Dose Escalation Study of MLN0128 in Participants With Advanced 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 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
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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.

Official Title
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A Phase I, Open Label, Dose Escalation Study of Oral Administration of Single Agent INK128 in Subjects With Advanced Malignancies Followed by an Expansion in Subjects With Measurable Disease

Conditions
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Advanced Solid Malignancies

Intervention / Treatment
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* Drug: MLN0128


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 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 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: Sequential Assignment
Interventional Model Description: The Escalation Phase was sequential and the Expansion Phase was parallel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MLN0128 QD<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|
| Experimental: MLN0128 QW<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|
| Experimental: MLN0128 QDx3d QW<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|
| Experimental: MLN0128 QDx5d QW<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|
| Experimental: MLN0128 5 mg QD<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|
| Experimental: MLN0128 30 mg QW<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|
| Experimental: MLN0128 40 mg QW<br>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). | Drug: MLN0128<br>* MLN0128 capsules<br>* Other names: TAK-128;|

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 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. | Cycle 1 (28 Days) | 
| 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. | Cycle 1 (28 days) | 
| 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. | First dose of study drug through 30 days after the administration of the last dose of study drug (Up to approximately 244 weeks) | 
| 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. | From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks) | 
| 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). | From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks) | 
| 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). | From the first dose of study drug up to disease progression or death (Up to approximately 240 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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. | Baseline, Cycle 1 Week 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors, MLN0128, TORC1/2 inhibitors