MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma

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

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT02575339

Enrollment

Registered

2015-10-14

Start date

2016-07-18

Completion date

2020-11-24

Last updated

2022-07-26

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

HCC, Hepatocellular Carcinoma, Liver Cancer

Keywords

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

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.

Detailed description

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%

Interventions

DRUGMLN0128

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

DRUGMLN0128 (RP2D)

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

DRUGSorafenib

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

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

NONE

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Phase I: Maximum Tolerated Dose (MTD) of MLN0128	From start of treatment Day 1 (D1) until completion of two cycles of treatment (maximum 56 days)	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).
Phase II: 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 7 months (estimated).	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.

Secondary

Measure	Time frame	Description
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)	Toxicity assessed using Common Terminology Criteria for Adverse Events v4.0 (CTCAE) criteria
Phase I: Overall Survival (OS) Rate	From date of registration until death from any cause, up to a maximum of 27 months	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.
Phase II: Overall Survival (OS) Rate	From date of registration until death from any cause, up to a maximum of 24 months	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.
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).	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.
Phase I: Disease Control Rate (DCR)	Disease Control Rate is assessed at 16 weeks and 24 weeks from start of treatment cycle until Progressive disease is documented.	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.
Phase II: Progression Free Survival (PFS)	From date of randomization to tumor progression or death from any cause, up to a maximum of 24 months	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.
Phase I: Objective Response Rate (ORR)	Objective Response Rate is assessed at 16 weeks and 24 weeks from start of treatment cycle until Progressive disease is documented.	Objective Response Rate (ORR) of subjects receiving MLN0128 defined as complete response (CR)+partial response (PR), as defined by RECIST v1.1.
Phase II: Radiographic Response Rate (RRR)	Radiographic Response Rate is assessed at 16 weeks and 24 weeks from start of treatment cycle until Progressive disease is documented.	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.
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	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.
Phase II: Characterize Adverse Effects (AE)	From date of first dose until 30 days after the last treatment, assessed for estimated 7 cycles (est. 196 days)	Toxicity for subjects randomized to both MLN0128 and sorafenib arms, assessed using CTCAE v4 criteria

Countries

United States

Participant flow

Participants by arm

Arm	Count
Phase I, Level 1: 15 mg of MLN0128 Subjects at Phase I, level 1 will receive 15mg of MLN0128 orally once weekly per dose level	7
Phase I, Level 2: 20mg of MLN0128 Subjects at Phase I, level 2 will receive 20mg of MLN0128 orally once weekly per dose level	4
Phase I, Level 3: 30mg of MLN0128 Subjects at Phase I, level 3 will receive 30mg of MLN0128 orally once weekly per dose level	0
Total	11

Withdrawals & dropouts

Period	Reason	FG000	FG001
Follow up	Death	6	2
Follow up	Death due to progressive disease after coming off treatment early	1	0
Follow up	Study Terminated	0	2
Study Treatment	Adverse Event	1	2
Study Treatment	Disease Progression	5	2
Study Treatment	Patient Withdrawal After Therapy Start	1	0

Baseline characteristics

Characteristic	Phase I, Level 2: 20mg of MLN0128	Total	Phase I, Level 1: 15 mg of MLN0128
Age, Continuous	64.3 year STANDARD_DEVIATION 3	64.8 year STANDARD_DEVIATION 9.9	65.1 year STANDARD_DEVIATION 12.6
ECOG PS, n(%) 0	0 Participants	4 Participants	4 Participants
ECOG PS, n(%) 1	4 Participants	7 Participants	3 Participants
Race/Ethnicity, Customized Ethnicity Hispanic	0 Participants	1 Participants	1 Participants
Race/Ethnicity, Customized Ethnicity Non-Hispanic	3 Participants	9 Participants	6 Participants
Race/Ethnicity, Customized Ethnicity Unknown	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Race Unknown	1 Participants	1 Participants	0 Participants
Race/Ethnicity, Customized Race White	3 Participants	10 Participants	7 Participants
Sex: Female, Male Female	1 Participants	3 Participants	2 Participants
Sex: Female, Male Male	3 Participants	8 Participants	5 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	7 / 7	2 / 4	0 / 0
other Total, other adverse events	7 / 7	4 / 4	0 / 0
serious Total, serious adverse events	1 / 7	0 / 4	0 / 0

Outcome results

Primary

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.

Time frame: 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).

Population: Data for this primary objective was neither collected nor analyzed due to the early termination of the study by the funder.

Primary

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).

Time frame: From start of treatment Day 1 (D1) until completion of two cycles of treatment (maximum 56 days)

Population: Data for this primary objective was neither collected nor analyzed due to the early termination of the study by the funder.

Secondary

Phase I: Characterize Adverse Effects (AE)

Toxicity assessed using Common Terminology Criteria for Adverse Events v4.0 (CTCAE) criteria

Time frame: From date of first dose until 30 days after the last treatment, assessed for estimated 7 cycles (est. 196 days)