 3: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI: Day 3: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	40.40 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 2hr post-dose (n= 1,0,0,0,0,0,1)	29.84 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D16: 24hr postdose (n= 0,0,0,0,1,0,1)	0.98 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 4hr post-dose (n= 1,0,0,0,0,0,1)	1.03 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: 2hr post-dose (n= 1,0,0,0,0,0,1)	34.06 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 24hr post-dose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 8 hr post-dose(n= 1, 0, 0, 0, 0, 0, 1)	44.88 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: 2hr postdose (n= 1,0,0,0,0,0,0)	NA fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D19: pre-dose (n= 1,1,1,1,1,0,1)	49.62 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: 4hr post-dose (n= 1,0,0,0,0,0,1)	30.28 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 4hr postdose (n= 1,1,1,1,1,0,1)	1.03 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 1: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	33.78 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 2hr postdose (n= 1,1,1,1,1,0,1)	1.06 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	DDI Day 3: Pre-dose (n= 1, 0, 0, 0, 0, 0, 1)	14.90 fluorescence intensity
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)	C1D15: 8hr postdose (n= 1,1,1,1,1,0,1)	0.88 fluorescence intensity

Secondary

Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (MEDIAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.275 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.750 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	0.765 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.000 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	2.000 hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	2.020 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.500 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.550 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.485 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	2.000 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.550 hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	NA hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.500 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.505 hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.530 hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.520 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.490 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.500 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 15 (n= 6, 9, 15, 9, 3, 1, 16, 17, 13, 10)	1.030 hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)	Day 1 (n= 6, 10, 25, 13, 4, 3, 25, 23, 18, 15 )	1.050 hour

Secondary

Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409

The time to reach maximum plasma concentration (Tmax) of SAR245409 was calculated.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (MEDIAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.510 hours
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.265 hours
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.750 hours
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.150 hours
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.970 hours
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.500 hours
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.500 hours
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA hours
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA hours
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	2.050 hours
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.540 hours
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.550 hours
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	2.030 hours
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.500 hours
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	2.000 hours
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.530 hours
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	2.000 hours
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.750 hours
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	1.050 hours
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409	Day 1 (n=6, 11, 36, 3, 3, 4, 26, 23, 18, 15)	1.500 hours

Secondary

Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)

The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the Dose with area under the plasma concentration time curve from time zero to infinity (AUC0 inf)=Dose/AUC0- inf.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here N signifies number of subjects evaluable for this outcome measure and n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	33.22 litre per hour (L/hr)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	23.06 litre per hour (L/hr)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	38.90 litre per hour (L/hr)
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	33.30 litre per hour (L/hr)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	37.99 litre per hour (L/hr)
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	37.11 litre per hour (L/hr)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	40.88 litre per hour (L/hr)
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	35.28 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	58.22 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	89.49 litre per hour (L/hr)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	NA litre per hour (L/hr)
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	NA litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	28.11 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	32.12 litre per hour (L/hr)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	32.75 litre per hour (L/hr)
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	31.73 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	30.75 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	30.20 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 1 (n=6, 10, 26, 13, 3, 0, 22, 22, 14, 13)	53.94 litre per hour (L/hr)
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)	Day 15 (n=6, 9, 15, 9, 3, 1, 16, 17, 10, 13)	39.81 litre per hour (L/hr)

Secondary

Total Body Clearance (CL/f) of SAR245409

The total body clearance of drug from plasma following oral administration (Cl/f) and the total body clearance of drug from plasma following intravenous administration was calculated by dividing the dose with area under the plasma concentration time curve from time zero to infinity (AUC 0-inf)=Dose/AUC 0-inf.

Time frame: Predose 0.5, 1, 1.5, 2, 3, 4, 8 and 24 hour post dose on Day 1, 15 for DSE Cohorts; Predose 0.5, 1, 1.5, 2, 3, 4, 8, 10 and 24 hour post dose on Day 1, 15 for DE cohorts

Population: The PK analysis set. Here n signifies the number of subjects evaluable at the specific time points.

Arm	Measure	Group	Value (GEOMETRIC_MEAN)
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	41.80 litre per hour
Pimasertib (MSC1936369B) 15mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	33.78 litre per hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	42.93 litre per hour
Pimasertib (MSC1936369B) 30mg and SAR245409 30mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	42.81 litre per hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	46.54 litre per hour
Pimasertib (MSC1936369B) 15mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	51.38 litre per hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	NA litre per hour
Pimasertib (MSC1936369B) 30mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	NA litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 50mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	NA litre per hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	92.90 litre per hour
Pimasertib (MSC1936369B) 30mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	151.4 litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	29.28 litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	35.43 litre per hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	48.40 litre per hour
Pimasertib (MSC1936369B) 90mg and SAR245409 70mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	48.69 litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	55.51 litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 90mg Once Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	51.24 litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Total Body Clearance (CL/f) of SAR245409	Day 1 (n=5, 9, 31, 2, 1, 3, 20, 17, 12, 12)	61.29 litre per hour
Pimasertib (MSC1936369B) 60mg and SAR245409 30mg Twice Daily	Total Body Clearance (CL/f) of SAR245409	Day 15 (n=6, 8, 25, 1, 1, 3, 17, 17, 10, 13)	65.16 litre per hour

Source: ClinicalTrials.gov · Data processed: Mar 10, 2026

Trial of MEK Inhibitor and PI3K/mTOR Inhibitor in Subjects With Locally Advanced or Metastatic Solid Tumors

Conditions

Keywords

Brief summary

Related papers

Interventions

Sponsors

Study design

Eligibility

Inclusion criteria

Exclusion criteria

Design outcomes

Primary

Secondary

Countries

Participant flow

Recruitment details

Pre-assignment details

Participants by arm

Baseline characteristics

Adverse events

Outcome results

Number of Subjects With Dose Limiting Toxicities (DLT)

Accumulation Ratio (Racc) for AUCtau of Pimasertib (MSC1936369B): Day 15

Accumulation Ratio (Racc) for AUCtau of SAR245409: Day 15

Accumulation Ratio (Racc) for Cmax of Pimasertib (MSC1936369B): Day 15

Accumulation Ratio (Racc) for Cmax of SAR245409: Day 15

Apparent Terminal Half-Life (t1/2) of SAR245409

Apparent Volume of Distribution of Total Pimasertib During the Terminal Phase Following Oral Administration (Vz/f) of Pimasertib

Apparent Volume of Distribution of Total SAR245409 During the Terminal Phase Following Oral Administration (Vz/f)

Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of Pimasertib (MSC1936369B)

Area Under the Concentration-Time Curve (AUC) During a Dosing Interval (Tau) of SAR245409

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Infinity (0-inf) of SAR245409: Day 1

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of Pimasertib (MSC1936369B)

Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to the Last Sampling Time (0-24 Hours) of SAR245409

Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC 0-inf) of Pimasertib (MSC1936369B) at Day 1

Half-Life (t1/2) of MSC1936369B (Pimasertib)

Maximum Observed Plasma Concentration (Cmax) for Pimasertib (MSC1936369B)

Maximum Observed Plasma Concentration (Cmax) for SAR245409

Number of Subjects Experiencing Any Treatment-Emergent Adverse Events (TEAEs)

Number of Subjects With Complete Tumor Response (CR), Partial Tumor Response (PR), or Stable Disease (SD)

pERK Concentrations in PBMCs

pS6 Concentrations in Peripheral Blood Mononuclear Cells (PBMCs)

Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib (MSC1936369B)

Time to Reach Maximum Plasma Concentration (Tmax) of SAR245409

Total Body Clearance (CL/f) of Pimasertib (MSC1936369B)

Total Body Clearance (CL/f) of SAR245409