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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Advanced Cancer

Intervention / Treatment
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* Drug: Mocetinostat - 50 mg
* Drug: Mocetinostat - 70 mg
* Drug: Mocetinostat - 90 mg
* Drug: Mocetinostat - Recommended Phase 2 Dose (70 mg)
* Drug: Durvalumab - 1500 mg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Dose Escalation - 50 mg<br>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<br>* Participants received mocetinostat three times weekly as an oral capsule.<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|
| Experimental: Phase 1: Dose Escalation - 70 mg<br>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 - 70 mg<br>* Participants received mocetinostat three times weekly as an oral capsule.<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|
| Experimental: Phase 1: Dose Escalation - 90 mg<br>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 - 90 mg<br>* Participants received mocetinostat three times weekly as an oral capsule.<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|
| Experimental: Phase 2: Combination Regimen - Cohort 1<br>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: Mocetinostat - Recommended Phase 2 Dose (70 mg)<br>* Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|
| Experimental: Phase 2: Combination Regimen - Cohort 2<br>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: Mocetinostat - Recommended Phase 2 Dose (70 mg)<br>* Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|
| Experimental: Phase 2: Combination Regimen - Cohort 3<br>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: Mocetinostat - Recommended Phase 2 Dose (70 mg)<br>* Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|
| Experimental: Phase 2: Combination Regimen - Cohort 4<br>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: Mocetinostat - Recommended Phase 2 Dose (70 mg)<br>* Participants received mocetinostat three times weekly as an oral capsule, at the dose recommended after Phase 1 (70 mg).<br>* Other names: MGCD0103;Drug: Durvalumab - 1500 mg<br>* Participants received durvalumab as an intravenous infusion every 4 weeks.<br>* Other names: MEDI4736;|

What is the study measuring?
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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, 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 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MGCD0103, MEDI4736, Mocetinostat, Durvalumab, HDAC Inhibitor, PD-L1 Inhibitor, Phase 1, Phase 2, Metastatic Solid Tumor, Non-small cell lung cancer, immunotherapy, checkpoint inhibitor