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MLN0128 Compared to Sorafenib in Advanced or Metastatic Hepatocellular Carcinoma

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ClinicalTrials.gov Identifier: NCT02575339
Recruitment Status : Active, not recruiting
First Posted : October 14, 2015
Last Update Posted : May 14, 2019
Sponsor:
Collaborators:
Millennium Pharmaceuticals, Inc.
Big Ten Cancer Research Consortium
Information provided by (Responsible Party):
Bert O'Neil, MD, Big Ten Cancer Research Consortium

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.

Condition or disease Intervention/treatment Phase
Hepatocellular Carcinoma Liver Cancer HCC Drug: MLN0128 Drug: MLN0128 (RP2D) Drug: Sorafenib Phase 1 Phase 2

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 11 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : July 2016
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase I MLN0128 Dose Escalation Study

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 I Dose Escalation Study Cohort 1 MLN0128 15mg QW; Cohort 2 MLN0128 20mg QW; Cohort 3 MLN0128 30mg QW
Other Name: Sapanisertib

Experimental: Phase II Arm A: MLN0128
Subjects randomized to experimental arm will receive MLN0128 orally at the recommended phase II dose (RP2D) once weekly.
Drug: MLN0128 (RP2D)

Phase II Arm A:

MLN0128 administered orally at the recommended phase II dose (RP2D) once weekly.

Other Name: Sapanisertib

Active Comparator: Phase II Arm B: Sorafenib
Subjects randomized to control arm will receive sorafenib 400mg by mouth (PO) twice a day (BID) daily.
Drug: Sorafenib

Phase II Arm B:

Sorafenib administered at 400mg PO BID daily

Other Name: Nexavar




Primary Outcome Measures :
  1. Phase I: Maximum Tolerated Dose (MTD) of MLN0128 [ Time Frame: From start of treatment Day 1 (D1) until completion of two cycles of treatment (maximum 56 days) ]
    Dose limiting toxicities (DLT) assessed to establish recommended phase 2 dose (RP2D)

  2. Phase II: Time to Progression (TTP) [ 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). ]
    TTP of subjects on each arm assessed using Response Evaluation Criteria In Solid Tumors v1.1 (RECIST) criteria


Secondary Outcome Measures :
  1. Phase I: Characterize Adverse Effects (AE) [ Time Frame: 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

  2. Phase I: Overall Survival (OS) Rate [ Time Frame: From date of registration until death from any cause, up to a maximum of 24 months ]
    OS of subjects receiving MLN0128

  3. Phase I: Time to Progression (TTP) [ 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). ]
    TTP of subjects receiving MLN0128 assessed using RECIST v1.1 criteria

  4. Phase I: Progression-free survival (PFS) [ Time Frame: From date of randomization to tumor progression or death from any cause, up to a maximum of 24 months ]
    PFS of subjects receiving MLN0128 assessed using RECIST v1.1 criteria

  5. Phase I: Objective Response Rate (ORR) [ Time Frame: Assessed at 16 weeks and 24 weeks from D1 of treatment ]
    ORR of subjects receiving MLN0128 assessed by RECIST v1.1

  6. Phase I: Disease Control Rate (DCR) [ Time Frame: Assessed at 16 weeks and 24 weeks from D1 of treatment ]
    DCR of subjects receiving MLN0128 assessed by RECIST v1.1

  7. Phase II: Overall Survival (OS) Rate [ Time Frame: From date of registration until death from any cause, up to a maximum of 24 months ]
    OS of subjects randomized to both MLN0128 and sorafenib arms

  8. Phase II: Progression Free Survival (PFS) [ Time Frame: From date of randomization to tumor progression or death from any cause, up to a maximum of 24 months ]
    PFS of subjects randomized to both MLN0128 and sorafenib arms, assessed using RECIST v1.1 criteria

  9. Phase II: Characterize Adverse Effects (AE) [ Time Frame: 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

  10. Phase II: Radiographic Response Rate (RRR) [ Time Frame: Assessed at 16 weeks and 24 weeks from D1 of treatment ]
    RRR for subjects randomized to both MLN0128 and sorafenib arms, determined utilizing ORR and DCR assessments



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02575339


Locations
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United States, Illinois
Northwestern University Feinberg School of Medicine
Chicago, Illinois, United States, 60611
University of Illinois Cancer Center
Chicago, Illinois, United States, 60612
United States, Indiana
Indiana University Melvin and Bren Simon Cancer Center
Indianapolis, Indiana, United States, 46202
United States, North Carolina
University of Noth Carolina at Chapel Hill
Chapel Hill, North Carolina, United States, 27514
United States, Pennsylvania
Penn State Cancer Institute
Hershey, Pennsylvania, United States, 17033
United States, Wisconsin
University of Wisconsin
Madison, Wisconsin, United States, 53705
Sponsors and Collaborators
Bert O'Neil, MD
Millennium Pharmaceuticals, Inc.
Big Ten Cancer Research Consortium
Investigators
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Study Chair: Bert O'Neil, M.D. Big Ten Cancer Research Consortium

Additional Information:
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Responsible Party: Bert O'Neil, MD, Sponsor-Investigator, Big Ten Cancer Research Consortium
ClinicalTrials.gov Identifier: NCT02575339     History of Changes
Other Study ID Numbers: BTCRC GI13-002
First Posted: October 14, 2015    Key Record Dates
Last Update Posted: May 14, 2019
Last Verified: May 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Bert O'Neil, MD, Big Ten Cancer Research Consortium:
MLN0128
Sapanisertib
TORC1/2 inhibitor
INK128
Nexavar
Sorafenib

Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Hepatocellular
Liver Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Adenocarcinoma
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Liver Diseases
Sorafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action