MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma

NCT02575339 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: BTCRC GI13-002
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Hepatocellular Carcinoma; Liver Cancer; HCC

Keywords

MLN0128; Sapanisertib; TORC1/2 inhibitor; INK128; Nexavar; Sorafenib

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (10)

• Phase I: Characterize Adverse Effects (AE)

  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

  From date of registration until death from any cause, up to a maximum of 27 months

• Phase II: Overall Survival (OS) Rate

  From date of registration until death from any cause, up to a maximum of 24 months

• Phase I: Time to Progression (TTP)

  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)

  From date of randomization to tumor progression or death from any cause, up to a maximum of 6 months

Study Arms (3)

Phase I MLN0128 Dose Escalation Study

EXPERIMENTAL

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

Phase II Arm A: MLN0128

EXPERIMENTAL

Subjects randomized to experimental arm will receive MLN0128 orally at the recommended phase II dose (RP2D) once weekly.

Drug: MLN0128 (RP2D)

Phase II Arm B: Sorafenib

ACTIVE COMPARATOR

Subjects randomized to control arm will receive sorafenib 400mg by mouth (PO) twice a day (BID) daily.

Drug: Sorafenib

Interventions

MLN0128 DRUG

Phase I Dose Escalation Study Cohort 1 MLN0128 15mg QW; Cohort 2 MLN0128 20mg QW; Cohort 3 MLN0128 30mg QW

Also known as: Sapanisertib

Phase I MLN0128 Dose Escalation Study

MLN0128 (RP2D) DRUG

Phase II Arm A: MLN0128 administered orally at the recommended phase II dose (RP2D) once weekly.

Also known as: Sapanisertib

Phase II Arm A: MLN0128

Sorafenib DRUG

Phase II Arm B: Sorafenib administered at 400mg PO BID daily

Also known as: Nexavar

Phase II Arm B: Sorafenib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Kathy Miller: lead
• Millennium Pharmaceuticals, Inc.: collaborator
• Big Ten Cancer Research Consortium: collaborator

Study Sites (6)

Northwestern University Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

University of Illinois Cancer Center

Chicago, Illinois, 60612, United States

Location

Indiana University Melvin and Bren Simon Cancer Center

Indianapolis, Indiana, 46202, United States

Location

University of Noth Carolina at Chapel Hill

Chapel Hill, North Carolina, 27514, United States

Location

Penn State Cancer Institute

Hershey, Pennsylvania, 17033, United States

Location

University of Wisconsin

Madison, Wisconsin, 53705, United States

Location

Related Links

• Big Ten Cancer Research Consortium Website

MeSH Terms

Conditions

Carcinoma, Hepatocellular; Liver Neoplasms

Interventions

sapanisertib; Sorafenib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Phenylurea Compounds; Urea; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Niacinamide; Nicotinic Acids; Acids, Heterocyclic; Heterocyclic Compounds; Pyridines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Annesha Majumdar
• Organization: Hoosier Cancer Research Network

amajumdar@hoosiercancer.org

3179212050

Study Officials

• Kathy D Miller, M.D.

  Big Ten Cancer Research Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: October 9, 2015
• First Posted: October 14, 2015
• Study Start: July 18, 2016
• Primary Completion: June 26, 2018
• Study Completion: November 24, 2020
• Last Updated: July 26, 2022
• Results First Posted: March 31, 2022

Record last verified: 2022-07

Locations

US (6)