Phase 1/2 Study of Mocetinostat and Durvalumab in Patients With Advanced Solid Tumors and NSCLC
- Conditions
- Advanced Cancer
- Interventions
- Registration Number
- NCT02805660
- Lead Sponsor
- Mirati Therapeutics Inc.
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 83
- 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
- Impaired heart function
- Uncontrolled tumor in the brain
- Other active cancer
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Phase 1: Dose Escalation - 70 mg Mocetinostat - 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. Phase 2: Combination Regimen - Cohort 2 Mocetinostat - Recommended Phase 2 Dose (70 mg) 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. Phase 2: Combination Regimen - Cohort 4 Mocetinostat - Recommended Phase 2 Dose (70 mg) 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. Phase 1: Dose Escalation - 70 mg Durvalumab - 1500 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. Phase 1: Dose Escalation - 90 mg Durvalumab - 1500 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. Phase 2: Combination Regimen - Cohort 1 Durvalumab - 1500 mg 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. Phase 2: Combination Regimen - Cohort 2 Durvalumab - 1500 mg 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. Phase 2: Combination Regimen - Cohort 3 Durvalumab - 1500 mg 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. Phase 2: Combination Regimen - Cohort 4 Durvalumab - 1500 mg 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. Phase 1: Dose Escalation - 50 mg Durvalumab - 1500 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. Phase 1: Dose Escalation - 90 mg Mocetinostat - 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. Phase 2: Combination Regimen - Cohort 1 Mocetinostat - Recommended Phase 2 Dose (70 mg) 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. Phase 1: Dose Escalation - 50 mg Mocetinostat - 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. Phase 2: Combination Regimen - Cohort 3 Mocetinostat - Recommended Phase 2 Dose (70 mg) 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.
- Primary Outcome Measures
Name Time Method Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) During the First 28-day Cycle of Combination Treatment In Phase 1 28 days 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, or
* Did 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 diarrheaObjective Response Rate (ORR) Up to approximately 10 months 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.
- Secondary Outcome Measures
Name Time Method 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) 1-Year Survival Rate 1 year Concentration of Durvalumab in Blood Plasma 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) Plasma concentration of Durvalumab was evaluated. All participants received the same Durvalumab dose regardless of Mocetinistat dose group.
Clinical Benefit Rate (CBR) Up to approximately 10 months 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.
Progression-Free Survival (PFS) Randomization until progressive disease or death due to any cause (up to 42 months) 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
Overall Survival (OS) From date of first study treatment until death due to any cause (up to 42 months) OS was defined as the time from first dose of study treatment to the date of death due to any cause.
Number of Participants With Tumor Expression of Programmed Cell Death Ligand 1 (PD-L1) at Baseline Baseline Duration of Response (DR) Up to approximately 10 months 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.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) Number of Participants With the Presence of Anti-Drug Antibody (ADA) in the Blood Up to approximately 10 months
Trial Locations
- Locations (15)
Southern Cancer Center, PC
🇺🇸Mobile, Alabama, United States
David Geffen School of Medicine at UCLA
🇺🇸Los Angeles, California, United States
NorthShore University Health System
🇺🇸Evanston, Illinois, United States
Woodlands Medical Specialists - Pensacola
🇺🇸Pensacola, Florida, United States
Mary Crowley Cancer Research Centers
🇺🇸Dallas, Texas, United States
Shenandoah Oncology - Winchester
🇺🇸Winchester, Virginia, United States
Texas Oncology - Denton South
🇺🇸Denton, Texas, United States
Virginia Cancer Specialists
🇺🇸Fairfax, Virginia, United States
Texas Oncology-Plano West
🇺🇸Plano, Texas, United States
Robert H. Lurie Comprehensive Cancer Center of Northwestern University
🇺🇸Chicago, Illinois, United States
Seattle Cancer Care Alliance
🇺🇸Seattle, Washington, United States
Unniversity of Minnesota Masonic Cancer Center
🇺🇸Minneapolis, Minnesota, United States
Hackensack University Medical Center
🇺🇸Hackensack, New Jersey, United States
Sarah Cannon Research Institute
🇺🇸Nashville, Tennessee, United States
Montefiore Medical Center
🇺🇸Bronx, New York, United States