Dose Escalation Study of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

Study Overview
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Brief Summary
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This is a Phase I, open label, dose escalation study of oral administration of MLN0128 in combination with paclitaxel, with/without trastuzumab, in participants with advanced solid malignancies.

Detailed Description
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This is a Phase I, open-label study consisting of a dose escalation phase in advanced solid malignancies to determine the maximum tolerated dose (MTD) of oral administration of MLN0128 in 1 or more dosing schedules, combined with paclitaxel on Days 1, 8 and 15 of each cycle, followed by an expansion phase for further safety and preliminary efficacy. Once the MTD is determined for each of the dosing schedules evaluated, a dose and schedule will be selected for the expansion phase, which may enroll participants into 2 arms in parallel: Arm A will consist of HER2- unknown cancer participants receiving MLN0128+paclitaxel Arm B will consist of HER2+ cancer participants receiving MLN0128+paclitaxel plus weekly trastuzumab

Official Title
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A Phase I, Open Label, Dose Escalation Study of Oral Administration of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

Conditions
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Advanced Solid Malignancies, Hematologic Malignancies

Intervention / Treatment
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* Drug: MLN0128
* Drug: paclitaxel
* Drug: trastuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary written consent Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed or are not eligible for 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 30 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 30 days following the last study drug administration Clinical laboratory values as specified in the protocol For expansion phase (Arm A) - HER2-/unknown participants will be enrolled For expansion phase (Arm B) - HER2+ cancer participants will be enrolled 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 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 exclusion criteria. The study center will determine if you meet all of the criteria. Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN0128P 30 mg QW<br>MLN0128 and paclitaxel (MLN0128P): MLN0128 30 mg, capsule, orally, once weekly (QW) + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 40 mg QW<br>MLN0128 40 mg, capsule, orally, once a week (QW) + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 6 mg QD×3d QW<br>MLN0128 6 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 7 mg QD×3d QW<br>MLN0128 7 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 8 mg QD×3d QW<br>MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 9 mg QD×3d QW<br>MLN0128 9 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 10 mg QD×3d QW<br>MLN0128 10 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 7 mg QD×5d QW<br>MLN0128 7 mg, capsule, orally, once daily 5 days on/2 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in the Dose Escalation Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128P 8 mg QD×3d QW HER2-<br>MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 of a 4-week cycle in human epidermal growth factor receptor 2 negative (HER-) cancer participants until disease progression or unacceptable toxicity for up to 1 year in the Expansion Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>|
| Experimental: MLN0128PH 8 mg QD×3d QW HER2+<br>MLN0128 + paclitaxel + trastuzumab (MLN0128PH): MLN0128 8 mg, capsule, orally, once daily 3 days on/4 days off each week + paclitaxel 80 mg/m^2, 1 hour infusion, on Days 1, 8 and 15 plus trastuzumab 4 mg/kg loading dose on Day 1 followed by 2 mg/kg, intravenous each week of a 4-week cycle in HER+ cancer participants until disease progression or unacceptable toxicity for up to 1 year in the Expansion Phase. | Drug: MLN0128<br>* MLN0128 capsules<br>Drug: paclitaxel<br>* paclitaxel intravenous infusion<br>Drug: trastuzumab<br>* trastuzumab intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose Escalation Phase: Maximum Tolerated Dose (MTD) | MTD is the highest dose level at which the participants tolerate treatment without dose-limiting toxicities during the first cycle (28 days) of therapy. | Cycle 1: Days 1 to 28 | 
| Dose Escalation Phase: Number of Participants With at Least 1 Dose Limiting Toxicity (DLT) | DLT was defined as any of the following occurring during Cycle 1 (Days 1-28) and attributable to MLN0128P: Grade ≥ 3 nonhematologic toxicity; Grade 3 thrombocytopenia with hemorrhage; Grade 4 neutropenia lasting > 7 days in the absence of growth factor support; Grade 4 neutropenia of any duration associated with fever 38.5 degrees C and/or infection; Any other Grade 4 hematologic toxicity; Inability to administer at least 75 % of doses of MLN0128 within Cycle 1 due to drug-related toxicity; Any clinically significant occurrence which the investigators and sponsor agree would place participants at undue safety risk; Participants who experienced an adverse event (AE) that met the definition for a DLT. | Cycle 1: Days 1 to 28 | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants with Complete Response (CR) and Partial Response (PR) based on Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Each cycle was a 28 day cycle. CR was defined as the disappearance of all target lesions and for non-target lesions, the disappearance of all non-target lesions and normalization of tumor marker level. 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. | At screening and thereafter every 2 cycles of treatment until disease progression (Up to 65.8 weeks) | 
| Percentage of Participants With 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. | First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 91.4 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax: Maximum Observed Plasma Concentration for MLN0128 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. | Cycles 1 and 2: Day 1 or 2 | 
| Cmin: Minimum Observed Plasma Concentration for MLN0128 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. | Cycles 1 and 2: Day 1 or 2 | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i.e., C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. | Cycles 1 and 2: Day 1 or 2 | 
| Terminal Phase Elimination Half-life (T1/2) for MLN0128 |  | Cycle 1 Day 1 | 
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for MLN0128 |  | Cycle 1 Day 1 | 
| AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for MLN0128 | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 30 and 40 mg QW arms. | Cycles 1 and 2: Day 1 or 2 | 
| Cmax: Maximum Observed Plasma Concentration for Paclitaxel |  | Cycles 1 and 2: Day 1 | 
| Cmin: Minimum Observed Plasma Concentration for Paclitaxel | Participants in the 6 mg QD×3d QW and 9 mg QD×3d QW were dosed with MLN0128 in conjunction with paclitaxel during Cycle 1 and Cycle 2 when PK was collected. Participants in the 7 mg QD×3d QW cohorts were dosed with paclitaxel during Cycle 1, but were subsequently switched to MLN0128 being dosed 24 hours after paclitaxel infusion Cycle 2 (i e, C2D2). In all the other dosing cohorts, MLN0128 was dosed 24 hours after paclitaxel infusion. Cycle 1: Data was collected at Day 1 for the 6, 7 and 9 mg QD×3d QW arms and at Day 2 for the 8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. Cycle 2: Data was collected at Day 1 for the 6 and 9 mg QD×3d QW arms and at Day 2 for the 7,8 and 10 mg QD×3d QW, 7 mg QD×5d QW, 30 and 40 mg QW arms. | Cycles 1 and 2: Day 1 or 2 | 
| Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Paclitaxel |  | Cycles 1 and 2: Day 1 | 
| Terminal Phase Elimination Half-life (T1/2) for Paclitaxel |  | Cycle 1 Day 1 | 
| AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel |  | Cycle 1 Day 1 | 
| AUC(0-6): Area Under the Plasma Concentration-time Curve From Time 0 to 6 Hours for Paclitaxel |  | Cycle 1 Day 1 | 
| AUC(0-24): Area Under the Plasma Concentration-time Curve Extrapolated to 24 Hours for Paclitaxel |  | Cycle 1 Day 1 | 
| CL: Total Clearance Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel |  | Cycle 1 Day 1 | 
| Vss: Volume of Distribution at Steady State Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel |  | Cycle 1 Day 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumor, mTORC1/2 inhibitors, HER2