Phase 1/2 Study of Mocetinostat and Durvalumab in Patients With Advanced Solid Tumors and NSCLC

A Phase 1/2 Study of HDAC Inhibitor, Mocetinostat, in Combination With PD-L1 Inhibitor, Durvalumab, in Advanced or Metastatic Solid Tumors and Non-Small Cell Lung Cancer

Mocetinostat (MGCD0103) is an orally administered HDAC inhibitor. Durvalumab (MEDI4736) is a human monoclonal antibody that is an inhibitor of the Programmed Cell Death Ligand (or PD-L1). Durvalumab is also known as a checkpoint inhibitor.

This study is evaluating the combination regimen of mocetinostat and durvalumab in participants with Advanced or Metastatic Solid Tumors and Non-Small Cell Lung Cancer.

Study Overview

• Status: Terminated
• Conditions: Advanced Cancer
• Intervention / Treatment: Drug: Mocetinostat - 50 mg; Drug: Durvalumab - 1500 mg; Drug: Mocetinostat - 70 mg; Drug: Mocetinostat - 90 mg; Drug: Mocetinostat - Recommended Phase 2 Dose (70 mg)

• Study Type: Interventional
• Enrollment (Actual): 83
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • Southern Cancer Center, PC
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
  • Florida
    • Pensacola, Florida, United States, 32503
      • Woodlands Medical Specialists - Pensacola
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Robert H. Lurie Comprehensive Cancer Center of Northwestern University
    • Evanston, Illinois, United States, 60201
      • NorthShore University Health System
  • Minnesota
    • Minneapolis, Minnesota, United States, 55414
      • Unniversity of Minnesota Masonic Cancer Center
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute
  • Texas
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research Centers
    • Denton, Texas, United States, 76210
      • Texas Oncology - Denton South
    • Plano, Texas, United States, 75093
      • Texas Oncology-Plano West
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists
    • Winchester, Virginia, United States, 22601
      • Shenandoah Oncology - Winchester
  • Washington
    • Seattle, Washington, United States, 98109
      • Seattle Cancer Care Alliance

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Phase 1-Diagnosis of advanced or metastatic solid tumor; Phase 2-Diagnosis of NSCLC
• Not amenable to treatment with curative intent
• Adequate bone marrow and organ function

Exclusion Criteria:

• Impaired heart function
• Uncontrolled tumor in the brain
• Other active cancer

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1: Dose Escalation - 50 mg; The Phase 1 dose escalation established the recommended phase 2 dose (RP2D) of mocetinostat. Participants with advanced solid tumors were included in this Phase.	Drug: Mocetinostat - 50 mg; Participants received mocetinostat three times weekly as an oral capsule.; Other Names: MGCD0103; Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736
Experimental: Phase 1: Dose Escalation - 70 mg; The Phase 1 dose escalation established the recommended phase 2 dose (RP2D) of mocetinostat. Participants with advanced solid tumors were included in this Phase.	Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736; Drug: Mocetinostat - 70 mg; Participants received mocetinostat three times weekly as an oral capsule.; Other Names: MGCD0103
Experimental: Phase 1: Dose Escalation - 90 mg; The Phase 1 dose escalation established the recommended phase 2 dose (RP2D) of mocetinostat. Participants with advanced solid tumors were included in this Phase.	Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736; Drug: Mocetinostat - 90 mg; Participants received mocetinostat three times weekly as an oral capsule.; Other Names: MGCD0103
Experimental: Phase 2: Combination Regimen - Cohort 1; Participants with non-small cell lung cancer (NSCLC) who were naïve to treatment with immunotherapy, and had a tumor with no/low programmed cell death ligand 1 (PD-L1) expression were included in this cohort.	Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736; Drug: Mocetinostat - Recommended Phase 2 Dose (70 mg); Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).; Other Names: MGCD0103
Experimental: Phase 2: Combination Regimen - Cohort 2; Participants with non-small cell lung cancer (NSCLC) who were naïve to treatment with immunotherapy, and had a tumor with high programmed cell death ligand 1 (PD-L1) expression were included in this cohort.	Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736; Drug: Mocetinostat - Recommended Phase 2 Dose (70 mg); Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).; Other Names: MGCD0103
Experimental: Phase 2: Combination Regimen - Cohort 3; Participants with non-small cell lung cancer (NSCLC) who have been previously treated with an anti-programmed cell death ligand 1 (PD-L1) or anti-programmed cell death 1 (PD-1) agent with clinical benefit response followed by progression of disease were included in this cohort.	Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736; Drug: Mocetinostat - Recommended Phase 2 Dose (70 mg); Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).; Other Names: MGCD0103
Experimental: Phase 2: Combination Regimen - Cohort 4; Participants with non-small cell lung cancer (NSCLC) who have been previously treated with an anti-programmed cell death ligand 1 (PD-L1) or anti-programmed cell death 1 (PD-1) agent who had progression of disease ≤ 16 weeks after initiation of treatment were included in this cohort.	Drug: Durvalumab - 1500 mg; Participants received durvalumab as an intravenous infusion every 4 weeks.; Other Names: MEDI4736; Drug: Mocetinostat - Recommended Phase 2 Dose (70 mg); Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).; Other Names: MGCD0103

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) During the First 28-day Cycle of Combination Treatment In Phase 1	Toxicities were graded using the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 4.03. Any of the following events considered to be causally related to treatment with mocetinostat in combination with durvalumab that occurred during Phase 1 were considered a DLT: Any Grade 4 immune-related adverse event (irAE); Grade 3 or greater colitis; Grade 3 or greater noninfectious pneumonitis; Grade 2 pneumonitis that did not resolve to ≤ Grade 1 within 3 days of the initiation of maximal supportive care; Grade 3 irAE (excluding colitis or pneumonitis) that:Did not resolve to Grade 2 within 3 days after onset of the event despite optimal medical management including systemic corticosteroids, orDid not resolve to Grade ≤1 or Baseline within 14 days; Liver transaminase elevation >8×upper limit of normal (ULN) or total bilirubin >5×ULN; Grade 3 or greater non-irAE, except nausea, vomiting, anorexia, dehydration, or diarrhea	28 days
Objective Response Rate (ORR)	Objective Response Rate (ORR) was defined as the number of participants documented to have a confirmed Complete Response (CR) or Partial Response (PR). Complete Response was defined as the complete disappearance of all target lesions with the exception of nodal disease. Partial Response was defined at least a 30% decrease in the sum of diameters of target measurable lesions. Responses were determined by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants without response data were counted as non-responders. Inferential statistical analyses were conducted for Phase 2 only, as efficacy was not part of the Phase 1 objectives.	Up to approximately 10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Experiencing Treatment-Emergent Adverse Events		Day 1 to 28 days after last dose of study treatment (up to a maximum of 125 weeks in phase 1 and a maximum of 92 weeks in phase 2)
Duration of Response (DR)	DR was defined as the time in days from date of the first documentation of objective response (Complete Response [CR] or Partial Response [PR]) to the first documentation of objective Progressive Disease (PD) or to death due to any cause in the absence of documented PD. DR was only calculated for the subgroup of participants who achieved a Best Overall Response of CR or PR and was presented for responses assessed by Investigator's assessment. Data is displayed for Phase 2 only, as no participants experienced an objective response (CR or PR) during Phase 1.	Up to approximately 10 months
Clinical Benefit Rate (CBR)	Clinical benefit rate (CBR) was defined as the number of participants documented to have a confirmed Complete Response (CR), Partial Response (PR), or Stable Disease (SD) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Participants who were not be able to be assessed for response were counted as non-responders.	Up to approximately 10 months
Progression-Free Survival (PFS)	Progression-free survival (PFS) was defined as the time from date of first study treatment to first Progressive Disease (PD) or death due to any cause in the absence of documented PD per RECIST v1.1	Randomization until progressive disease or death due to any cause (up to 42 months)
1-Year Survival Rate		1 year
Overall Survival (OS)	OS was defined as the time from first dose of study treatment to the date of death due to any cause.	From date of first study treatment until death due to any cause (up to 42 months)
Concentration of Mocetinistat in Blood Plasma		Cycle 1 Day 1 pre-dose, 1, 3, and 7 hours post-dose, Cycle 1 Day 15 pre-dose and 1 hour post-dose, Cycle 2 Day 1 pre-dose and 1 hour post-dose, Cycle 3 Day 1 pre-dose and 1 hour post-dose and Cycle 7 Day 1 pre-dose (each cycle is 28 days)
Concentration of Durvalumab in Blood Plasma	Plasma concentration of Durvalumab was evaluated. All participants received the same Durvalumab dose regardless of Mocetinistat dose group.	Cycle 1 Day 1 pre-dose + end of infusion, Cycle 1 Day 15 pre-mocetinostat dose, Cycle 2 Day 1 pre-dose, Cycle 3 Day 1 pre-dose, Cycle 4 Day 1 pre-dose + end of infusion, Cycle 7 Day 1 pre-dose + 90 days after participant's last dose (Up to max 133 weeks)
Number of Participants With the Presence of Anti-Drug Antibody (ADA) in the Blood		Up to approximately 10 months
Number of Participants With Tumor Expression of Programmed Cell Death Ligand 1 (PD-L1) at Baseline		Baseline

Collaborators and Investigators

• Sponsor: Mirati Therapeutics Inc.

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2016
• Primary Completion (Actual): December 14, 2019
• Study Completion (Actual): December 20, 2019

Study Registration Dates

• First Submitted: June 10, 2016
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (Estimate): June 20, 2016

Study Record Updates

• Last Update Posted (Actual): April 6, 2021
• Last Update Submitted That Met QC Criteria: March 10, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: immunotherapy; Non-small cell lung cancer; Phase 1; Metastatic Solid Tumor; checkpoint inhibitor; Durvalumab; Phase 2; PD-L1 Inhibitor; MEDI4736; Mocetinostat; MGCD0103; HDAC Inhibitor
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Histone Deacetylase Inhibitors; Durvalumab; Mocetinostat
• Other Study ID Numbers: 0103-020