MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma

Study Overview
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Brief Summary
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This is an open label, multi-center, randomized phase I/II study of MLN0128 versus standard sorafenib. Eligible subjects in the phase I trial will receive MLN0128 in escalating doses. Eligible subjects in the phase II trial will be 1:1 randomized to either the MLN0128 arm or the sorafenib arm.

Detailed Description
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OUTLINE: This is a multi-center trial. The phase 1 dose escalation trial will evaluate MLN0128 in a standard 3+3 successive cohort design to identify the highest planned dose level. Phase II trial subjects will be 1:1 randomized to receive either MLN0128 (investigational arm) or sorafenib (control arm). PHASE I DOSE ESCALATION INVESTIGATIONAL TREATMENT: Cohort 1 (dose level +1) will consist of 3-6 evaluable patients who will receive MLN0128 15mg on day 1 of the 28-day cycle. Cohort 2 (dose level +2) will consist of 3-6 evaluable patients who will receive MLN0128 20mg on day 1 of the 28-day cycle. Cohort 3 (dose level +3) will consist of 3-6 evaluable patients who will receive MLN0128 30mg on day 1 of the 28-day cycle. Subjects will be evaluated for dose limiting toxicity (DLT) in the first 28 days of treatment (1 cycle). However, decisions to move to next dose escalation cohort will not be made until all subjects complete 2 cycles of therapy at a given dose. There will be no further dose escalation beyond dose level +3. PHASE II INVESTIGATIONAL TREATMENT: Randomization will take place following completion of the screening evaluations and eligibility assessments. Stratification factors will be employed during randomization to minimize between-arm assignment imbalance. 1 Child-Pugh score 5-6 2 Child-Pugh score 7 Within the strata, subjects will be randomly assigned with equal probability to either the investigational arm (Arm A: MLN0128) or the control arm (Arm B: sorafenib). Arm A: MLN0128 will be administered orally at the recommended phase II dose (RP2D) once weekly. Arm B: Sorafenib will be administered at 400mg PO BID daily, with dose adjustment per standard of care. A new treatment cycle (1 cycle = 28 days) will only be initiated when all of the following conditions are met: Absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L Platelets ≥ 50 x 10*9/L Non-hematologic treatment related toxicities have improved to grade 1 or resolved per Common Terminology Criteria for Adverse Events v4.0 (CTCAE) Treatment may continue until progression, unacceptable toxicity, or withdrawal from study. Estimated Life Expectancy: ≥ 3 months Subjects must have adequate organ function, as specified below, within 7 days before study registration: Bone marrow reserve consistent with: Absolute neutrophil count (ANC) ≥ 1.5 x 10*9/L Platelet count ≥ 50 x 10*9/L Hemoglobin ≥ 9 g/dL Hepatic: Total bilirubin ≤ 2 x upper limit of normal (ULN) Transaminases (aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT) ≤ 5 x ULN Renal: Creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour) Metabolic: Fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL. Glycosylated hemoglobin (HbA1c) <7.0%

Official Title
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An Open Label Randomized Phase I/II Trial of MLN0128 Compared to Sorafenib in Patients With Advanced or Metastatic Hepatocellular Carcinoma: Big Ten Cancer Research Consortium BTCRC-GI13-002

Conditions
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Hepatocellular Carcinoma, Liver Cancer, HCC

Intervention / Treatment
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* Drug: MLN0128
* Drug: MLN0128 (RP2D)
* Drug: Sorafenib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subjects 18 years or older at the time of informed consent. Voluntary written consent must be signed before performance of any study related procedure not part of standard medical care, with the understanding that the subject may withdraw consent at any time without prejudice to future medical care. Females of childbearing potential must agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 90 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Females of childbearing potential must have a negative serum pregnancy test within 7 days prior to prior to registration for protocol therapy. NOTE: Female subjects are considered of childbearing potential unless they are surgically sterile (they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Male subjects, even if surgically sterilized (i.e., status post-vasectomy), must agree to practice effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse. Subjects must have a diagnosis of measurable advanced or metastatic hepatocellular carcinoma (HCC). Advanced HCC is defined as disease not amenable to surgery, ablation, transplant, or embolic therapy. Phase II subjects must be willing to provide a tissue biopsy prior to registration if archived HCC tumor tissue is not available for correlative studies. For the phase I cohort, subjects with one prior systemic treatment are eligible. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. Adequate organ function, as specified below, within 28 days before study registration: Bone marrow reserve consistent with: absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥ 50 x 10^9/L; hemoglobin ≥ 9 g/dL; Hepatic: total bilirubin ≤ 2 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 5 x ULN Renal: creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour); Metabolic: Glycosylated hemoglobin (HbA1c) ≤7.0%, fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL. Ability to swallow oral medications. Measurable disease according to RECIST v1.1 and obtained by imaging within 28 days prior to registration for protocol therapy. Subjects who have a history of brain metastasis are eligible for the study provided all the following criteria are met: Must have completed their treatment for brain metastasis Must be asymptomatic Must not have evidence of disease progression for ≥3 months or hemorrhage after treatment; Must be off-treatment from dexamethasone for 4 weeks prior to study registration and Must not have an ongoing requirement for dexamethasone or anti-epileptic drugs. Prior locoregional liver directed therapy is allowed as long as treatment was at least 6 weeks prior to study registration, and clear progression is demonstrated by RECIST v1.1 criteria. Subject must have recovered from the acute toxic effects (≤ grade 1 CTCAE v4) of previous anti-cancer treatment prior to study enrollment; the only exception is that grade 2 neuropathy is permitted. Prior radiation therapy is allowed to < 25% of the bone marrow, but is not permitted within 28 days prior to study registration. Estimated life expectancy > 3 months as determined by the treating physician. Exclusion Criteria: Subjects meeting any of the following exclusion criteria are not to be enrolled in the study: Female subjects who are both lactating and breastfeeding Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. Treatment with any investigational products within 28 days prior to study registration. No prior systemic treatment is allowed, except for subjects in the phase I cohort who are permitted one prior systemic treatment. Failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia and grade 2 neuropathy. Have initiated treatment with bisphosphonates less than 30 days prior to study registration. Concurrent bisphosphonate use is only allowed if the bisphosphonate was initiated at least 30 days prior to study registration. Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128. No condition that could affect the absorption of study drug, including any of the following: Malabsorption syndrome Disease significantly affecting gastrointestinal function Bowel obstruction or sub-obstruction History of any of the following within the last 6 months prior to study registration: Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures Ischemic cerebrovascular event, including transient ischemic attack (TIA) and artery revascularization procedures Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) Placement of a pacemaker for control of rhythm New York Heart Association (NYHA) Class III or IV heart failure Pulmonary embolism Significant active cardiovascular or pulmonary disease at the time of study registration, including: Uncontrolled high blood pressure (i.e., systolic blood pressure >160 mm Hg, diastolic blood pressure > 95 mm Hg) Pulmonary hypertension Uncontrolled asthma or O2 saturation < 90% by ABG (Arterial Blood Gas) analysis or pulse oximetry on room air Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement Medically significant (symptomatic) bradycardia History of arrhythmia requiring an implantable cardiac defibrillator Baseline prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsades de pointes) Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week prior to study registration (subjects already receiving erythropoietin on a chronic basis for ≥ 28 days are eligible). Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the subject in the study. Cirrhosis with Child-Pugh score > 7 Variceal bleeding within 1 month prior to study registration. Refractory encephalopathy or ascites Known HIV positivity Hepatitis B surface antigen (HBsAg) positivity without active treatment. A subject found to be HBsAg positive should be on antiviral therapy for at least two weeks prior to study registration. Treatment with strong inhibitors and/or inducers of cytochrome P450 (CYP) 3A4, CYP2C19 or CYP2C19 within 7 days prior to study registration. Subjects requiring daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within 7 days prior to study registration.

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I MLN0128 Dose Escalation Study<br>Subjects will receive MLN0128 orally on days 1, 8, 15 and 22 in successive cohorts. Cohort 1 MLN0128 15mg each week (QW); Cohort 2 MLN0128 20mg QW; Cohort 3 MLN0128 30mg QW | Drug: MLN0128<br>* Phase I Dose Escalation Study Cohort 1 MLN0128 15mg QW; Cohort 2 MLN0128 20mg QW; Cohort 3 MLN0128 30mg QW<br>* Other names: Sapanisertib;|
| Experimental: Phase II Arm A: MLN0128<br>Subjects randomized to experimental arm will receive MLN0128 orally at the recommended phase II dose (RP2D) once weekly. | Drug: MLN0128 (RP2D)<br>* Phase II Arm A: MLN0128 administered orally at the recommended phase II dose (RP2D) once weekly.<br>* Other names: Sapanisertib;|
| Active Comparator: Phase II Arm B: Sorafenib<br>Subjects randomized to control arm will receive sorafenib 400mg by mouth (PO) twice a day (BID) daily. | Drug: Sorafenib<br>* Phase II Arm B: Sorafenib administered at 400mg PO BID daily<br>* Other names: Nexavar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Maximum Tolerated Dose (MTD) of MLN0128 | The primary objective for phase I of this study is to determine the maximum tolerated dose (MTD) of MLN0128. Maximum Tolerated Dose is defined as the dose level at which fewer than 33% of subjects experience a dose limiting toxicity (DLT). | From start of treatment Day 1 (D1) until completion of two cycles of treatment (maximum 56 days) | 
| Phase II: Time to Progression (TTP) | The primary endpoint of Phase II of the study is to evaluate the time to progression, which is defined as the time from randomization until tumor progression as defined by RECIST v1.1. | From date of randomization until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 7 months (estimated). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Characterize Adverse Effects (AE) | Toxicity assessed using Common Terminology Criteria for Adverse Events v4.0 (CTCAE) criteria | From date of first dose until 30 days after the last treatment, assessed for estimated 7 cycles (est. 196 days) | 
| Phase I: Overall Survival (OS) Rate | Overall Survival of subjects receiving MLN0128 is defined by the time from randomization to date of death from any cause.Here median overall survival in months has been reported for subjects per dose level with 95% confidence interval. | From date of registration until death from any cause, up to a maximum of 27 months | 
| Phase II: Overall Survival (OS) Rate | Overall Survival of subjects randomized to both MLN0128 and sorafenib arms is defined by the time from randomization to date of death from any cause. | From date of registration until death from any cause, up to a maximum of 24 months | 
| Phase I: Time to Progression (TTP) | Time to progression (TTP) of subjects receiving MLN0128 assessed using RECIST v1.1 criteria is defined as the time from randomization until tumor progression as defined by RECIST v1.1. Here median Time to Progression in months has been reported for subjects per dose level with 95% confidence interval. | From date of randomization until the date of first documented progression or date of death from any cause, whichever occurs first, assessed up to 6 months (estimated). | 
| Phase I: Progression-free Survival (PFS) | Progression free survival (PFS) of subjects receiving MLN0128 assessed using RECIST v1.1 criteria is defined by time from randomization to tumor progression or death from any cause. Here median Progression-free survival in months has been reported for subjects per dose level with 95% confidence interval. | From date of randomization to tumor progression or death from any cause, up to a maximum of 6 months | 
| Phase II: Progression Free Survival (PFS) | Progression Free Survival of subjects randomized to both MLN0128 and sorafenib arms assessed using RECIST v1.1 criteria, is defined as time from randomization to tumor progression or death from any cause. | From date of randomization to tumor progression or death from any cause, up to a maximum of 24 months | 
| Phase I: Objective Response Rate (ORR) | Objective Response Rate (ORR) of subjects receiving MLN0128 defined as complete response (CR)+partial response (PR), as defined by RECIST v1.1. | Objective Response Rate is assessed at 16 weeks and 24 weeks from start of treatment cycle until Progressive disease is documented. | 
| Phase I: Disease Control Rate (DCR) | Disease Control Rate (DCR) of subjects receiving MLN0128 as a sum of stable disease (SD for 8 weeks or longer), partial response (PR), and complete response (CR), as defined by RECIST v1.1. | Disease Control Rate is assessed at 16 weeks and 24 weeks from start of treatment cycle until Progressive disease is documented. | 
| Phase II: Characterize Adverse Effects (AE) | Toxicity for subjects randomized to both MLN0128 and sorafenib arms, assessed using CTCAE v4 criteria | From date of first dose until 30 days after the last treatment, assessed for estimated 7 cycles (est. 196 days) | 
| Phase II: Radiographic Response Rate (RRR) | Radiographic Response Rate for subjects randomized to both MLN0128 and sorafenib arms, determined utilizing objective response rate (ORR) and disease control rate (DCR) at 16 and 24 weeks. | Radiographic Response Rate is assessed at 16 weeks and 24 weeks from start of treatment cycle until Progressive disease is documented. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MLN0128, Sapanisertib, TORC1/2 inhibitor, INK128, Nexavar, Sorafenib