Advanced Solid Malignancies
Conditions
Keywords
Solid tumors, MLN0128, TORC1/2 inhibitors
Brief summary
This is a Phase I, open label, Dose Escalation study of oral administration of single agent MLN0128 in participants with Advanced Malignancies followed by an Expansion Phase in participants with renal cell carcinoma, endometrial cancer or urothelial cancer who have measurable disease.
Detailed description
The drug being tested in this study is called MLN0128. MLN0128 is being tested to treat people who have Advanced Malignancies. The study enrolled approximately 198 patients. Participants were assigned to one of the following dose regimens in the Dose Escalation Phase to establish the Maximum Tolerated Dose (MTD): * MLN0128 QD * MLN0128 QW * MLN0128 QDx3dQW * MLN0128 QDx5dQW MLN0128 capsule, orally, once daily (QD) or Once weekly (QW) in the Dose Escalation Phase until MTD was established. Once MTD was determined, participants were then enrolled in the Dose Expansion Phase to receive: * MLN0128 5 mg QD * MLN0128 30 mg QW * MLN0128 40 mg QW This multi-centre trial was conducted worldwide. The overall time to participate in this study was approximately 244 weeks. Participants will make multiple visits to the clinic, and were contacted by telephone OR plus a final visit after last dose of study drug for a follow-up assessment.
Interventions
DRUGMLN0128
MLN0128 capsules
Sponsors
Millennium Pharmaceuticals, Inc.
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The Escalation Phase was sequential and the Expansion Phase was parallel.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Voluntary written consent * Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed standard of care therapy * Eastern Cooperative Oncology Group (ECOG) performance status 0-1 * Ability to swallow oral medications * For women of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to 90 days following the last study drug administration * Male participants must be surgically sterile or must agree to use physician-approved contraception during the study and for 90 days following the last study drug administration * Clinical laboratory values as specified in the protocol Additionally, to be eligible for the Dose Expansion portion of the study: * Participants must have evidence of measurable disease per response evaluation criteria in solid tumors (RECIST) version 1.1 by radiographic techniques or magnetic resonance imaging * Participants must have a pathologic diagnosis of advanced or recurrent endometrial adenocarcinoma and must have failed at least 1 prior line of standard chemotherapy * Participants must have a pathologic diagnosis of advanced/metastatic urothelial cancer (carcinoma of the bladder, ureter, and/or renal pelvis) and must have failed at least 1 line of prior therapy in the metastatic/unresectable setting * Participants must have a pathologic diagnosis of advanced renal cell carcinoma (RCC), with histological or cytological confirmation of RCC and must have failed at least 1 prior line of anti-vascular endothelial growth factor therapy (VEGF) therapy (including but not limited to sunitinib, and/or sorafenib, and/or bevacizumab and/or pazopanib, and/or axitinib) and must not have received prior therapy with a target of rapamycin complex 1 (TORC1) inhibitor (such as temsirolimus or everolimus); or * Participants must have a pathologic diagnosis of advanced renal cell carcinoma (RCC) and must have progressed on treatment with a TORC1 inhibitor (such as temsirolimus or everolimus).
Exclusion criteria
* Diagnosis of primary brain tumor * Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug * Known impaired cardiac function or clinically significant cardiac disease * Known treatment with systemic corticosteroid within one week prior to the first administration of study drug * Diabetes mellitus * Human immunodeficiency virus (HIV) infection * Known active cardiovascular disease condition as specified in protocol * Failed to recover from the reversible effects of prior anticancer therapies * Pregnancy (positive serum or urine pregnancy test) or breast feeding * Malabsorption due to prior gastrointestinal (GI) surgery, GI disease * Other clinically significant co-morbidities Please note that there are additional inclusion and
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Maximum Tolerated Dose (MTD) | Cycle 1 (28 Days) | MTD was defined as the highest dose level of MLN0128 at which no more than 1 out of 6 evaluable participants experienced a DLT during the first cycle (28 days) of therapy. |
| Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs) | Cycle 1 (28 days) | DLTs were defined as MLN0128-related treatment-emergent adverse events (TEAEs) that occurred within the Cycle 1 (first 28 days of treatment) as per Common Terminology Criteria for Adverse Events (CTCAE): Any ≥Grade 3 or non-hematologic toxicity except for Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting ≤ 14 days, Grade 3 rash lasting ≤ 3 days; Grade 4 neutropenia lasting \>7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever ≥38.5 degree celsius and/or systemic infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to drug-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk. |
| Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks) | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant. |
| Dose Expansion: Objective Response Rate (ORR) | From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks) | ORR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR is defined as disappearance of all target lesions and PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. Data was categorized as per type of cancer. |
| Dose Expansion Phase: Duration of Objective Response | From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks) | Duration of objective response is defined as the number of months from the start date of CR or PR (whichever occurred first) based on RECIST Criteria version 1.1 to the first date of objectively documented progressive disease (PD) for participants who achieved CR or PR. PD is defined as 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). |
| Dose Expansion: Duration of Stable Disease (SD) | From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks) | Duration of SD was evaluated for participants with best response of SD and is defined as number of months from date of first dose to date of PD. As per RECIST 1.1, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR was defined of at least a 30% decrease in sum of longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. PD is defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is smallest on study). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Area Under Plasma Concentration Time Curve Extrapolated | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
| Cmax: Maximum Observed Plasma Concentration for MLN0128 | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
| Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | Baseline, Cycle 1 Week 2 | P4EBP, PAKT and PS6 were assayed in skin biopsies. A negative percentage change from Baseline indicates improvement. |
| Ctrough: Observed Concentration at the End of a Dosing Interval | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
| Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
| AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
| Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2 | — |
Countries
Spain, United States
Participant flow
Recruitment details
Participants took part in the study at 15 investigative sites in Spain and the United States from 4 January 2010 to 7 February 2019.
Pre-assignment details
Participants with a diagnosis of advanced malignancies were enrolled and received rising doses of MLN0128 in the Dose Escalation Phase to determine Maximum Tolerated Dose (MTD). In the Dose Expansion Phase participants were enrolled to receive one of 3 dose regimens: MLN0128 5 mg once daily (QD), 30 mg once weekly (QW) or 40 mg QW.
Participants by arm
| Arm | Count |
|---|---|
| MLN0128 QD MLN0128 2 mg, 4 mg, 6 mg or 7 mg, capsule, orally, once daily (QD) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 52.1 weeks). | 31 |
| MLN0128 QW MLN0128 7 mg, 10 mg, 15 mg, 20 mg, 30 mg or 40 mg capsule, orally, once weekly (QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 139.4 weeks). | 30 |
| MLN0128 QDx3d QW MLN0128 6 mg, 9 mg, 12 mg, 16 mg or 20 mg capsule, orally, once daily every 3 days a week (QDx3d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 129.4 weeks). | 33 |
| MLN0128 QDx5d QW MLN0128 7 mg, 10 mg or 13 mg capsule, orally, once daily every 5 days a week (QDx5d QW) in 28-day cycle in the Dose Escalation Phase until Maximum Tolerated Dose (MTD) was established (Up to 161.9 weeks). | 22 |
| MLN0128 5 mg QD MLN0128 5 mg, capsule, orally, QD in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 98.3 weeks). | 39 |
| MLN0128 30 mg QW MLN0128 30 mg, capsule, orally QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 240 weeks). | 17 |
| MLN0128 40 mg QW MLN0128 40 mg, capsule, orally, QW in 28-day cycle until disease progression or unacceptable toxicity in the Dose Expansion Phase (Up to 100.1 weeks). | 26 |
| Total | 198 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 11 | 4 | 7 | 6 | 7 | 3 | 1 |
| Overall Study | Disease Progression | 15 | 20 | 20 | 15 | 23 | 10 | 12 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Reason Not Specified | 0 | 3 | 2 | 0 | 7 | 1 | 7 |
| Overall Study | Subject Decision | 5 | 3 | 3 | 1 | 2 | 3 | 6 |
Baseline characteristics
| Characteristic | MLN0128 QD | Total | MLN0128 40 mg QW | MLN0128 30 mg QW | MLN0128 5 mg QD | MLN0128 QDx5d QW | MLN0128 QDx3d QW | MLN0128 QW |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 59.7 years | 58.31 years | 63.2 years | 59.7 years | 58.8 years | 58.1 years | 56.1 years | 53.8 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 11 Participants | 49 Participants | 2 Participants | 1 Participants | 8 Participants | 9 Participants | 7 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants | 148 Participants | 24 Participants | 16 Participants | 30 Participants | 13 Participants | 26 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 6 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 28 Participants | 188 Participants | 25 Participants | 17 Participants | 37 Participants | 22 Participants | 30 Participants | 29 Participants |
| Region of Enrollment Spain | 10 Participants | 56 Participants | 1 Participants | 2 Participants | 7 Participants | 10 Participants | 14 Participants | 12 Participants |
| Region of Enrollment United States | 21 Participants | 142 Participants | 25 Participants | 15 Participants | 32 Participants | 12 Participants | 19 Participants | 18 Participants |
| Sex: Female, Male Female | 16 Participants | 105 Participants | 14 Participants | 6 Participants | 16 Participants | 13 Participants | 22 Participants | 18 Participants |
| Sex: Female, Male Male | 15 Participants | 93 Participants | 12 Participants | 11 Participants | 23 Participants | 9 Participants | 11 Participants | 12 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 |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 31 | 2 / 30 | 2 / 33 | 0 / 22 | 2 / 39 | 2 / 17 | 3 / 26 |
| other Total, other adverse events | 31 / 31 | 30 / 30 | 33 / 33 | 22 / 22 | 39 / 39 | 17 / 17 | 26 / 26 |
| serious Total, serious adverse events | 13 / 31 | 10 / 30 | 17 / 33 | 10 / 22 | 19 / 39 | 6 / 17 | 9 / 26 |
Outcome results
Primary
Dose Escalation Phase: Maximum Tolerated Dose (MTD)
MTD was defined as the highest dose level of MLN0128 at which no more than 1 out of 6 evaluable participants experienced a DLT during the first cycle (28 days) of therapy.
Time frame: Cycle 1 (28 Days)
Population: Dose Escalation-Evaluable Population included participants who received ≥ 75% or more of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of doses because of study drug-related AEs considered a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLN0128 QD | Dose Escalation Phase: Maximum Tolerated Dose (MTD) | 6 milligrams (mg) |
| MLN0128 QW | Dose Escalation Phase: Maximum Tolerated Dose (MTD) | 40 milligrams (mg) |
| MLN0128 QDx3d QW | Dose Escalation Phase: Maximum Tolerated Dose (MTD) | 9 milligrams (mg) |
| MLN0128 QDx5d QW | Dose Escalation Phase: Maximum Tolerated Dose (MTD) | 7 milligrams (mg) |
Primary
Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs)
DLTs were defined as MLN0128-related treatment-emergent adverse events (TEAEs) that occurred within the Cycle 1 (first 28 days of treatment) as per Common Terminology Criteria for Adverse Events (CTCAE): Any ≥Grade 3 or non-hematologic toxicity except for Grade 3 nausea and/or vomiting and diarrhea, Grade 3 hyperglycemia lasting ≤ 14 days, Grade 3 rash lasting ≤ 3 days; Grade 4 neutropenia lasting \>7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever ≥38.5 degree celsius and/or systemic infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75% of planned doses of MLN0128 within Cycle 1 due to drug-related toxicity and any clinically significant occurrence that the investigators and sponsor agreed would place participants at an undue safety risk.
Time frame: Cycle 1 (28 days)
Population: Dose Escalation-Evaluable Population included participants who received ≥ 75% or more of planned doses of MLN0128 in Cycle 1 or stopped study drug before receiving 75% of doses because of study drug-related AEs considered a DLT.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLN0128 QD | Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs) | 7 Participants |
| MLN0128 QW | Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs) | 2 Participants |
| MLN0128 QDx3d QW | Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs) | 6 Participants |
| MLN0128 QDx5d QW | Dose Escalation Phase: Number of Participants With Dose Limiting Toxicities (DLTs) | 7 Participants |
Primary
Dose Expansion: Duration of Stable Disease (SD)
Duration of SD was evaluated for participants with best response of SD and is defined as number of months from date of first dose to date of PD. As per RECIST 1.1, SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study. PR was defined of at least a 30% decrease in sum of longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. PD is defined as at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes baseline sum if that is smallest on study).
Time frame: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
Population: Response-Evaluable Population: participants who received ≥1 dose of MLN0128, had measurable disease at Baseline (BL), underwent ≥1 post-BL disease assessment. Participants without post-BL disease assessment but discontinued study drug due to symptomatic and/or clinical deterioration were included. SD participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN0128 QD | Dose Expansion: Duration of Stable Disease (SD) | 3.68 months |
| MLN0128 QW | Dose Expansion: Duration of Stable Disease (SD) | 2.20 months |
| MLN0128 QDx3d QW | Dose Expansion: Duration of Stable Disease (SD) | 3.55 months |
Primary
Dose Expansion: Objective Response Rate (ORR)
ORR is defined as the percentage of participants who achieved complete response (CR) or partial response (PR based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CR is defined as disappearance of all target lesions and PR was defined of at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD and for non-target lesions. Data was categorized as per type of cancer.
Time frame: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
Population: Response-Evaluable Population included participants who received at least 1 dose of MLN0128, had measurable disease at Baseline, and underwent at least 1 post-Baseline disease assessment. Participants without a post-Baseline disease assessment but discontinued study drug due to symptomatic and/or clinical deterioration were included.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MLN0128 QD | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Endometrial | 9 percentage of participants |
| MLN0128 QD | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Renal | 15 percentage of participants |
| MLN0128 QD | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Bladder | 0 percentage of participants |
| MLN0128 QW | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Bladder | 0 percentage of participants |
| MLN0128 QW | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Endometrial | 0 percentage of participants |
| MLN0128 QW | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Renal | 13 percentage of participants |
| MLN0128 QDx3d QW | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Renal | 15 percentage of participants |
| MLN0128 QDx3d QW | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Endometrial | 0 percentage of participants |
| MLN0128 QDx3d QW | Dose Expansion: Objective Response Rate (ORR) | Cancer Type: Bladder | 0 percentage of participants |
Primary
Dose Expansion Phase: Duration of Objective Response
Duration of objective response is defined as the number of months from the start date of CR or PR (whichever occurred first) based on RECIST Criteria version 1.1 to the first date of objectively documented progressive disease (PD) for participants who achieved CR or PR. PD is defined as 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).
Time frame: From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks)
Population: Response-Evaluable Population:participants who received ≥1 dose of MLN0128,had measurable disease at Baseline,had ≥1 post-Baseline disease assessment.Participants without post-Baseline disease assessment but discontinued study drug due to symptomatic and/or clinical deterioration were included.CR/PR participants with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| MLN0128 QD | Dose Expansion Phase: Duration of Objective Response | 8.90 months |
| MLN0128 QW | Dose Expansion Phase: Duration of Objective Response | 56.05 months |
| MLN0128 QDx3d QW | Dose Expansion Phase: Duration of Objective Response | 20.73 months |
Primary
Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. A treatment-emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event is any experience that suggests a significant hazard, contraindication, side effect or precaution that: results in death, is life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect or is medically significant.
Time frame: First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks)
Population: ASaT population included all participants who received at least 1 dose of MLN0128.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLN0128 QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 11 Participants |
| MLN0128 QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 13 Participants |
| MLN0128 QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 1 Participants |
| MLN0128 QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 31 Participants |
| MLN0128 QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 30 Participants |
| MLN0128 QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 10 Participants |
| MLN0128 QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 4 Participants |
| MLN0128 QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 1 Participants |
| MLN0128 QDx3d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 33 Participants |
| MLN0128 QDx3d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 17 Participants |
| MLN0128 QDx3d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 7 Participants |
| MLN0128 QDx3d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 2 Participants |
| MLN0128 QDx5d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 0 Participants |
| MLN0128 QDx5d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 6 Participants |
| MLN0128 QDx5d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 22 Participants |
| MLN0128 QDx5d QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 10 Participants |
| MLN0128 5 mg QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 39 Participants |
| MLN0128 5 mg QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 19 Participants |
| MLN0128 5 mg QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 0 Participants |
| MLN0128 5 mg QD | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 7 Participants |
| MLN0128 30 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 17 Participants |
| MLN0128 30 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 2 Participants |
| MLN0128 30 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 3 Participants |
| MLN0128 30 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 6 Participants |
| MLN0128 40 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | AEs Resulting in Discontinuation of MLN0128 | 2 Participants |
| MLN0128 40 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | TEAE | 26 Participants |
| MLN0128 40 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | SAE | 9 Participants |
| MLN0128 40 mg QW | Number of Participants Experiencing One or More Treatment-Emergent Adverse Events (AEs), Serious Adverse Events (SAEs), AEs Resulting in Discontinuation of MLN0128 and Fatal AEs Within 30 Days of Last Dose of Study Drug | Fatal AEs within 30 Days of Last Dose Study Drug | 1 Participants |
Secondary
AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MLN0128 QD | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 185.00 ng*hr/mL |
| MLN0128 QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 205.3 ng*hr/mL |
| MLN0128 QDx3d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 390.6 ng*hr/mL |
| MLN0128 QDx5d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 459.5 ng*hr/mL |
| MLN0128 5 mg QD | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 440.00 ng*hr/mL |
| MLN0128 5 mg QD | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 2 Day 1 | 371.0 ng*hr/mL |
| MLN0128 30 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 609.0 ng*hr/mL |
| MLN0128 40 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 2 Day 1 | 510.00 ng*hr/mL |
| MLN0128 40 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 1014.5 ng*hr/mL |
| MLN0128 20 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 1172.7 ng*hr/mL |
| MLN0128 20 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 2 Day 1 | 1030.00 ng*hr/mL |
| MLN0128 30 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 1316.3 ng*hr/mL |
| MLN0128 30 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 2 Day 1 | 1427.5 ng*hr/mL |
| MLN0128 40 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 2 Day 1 | 2876.6 ng*hr/mL |
| MLN0128 40 mg QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 2149.8 ng*hr/mL |
| MLN0128 6 mg QDx3dQW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 494.0 ng*hr/mL |
| MLN0128 9 mg QDx3d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 725.2 ng*hr/mL |
| MLN0128 12 mg QDx3d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 922.8 ng*hr/mL |
| MLN0128 16 mg QDx3d QW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 820.1 ng*hr/mL |
| MLN0128 20 mg QDx3dQW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 1245.0 ng*hr/mL |
| MLN0128 7 mg QDx5dQW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 326.2 ng*hr/mL |
| MLN0128 10 mg QDx5dQW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 388.5 ng*hr/mL |
| MLN0128 13 mg QDx5dQW | AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 | Cycle 1 Day 1 | 941.5 ng*hr/mL |
Secondary
AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MLN0128 QD | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 65.4 ng*hr/mL |
| MLN0128 QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 2 Day 1 | 62.2 ng*hr/mL |
| MLN0128 QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 65.3 ng*hr/mL |
| MLN0128 QDx3d QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 95.30 ng*hr/mL |
| MLN0128 5 mg QD | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 72.80 ng*hr/mL |
| MLN0128 30 mg QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 2 Day 1 | 105.00 ng*hr/mL |
| MLN0128 30 mg QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 106.00 ng*hr/mL |
| MLN0128 6 mg QDx3dQW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 2 Day 1 | 182.00 ng*hr/mL |
| MLN0128 6 mg QDx3dQW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 162.00 ng*hr/mL |
| MLN0128 9 mg QDx3d QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 207.5 ng*hr/mL |
| MLN0128 16 mg QDx3d QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 130.2 ng*hr/mL |
| MLN0128 16 mg QDx3d QW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 2 Day 1 | 197.00 ng*hr/mL |
| MLN0128 10 mg QDx5dQW | AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for MLN0128 | Cycle 1 Day 1 | 221.00 ng*hr/mL |
Secondary
Cmax: Maximum Observed Plasma Concentration for MLN0128
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: Pharmacokinetic (PK) population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MLN0128 QD | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 16.2 ng/mL |
| MLN0128 QD | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 13.7 ng/mL |
| MLN0128 QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 20.5 ng/mL |
| MLN0128 QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 22.1 ng/mL |
| MLN0128 QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 39.4 ng/mL |
| MLN0128 QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 48.9 ng/mL |
| MLN0128 QDx5d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 65.0 ng/mL |
| MLN0128 QDx5d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 67.8 ng/mL |
| MLN0128 5 mg QD | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 66.7 ng/mL |
| MLN0128 5 mg QD | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 43.6 ng/mL |
| MLN0128 30 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 75.9 ng/mL |
| MLN0128 30 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 40.5 ng/mL |
| MLN0128 40 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 66.9 ng/mL |
| MLN0128 40 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 80.2 ng/mL |
| MLN0128 20 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 136.6 ng/mL |
| MLN0128 20 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 134.00 ng/mL |
| MLN0128 30 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 174.0 ng/mL |
| MLN0128 30 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 142.6 ng/mL |
| MLN0128 40 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 249.8 ng/mL |
| MLN0128 40 mg QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 193.8 ng/mL |
| MLN0128 6 mg QDx3dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 60.0 ng/mL |
| MLN0128 6 mg QDx3dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 88.5 ng/mL |
| MLN0128 9 mg QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 87.7 ng/mL |
| MLN0128 9 mg QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 82.9 ng/mL |
| MLN0128 12 mg QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 124.3 ng/mL |
| MLN0128 12 mg QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 115.1 ng/mL |
| MLN0128 16 mg QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 113.6 ng/mL |
| MLN0128 16 mg QDx3d QW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 78.5 ng/mL |
| MLN0128 20 mg QDx3dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 194.0 ng/mL |
| MLN0128 20 mg QDx3dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 183.00 ng/mL |
| MLN0128 7 mg QDx5dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 60.1 ng/mL |
| MLN0128 7 mg QDx5dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 46.9 ng/mL |
| MLN0128 10 mg QDx5dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 48.5 ng/mL |
| MLN0128 10 mg QDx5dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 60.0 ng/mL |
| MLN0128 13 mg QDx5dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 96.50 ng/mL |
| MLN0128 13 mg QDx5dQW | Cmax: Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 110.1 ng/mL |
Secondary
Ctrough: Observed Concentration at the End of a Dosing Interval
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| MLN0128 QD | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 0.9 ng/mL |
| MLN0128 QD | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 4.5 ng/mL |
| MLN0128 QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 1.2 ng/mL |
| MLN0128 QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 3.7 ng/mL |
| MLN0128 QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 3.5 ng/mL |
| MLN0128 QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 4.5 ng/mL |
| MLN0128 QDx5d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 4.4 ng/mL |
| MLN0128 QDx5d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 3.0 ng/mL |
| MLN0128 6 mg QDx3dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 10.3 ng/mL |
| MLN0128 6 mg QDx3dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 2.5 ng/mL |
| MLN0128 9 mg QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 6.8 ng/mL |
| MLN0128 9 mg QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 10.8 ng/mL |
| MLN0128 12 mg QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 4.4 ng/mL |
| MLN0128 12 mg QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 9.9 ng/mL |
| MLN0128 16 mg QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 8.1 ng/mL |
| MLN0128 16 mg QDx3d QW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 10.0 ng/mL |
| MLN0128 20 mg QDx3dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 44.7 ng/mL |
| MLN0128 20 mg QDx3dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 11.40 ng/mL |
| MLN0128 7 mg QDx5dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 3.1 ng/mL |
| MLN0128 7 mg QDx5dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 5.2 ng/mL |
| MLN0128 10 mg QDx5dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 3.0 ng/mL |
| MLN0128 10 mg QDx5dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 3.6 ng/mL |
| MLN0128 13 mg QDx5dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 2 Day 1 | 6.58 ng/mL |
| MLN0128 13 mg QDx5dQW | Ctrough: Observed Concentration at the End of a Dosing Interval | Cycle 1 Day 1 | 21.7 ng/mL |
Secondary
Percentage Area Under Plasma Concentration Time Curve Extrapolated
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: The study was acquired from another organization and limited results data are available.
Secondary
Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6)
P4EBP, PAKT and PS6 were assayed in skin biopsies. A negative percentage change from Baseline indicates improvement.
Time frame: Baseline, Cycle 1 Week 2
Population: ASaT population included all participants who received at least 1 dose of MLN0128 in dose escalation phase. Participants with data at Baseline and Cycle 1 Week 2 are included. Number analyzed is the number of participants with data available at the given time-point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MLN0128 QD | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pS6 | -50.2 percentage change | Standard Deviation 43.89 |
| MLN0128 QD | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pAKT | 27.1 percentage change | Standard Deviation 73.78 |
| MLN0128 QD | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | p4EBP1 | -64.1 percentage change | Standard Deviation 47.65 |
| MLN0128 QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pS6 | -42.7 percentage change | Standard Deviation 59.64 |
| MLN0128 QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | p4EBP1 | -15.5 percentage change | Standard Deviation 378.88 |
| MLN0128 QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pAKT | 26.9 percentage change | Standard Deviation 139.75 |
| MLN0128 QDx3d QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pS6 | -68.2 percentage change | Standard Deviation 37.98 |
| MLN0128 QDx3d QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pAKT | 73.3 percentage change | Standard Deviation 115.55 |
| MLN0128 QDx3d QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | p4EBP1 | -99.5 percentage change | Standard Deviation 2.75 |
| MLN0128 QDx5d QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pS6 | -82.5 percentage change | Standard Deviation 12.15 |
| MLN0128 QDx5d QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | pAKT | 168.9 percentage change | Standard Deviation 514.88 |
| MLN0128 QDx5d QW | Percentage Change From Baseline in Eukaryotic Initiation Factor 4E-binding Protein 1 (P4EBP1), Serine/Threonine Protein Kinase B (PAKT) and Ribosomal Protein S6 (PS6) | p4EBP1 | 87.4 percentage change | Standard Deviation 43.83 |
Secondary
Terminal Phase Elimination Half-life (T1/2) for MLN0128
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MLN0128 QD | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 10.3 hours |
| MLN0128 QD | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 8.1 hours |
| MLN0128 QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 9.7 hours |
| MLN0128 QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 7.4 hours |
| MLN0128 QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 7.9 hours |
| MLN0128 QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 6.3 hours |
| MLN0128 QDx5d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 6.2 hours |
| MLN0128 QDx5d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 4.9 hours |
| MLN0128 5 mg QD | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 6.47 hours |
| MLN0128 5 mg QD | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 5.6 hours |
| MLN0128 30 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 5.8 hours |
| MLN0128 40 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 8.01 hours |
| MLN0128 40 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 9.4 hours |
| MLN0128 20 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 5.7 hours |
| MLN0128 20 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 4.57 hours |
| MLN0128 30 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 5.7 hours |
| MLN0128 30 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 5.5 hours |
| MLN0128 40 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 5.6 hours |
| MLN0128 40 mg QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 7.1 hours |
| MLN0128 6 mg QDx3dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 9.1 hours |
| MLN0128 6 mg QDx3dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 5.5 hours |
| MLN0128 9 mg QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 7.0 hours |
| MLN0128 9 mg QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 7.9 hours |
| MLN0128 12 mg QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 4.9 hours |
| MLN0128 12 mg QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 6.4 hours |
| MLN0128 16 mg QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 6.4 hours |
| MLN0128 16 mg QDx3d QW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 7.2 hours |
| MLN0128 20 mg QDx3dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 5.5 hours |
| MLN0128 20 mg QDx3dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 6.28 hours |
| MLN0128 7 mg QDx5dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 6.8 hours |
| MLN0128 7 mg QDx5dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 7.8 hours |
| MLN0128 10 mg QDx5dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 5.6 hours |
| MLN0128 10 mg QDx5dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 6.5 hours |
| MLN0128 13 mg QDx5dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 1 Day 1 | 8.7 hours |
| MLN0128 13 mg QDx5dQW | Terminal Phase Elimination Half-life (T1/2) for MLN0128 | Cycle 2 Day 1 | 6.42 hours |
Secondary
Tmax: Time to Maximum Observed Plasma Concentration for MLN0128
Time frame: Pre-dose and multiple time-points up to 8 hours post-dose on Day 1 of Cycles 1 and 2
Population: PK population consisted of all participants included during the dose escalation phase of the study who received at least 1 dose of MLN0128. Number analyzed is the number of participants with data available for analysis at the given time-point.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| MLN0128 QD | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.0 hours |
| MLN0128 QD | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.0 hours |
| MLN0128 QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.0 hours |
| MLN0128 QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 3.8 hours |
| MLN0128 QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 1.0 hours |
| MLN0128 QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.0 hours |
| MLN0128 QDx5d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 4.0 hours |
| MLN0128 QDx5d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 1.5 hours |
| MLN0128 5 mg QD | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.1 hours |
| MLN0128 5 mg QD | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 1.02 hours |
| MLN0128 30 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 1.0 hours |
| MLN0128 30 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.9 hours |
| MLN0128 40 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.0 hours |
| MLN0128 40 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.0 hours |
| MLN0128 20 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.0 hours |
| MLN0128 20 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 4.0 hours |
| MLN0128 30 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 4.0 hours |
| MLN0128 30 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 1.0 hours |
| MLN0128 40 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.4 hours |
| MLN0128 40 mg QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.0 hours |
| MLN0128 6 mg QDx3dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 0.6 hours |
| MLN0128 6 mg QDx3dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 4.0 hours |
| MLN0128 9 mg QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 1.1 hours |
| MLN0128 9 mg QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.1 hours |
| MLN0128 12 mg QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 3.7 hours |
| MLN0128 12 mg QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.0 hours |
| MLN0128 16 mg QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.1 hours |
| MLN0128 16 mg QDx3d QW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.1 hours |
| MLN0128 20 mg QDx3dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 1.0 hours |
| MLN0128 20 mg QDx3dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 3.1 hours |
| MLN0128 7 mg QDx5dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 1.2 hours |
| MLN0128 7 mg QDx5dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 1.5 hours |
| MLN0128 10 mg QDx5dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.0 hours |
| MLN0128 10 mg QDx5dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 4.0 hours |
| MLN0128 13 mg QDx5dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 2 Day 1 | 2.02 hours |
| MLN0128 13 mg QDx5dQW | Tmax: Time to Maximum Observed Plasma Concentration for MLN0128 | Cycle 1 Day 1 | 2.1 hours |