Advanced Solid Tumor
Conditions
Keywords
MEK inhibitor, Temsirolimus, Neoplasms, Phase I, Pimasertib
Brief summary
The research trial is testing the experimental drug pimasertib and the drug Torisel, given together, in the treatment of advanced solid tumors. The primary purpose of the study is to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of the drug combination.
Interventions
DRUGPimasertib
Pimasertib will be administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.
DRUGTemsirolimus
Temsirolimus will be administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment will be continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent.
Sponsors
EMD Serono
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects with histologically or cytologically confirmed solid tumors, either refractory to standard therapy or for which no effective standard therapy is available. * Measurable or evaluable disease at baseline by RECIST 1.0. * Age \>= 18 years. * Subject has read and understands the informed consent form and is willing and able to give informed consent. * Performance Status score of less than or equal to (\<=) 1 according to the Eastern Cooperative Oncology Group (ECOG) scale. * Women of childbearing potential must have a negative blood pregnancy test at the screening visit. * Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to screening, during the trial and for 3 months after the last dose of trial medication. Additional inclusion criteria also apply.
Exclusion criteria
* The subject has previously been treated with mammalian target of rapamycin (mTOR) inhibitor or a mitogen-activated protein kinase (MEK) inhibitor and taken off treatment due to drug-related AEs. * The subject has received any of the following: * Chemotherapy, immunotherapy, hormonal therapy, biologic therapy, any investigational agent or any other anti-cancer therapy within 28 days (6 weeks for nitrosoureas or mitomycin C) of Day 1 of trial treatment; non-cytotoxic chemotherapy or investigational agent with limited potential for delayed toxicity is permitted if terminated at least 5 half-lives prior to Day 1 of trial treatment. * Extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation. * The subject has not recovered from toxicity due to prior therapy to baseline or CTCAE v4.0 of Grade 1 or less (except alopecia). * The subject has poor organ or marrow function as defined in protocol. * History of central nervous system (CNS) metastases or primary CNS tumor, unless subject has been previously treated for these conditions, is asymptomatic and has had no requirement for anticonvulsants or high dose corticosteroids for a minimum of 2 weeks prior to entry into the trial. * History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months of Day 1 of trial drug treatment. * Recent major surgery or trauma (within the last 28 days), unhealing/open wounds, diabetic ulcers, recent drainage of significant volume of ascites or pleural effusion. * History of congestive heart failure, unstable angina, myocardial infarction, symptomatic cardiac conduction abnormality, pacemaker, or other clinically significant cardiac disease or history of a stroke within 3 months prior to entering the trial. * Baseline corrected QT interval on screening electrocardiogram (ECG) (QTc) \>= 460 ms or left ventricular ejection fraction (LVEF) \< 40% on screening echocardiogram. * Other uncontrolled intercurrent diseases * Retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis or history of retinal vein occlusion, or medically relevant abnormal ophthalmology assessments at screening. * Known or suspected allergy to pimasertib, temsirolimus, other rapamycins (sirolimus, everolimus, etc.), their excipients, or any agent given in the course of this trial. * Immunization with attenuated live vaccines within one week of trial entry (examples of live vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, etc.). * Concomitant use of any medications or substances that are strong inhibitors or inducers of CYP3A enzyme, including, but not limited to, phenytoin, carbamazepine, barbiturates, azoles, rifampin, phenobarbital, or St. John's Wort. * Pregnant or lactating female. * Legal incapacity or limited legal capacity. Additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Dose Limiting Toxicities (DLTs) | Up to 21 Days (within Cycle 1) | DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade \>=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration \<= 48 hours and alopecia; Grade 4 neutropenia of \>5 days duration or febrile neutropenia of \>1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption \>2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) of Pimasertib | Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Maximum Plasma Concentration (Cmax) of Temsirolimus | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8 | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf | The AUCtau was defined as the area under the concentration curve divided by the dosing interval. AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Apparent Terminal Half-life (t1/2) of Pimasertib | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | From the start of the trial treatment until data cut-off date (23 February 2012) | An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. The TEAEs were those events that occur between first dose of trial treatment and up to 30 days after last dose of the trial treatment that were absent before treatment or that worsened relative to pretreatment state. |
| Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | Clearance (CL) of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The CL obtained after oral dose (CL/F) was influenced by the fraction of the dose absorbed (bioavailability). Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | The clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Apparent Volume of Distribution (Vz/F) of Pimasertib | DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | Volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The Vz after oral dose (Vz/F) was influenced by the fraction absorbed. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Volume of Distribution (Vz) of Temsirolimus | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | The Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
| Number of Subjects With Disease Control Rate | From the start of the trial treatment until data cut-off date (23 February 2012) | Disease control is defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) \>=12 weeks), based on tumor assessments as determined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. CR: The disappearance of all lesions and normalization of tumor marker level. PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline. SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started. |
| Phospho Extracellular Signal Regulated Kinase (pERK ) Levels and Phospho Ribosomal Protein S6 (pS6) Levels in in Peripheral Blood Mononuclear Cells (PBMCs) | DDI cohorts: Days 1, 9 and 10 of Cycle 1; Non-DDI cohorts: Days 1, 8 and 9 of Cycle 1 | During the first cycle (either Cycle 1 non-DDI or Cycle 1-DDI) blood samples will be collected for pharmacodynamic marker assessments by flow cytometry such as phospho-ERK and phospho- S6 activities in PBMCs |
| Apparent Terminal Half-life (t1/2) of Temsirolimus | DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 | The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan. |
Countries
United States
Participant flow
Recruitment details
First/last subject (informed consent): 27 May 2011/23 August 2012. Last subject completed: 23 February 2012; Subjects randomized at 2 centers in United States.
Pre-assignment details
46 screened for eligibility; 13 were excluded (mainly non-fulfillment of inclusion or exclusion criteria). 33 subjects were enrolled and treated in the study.
Participants by arm
| Arm | Count |
|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 12.5 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. | 4 |
| Pimasertib 45 mg+Temsirolimus 25 mg Pimasertib was administered in fasted state at a dose of 45 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. | 23 |
| Pimasertib 75 mg+Temsirolimus 25 mg Pimasertib was administered in fasted state at a dose of 75 mg once daily orally on Days 1 to 15. Temsirolimus was administered at a dose of 25 mg as intravenous infusion over a 30-60 minute period once a week within 10 minutes after administration of pimasertib on Days 1, 8 and 15 in successive 21-day cycles. Treatment was continued until disease progression, intolerable toxicity, investigator's decision to discontinue treatment, or withdrawal of consent. | 6 |
| Total | 33 |
Baseline characteristics
| Characteristic | Pimasertib 45 mg+Temsirolimus 25 mg | Pimasertib 75 mg+Temsirolimus 25 mg | Total | Pimasertib 45 mg+Temsirolimus 12.5 mg |
|---|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 14.09 | 55.5 years STANDARD_DEVIATION 6.19 | 58.1 years STANDARD_DEVIATION 12.61 | 63.3 years STANDARD_DEVIATION 11.3 |
| Sex: Female, Male Female | 16 Participants | 4 Participants | 22 Participants | 2 Participants |
| Sex: Female, Male Male | 7 Participants | 2 Participants | 11 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 23 / 23 | 6 / 6 |
| serious Total, serious adverse events | 3 / 4 | 17 / 23 | 5 / 6 |
Outcome results
Primary
Number of Subjects With Dose Limiting Toxicities (DLTs)
DLT was defined as any of the following toxicities graded as per National Cancer Institute (NCI) common terminology criteria for adverse events (NCI CTCAE v4.0) encountered within cycle 1 of treatment at any dose level and judged not to be related to the underlying disease or concomitant medications. A treatment emergent adverse event (TEAE) of potential clinical significance such that further dose escalation would expose subjects to unacceptable risk; any Grade \>=3 non-hematological toxicity except Grade 3 asymptomatic increases in liver function tests, diarrhea, nausea or vomiting with duration \<= 48 hours and alopecia; Grade 4 neutropenia of \>5 days duration or febrile neutropenia of \>1 day duration; Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia; any treatment interruption \>2 weeks due to adverse events; any severe, impairing daily functions or life-threatening, complication or abnormality not defined in NCI-CTCAE that is attributable to the therapy.
Time frame: Up to 21 Days (within Cycle 1)
Population: The dose escalation analysis set included all the subjects who received at least 80% of the planned doses of each treatment (pimasertib and temsirolimus) in the first cycle of treatment or who experienced DLT during the first cycle of treatment regardless of the received amount of drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Number of Subjects With Dose Limiting Toxicities (DLTs) | 0 subjects |
| Pimasertib 45 mg+Temsirolimus 25 mg | Number of Subjects With Dose Limiting Toxicities (DLTs) | 7 subjects |
| Pimasertib 75 mg+Temsirolimus 25 mg | Number of Subjects With Dose Limiting Toxicities (DLTs) | 2 subjects |
Secondary
Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib
Clearance (CL) of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. The CL obtained after oral dose (CL/F) was influenced by the fraction of the dose absorbed (bioavailability). Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure;Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | DDI: Day 1 | 81.25 liter/hour |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | DDI: Day 9 | 71.99 liter/hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | DDI: Day 1 | 54.36 liter/hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | DDI: Day 9 | 55.9 liter/hour |
| Pimasertib 75 mg+Temsirolimus 25 mg | Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | Non-DDI: Day 8 | 64.31 liter/hour |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Apparent Clearance From Plasma Following Oral Administration (CL/f) of Pimasertib | Non-DDI: Day 8 | 53.6 liter/hour |
Secondary
Apparent Terminal Half-life (t1/2) of Pimasertib
The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure; Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Terminal Half-life (t1/2) of Pimasertib | DDI: Day 1 | 5.915 hour |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Terminal Half-life (t1/2) of Pimasertib | DDI: Day 9 | 6.08 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Terminal Half-life (t1/2) of Pimasertib | DDI: Day 1 | 5.886 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Terminal Half-life (t1/2) of Pimasertib | DDI: Day 9 | 5.896 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg | Apparent Terminal Half-life (t1/2) of Pimasertib | Non-DDI: Day 8 | 7.746 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Apparent Terminal Half-life (t1/2) of Pimasertib | Non-DDI: Day 8 | 5.712 hour |
Secondary
Apparent Terminal Half-life (t1/2) of Temsirolimus
The t1/2 was defined as the time required for the plasma concentration of drug to decrease 50% in the final stage of its elimination. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. N=subjects evaluable for this outcome measure; Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Terminal Half-life (t1/2) of Temsirolimus | DDI: Day 9 | 25.57 hour |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Terminal Half-life (t1/2) of Temsirolimus | DDI: Day 16 | 20.62 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Terminal Half-life (t1/2) of Temsirolimus | DDI: Day 9 | 13.2 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Terminal Half-life (t1/2) of Temsirolimus | DDI: Day 16 | 19.14 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg | Apparent Terminal Half-life (t1/2) of Temsirolimus | Non-DDI: Day 8 | 29.08 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Apparent Terminal Half-life (t1/2) of Temsirolimus | Non-DDI: Day 8 | 10.42 hour |
Secondary
Apparent Volume of Distribution (Vz/F) of Pimasertib
Volume of distribution (Vz) was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. The Vz after oral dose (Vz/F) was influenced by the fraction absorbed. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure; Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Volume of Distribution (Vz/F) of Pimasertib | DDI: Day 1 | 691.3 liter |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Apparent Volume of Distribution (Vz/F) of Pimasertib | DDI: Day 9 | 517.6 liter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Volume of Distribution (Vz/F) of Pimasertib | DDI: Day 1 | 536.5 liter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Apparent Volume of Distribution (Vz/F) of Pimasertib | DDI: Day 9 | 519.5 liter |
| Pimasertib 75 mg+Temsirolimus 25 mg | Apparent Volume of Distribution (Vz/F) of Pimasertib | Non-DDI: Day 8 | 760.6 liter |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Apparent Volume of Distribution (Vz/F) of Pimasertib | Non-DDI: Day 8 | 416.5 liter |
Secondary
Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus
The AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure;Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | DDI: Day 9 | 2452 hour*nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | DDI: Day 16 | 2006 hour*nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | DDI: Day 9 | 2130 hour*nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | DDI: Day 16 | 2743 hour*nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg | Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | Non-DDI: Day 8 | 4026 hour*nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Area Under Plasma Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Temsirolimus | Non-DDI: Day 8 | 2194 hour*nanogram/milliliter |
Secondary
Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib
The AUCtau was defined as the area under the concentration curve divided by the dosing interval. AUC(0-inf) was estimated by determining the total area under the curve of the concentration versus time curve extrapolated to infinity. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1 for AUCtau; DDI cohorts: Day 1 of Cycle 1 AUC0-inf
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N'=subjects evaluable for this outcome measure; Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | DDI: AUCtau: Day 9 | 628 hour*nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | DDI: AUC0-inf: Day 1 | 573.2 hour*nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | DDI: AUCtau: Day 9 | 805 hour*nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | DDI: AUC0-inf: Day 1 | 828.6 hour*nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg | Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | Non-DDI: AUCtau: Day 8 | 706 hour*nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Area Under the Concentration Time Curve During a Dosing Interval (AUCtau) and Area Under the Concentration Time Curve From Time Zero to Infinity (AUC0-inf) of Pimasertib | Non-DDI: AUCtau: Day 8 | 1402 hour*nanogram/milliliter |
Secondary
Maximum Plasma Concentration (Cmax) of Pimasertib
Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: Drug-drug interaction (DDI) cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Maximum Plasma Concentration (Cmax) of Pimasertib | DDI: Day 1 | 185.2 nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Maximum Plasma Concentration (Cmax) of Pimasertib | DDI: Day 9 | 131 nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Maximum Plasma Concentration (Cmax) of Pimasertib | DDI: Day 1 | 193.5 nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Maximum Plasma Concentration (Cmax) of Pimasertib | DDI: Day 9 | 192.1 nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg | Maximum Plasma Concentration (Cmax) of Pimasertib | Non-DDI: Day 8 | 197.6 nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Maximum Plasma Concentration (Cmax) of Pimasertib | Non-DDI: Day 8 | 308.1 nanogram/milliliter |
Secondary
Maximum Plasma Concentration (Cmax) of Temsirolimus
Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 8
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Maximum Plasma Concentration (Cmax) of Temsirolimus | DDI: Day 9 | 457.5 nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Maximum Plasma Concentration (Cmax) of Temsirolimus | DDI: Day 16 | 281.1 nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Maximum Plasma Concentration (Cmax) of Temsirolimus | DDI: Day 9 | 505.3 nanogram/milliliter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Maximum Plasma Concentration (Cmax) of Temsirolimus | DDI: Day 16 | 511.8 nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg | Maximum Plasma Concentration (Cmax) of Temsirolimus | Non-DDI: Day 8 | 489.9 nanogram/milliliter |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Maximum Plasma Concentration (Cmax) of Temsirolimus | Non-DDI: Day 8 | 480.9 nanogram/milliliter |
Secondary
Number of Subjects With Disease Control Rate
Disease control is defined as confirmed complete response (CR), partial response (PR), or stable disease (SD) \>=12 weeks), based on tumor assessments as determined by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.0. CR: The disappearance of all lesions and normalization of tumor marker level. PR: At least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline. SD: Neither sufficient shrinkage to qualify for partial response nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum of the longest diameter since treatment started.
Time frame: From the start of the trial treatment until data cut-off date (23 February 2012)
Population: Data was not evaluated for this outcome as the subjects did not met the minimum criteria duration for the evaluation of the outcome measure due to the early termination of the trial
Secondary
Number of Subjects With Treatment-emergent Adverse Events (TEAEs)
An AE was defined as any new untoward medical occurrences/worsening of pre-existing medical condition, whether or not related to study drug. The TEAEs were those events that occur between first dose of trial treatment and up to 30 days after last dose of the trial treatment that were absent before treatment or that worsened relative to pretreatment state.
Time frame: From the start of the trial treatment until data cut-off date (23 February 2012)
Population: The safety analysis set included all the subjects who received at least one administration of trial medication.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | 4 subjects |
| Pimasertib 45 mg+Temsirolimus 25 mg | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | 23 subjects |
| Pimasertib 75 mg+Temsirolimus 25 mg | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) | 6 subjects |
Secondary
Phospho Extracellular Signal Regulated Kinase (pERK ) Levels and Phospho Ribosomal Protein S6 (pS6) Levels in in Peripheral Blood Mononuclear Cells (PBMCs)
During the first cycle (either Cycle 1 non-DDI or Cycle 1-DDI) blood samples will be collected for pharmacodynamic marker assessments by flow cytometry such as phospho-ERK and phospho- S6 activities in PBMCs
Time frame: DDI cohorts: Days 1, 9 and 10 of Cycle 1; Non-DDI cohorts: Days 1, 8 and 9 of Cycle 1
Population: As the trial was terminated early due to toxicities observed with the combination of pimasertib and temsirolimus, it was decided as per plan not to evaluate the biomarker data for this study
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib
Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 1 and 9 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | DDI: Day 1 | 1 hour |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | DDI: Day 9 | 2.3 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | DDI: Day 1 | 1.5 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | DDI: Day 9 | 1.133 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | Non-DDI: Day 8 | 1.5 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Time to Reach Maximum Plasma Concentration (Tmax) of Pimasertib | Non-DDI: Day 8 | 0.5833 hour |
Secondary
Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus
Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | DDI: Day 16 | 0.9333 hour |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | DDI: Day 9 | 0.7417 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | DDI: Day 9 | 0.5667 hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | DDI: Day 16 | 0.5 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg | Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | Non-DDI: Day 8 | 0.5 hour |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Time to Reach Maximum Plasma Concentration (Tmax) of Temsirolimus | Non-DDI: Day 8 | 0.55 hour |
Secondary
Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus
The clearance of a drug was a measure of the rate at which a drug was metabolized or eliminated by normal biological processes. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. 'N' =subjects evaluable for this outcome measure; Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | DDI: Day 9 | 5.378 liter/hour |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | DDI: Day 16 | 7.528 liter/hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | DDI: Day 9 | 11.73 liter/hour |
| Pimasertib 45 mg+Temsirolimus 25 mg | Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | DDI: Day 16 | 9.292 liter/hour |
| Pimasertib 75 mg+Temsirolimus 25 mg | Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | Non-DDI: Day 8 | 6.284 liter/hour |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Total Body Clearance From Plasma Following Intravenous Administration (CL) of Temsirolimus | Non-DDI: Day 8 | 11.39 liter/hour |
Secondary
Volume of Distribution (Vz) of Temsirolimus
The Vz was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired serum concentration of a drug. Pharmacokinetic parameters were reported based on DDI and non-DDI cohorts as per plan.
Time frame: DDI cohorts: Days 9 and 16 of Cycle 1; Non-DDI cohorts: Day 8 of Cycle 1
Population: Pharmacokinetic analysis was performed in all the subjects who received at least one administration of trial medication and whose plasma samples were collected. Number Analyzed signifies subjects evaluable for this measure for specified categories for each reporting group, respectively.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Volume of Distribution (Vz) of Temsirolimus | DDI: Day 9 | 152 liter |
| Pimasertib 45 mg+Temsirolimus 12.5 mg | Volume of Distribution (Vz) of Temsirolimus | DDI: Day 16 | 189.5 liter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Volume of Distribution (Vz) of Temsirolimus | DDI: Day 9 | 244.5 liter |
| Pimasertib 45 mg+Temsirolimus 25 mg | Volume of Distribution (Vz) of Temsirolimus | DDI: Day 16 | 233 liter |
| Pimasertib 75 mg+Temsirolimus 25 mg | Volume of Distribution (Vz) of Temsirolimus | Non-DDI: Day 8 | 309.7 liter |
| Pimasertib 75 mg+Temsirolimus 25 mg (Non-DDI) | Volume of Distribution (Vz) of Temsirolimus | Non-DDI: Day 8 | 172.9 liter |