A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006)

Study Overview
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Brief Summary
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This is a study to determine the recommended dose of birabresib (MK-8628)(formerly known as OTX015) for further studies in participants with advanced nuclear protein in testis (NUT) midline carcinoma (NMC), triple negative breast cancer (TNBC), non-small cell lung cancer (NSCLC), or castration-resistant prostate cancer (CRPC). This is a two-part parallel study: Part A will establish the recommended dose by evaluating dose limiting toxicity (DLT), safety, discontinuation, and early efficacy and Part B will enroll participants with NMC only and will evaluate safety and efficacy in this population.

Detailed Description
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The sponsor decided to terminate the program after evaluation of safety and efficacy data at the dose levels tested (Part A). The decision to discontinue the birabresib program was based on limited efficacy signals and was not due to safety-related concerns. No participants entered or were treated in Part B of the study.

Official Title
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A Phase IB Dose Exploration Trial With MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects With Selected Advanced Solid Tumors

Conditions
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NUT Midline Carcinoma (NMC), Triple Negative Breast Cancer (TNBC), Non-small Cell Lung Cancer (NSCLC), Castration-resistant Prostate Cancer (CRPC)

Intervention / Treatment
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* Drug: Birabresib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥18 years of age for NSCLC, TNBC, and CRPC Males and females ≥16 years of age for NMC Diagnosis of one of the following advanced solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the participant: NMC;TNBC; NSCLC; or CRPC Have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. CRPC participants may be enrolled with objective evidence of disease as per Prostate Cancer Working Group (PCWG2) criteria Life expectancy ≥3 months Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1 Have an interval of ≥3 weeks (or ≥2 weeks for NMC participants) since chemotherapy (≥6 weeks for nitrosoureas or mitomycin C), immunotherapy, hormone therapy or any other anticancer therapy or surgical intervention resection, or ≥3 half-lives for monoclonal antibodies, or ≥5 half-lives for other non-cytotoxic agents (whichever is longer) CRPC participants must maintain ongoing androgen deprivation therapy with a gonadotropin releasing hormone (GnRH) analogue, antagonist or orchiectomy providing serum testosterone is <50 ng/dL (<1.7 nmol/L) Participants receiving bisphosphonate or denosumab therapy must be on stable doses for at least 4 weeks before start of study therapy Females must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start) Females of childbearing potential and male participants must agree to use adequate contraception starting with the first dose of trial treatment through 90 days after the last dose of study medication Exclusion Criteria: Has inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of birabresib Has persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia). Stable sensory neuropathy ≤ grade 2 National Cancer Institute (NCI) - Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 is accepted Known primary central nervous system (CNS) malignancy or symptomatic or untreated CNS metastases. Treated and stable CNS metastases are allowed. History of prior or concomitant malignancies within 3 years of study start Have other serious illness or medical condition, such as active infection, unresolved bowel obstruction, psychiatric disorders, or cerebrovascular accident within 1 year of study start Known human immunodeficiency virus (HIV) and/or active Hepatitis B or C infections Have one of the following cardiac-related conditions: Congestive heart failure or angina pectoris (except if medically controlled); myocardial infarction (within 1 year of study start); uncontrolled hypertension; or uncontrolled arrhythmias Other concomitant anticancer treatment Participation in another clinical trial or treatment with any investigational drug (excluding anticancer treatments) within 30 days of study start Concomitant therapy with strong CYP3A4 inhibitors or inducers Therapeutic anticoagulation (e.g. warfarin, heparin, etc.) must be stopped at least 7 days prior to the first dose of birabresib. Low-dose low molecular weight heparin (LMWH) is permitted Is pregnant or breast-feeding

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Birabresib 20 mg CRPC Cohort-Part A<br>Participants in the CRPC cohort in Part A of the study received birabresib 20 mg orally (PO), twice a day (BID), in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months. | Drug: Birabresib<br>* Administered as an oral capsule in a fasted state<br>* Other names: MK-8628;|
| Experimental: Birabresib 20 mg NMC Cohort-Part A<br>Participants in the NMC cohort in Part A of the study received birabresib 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months. | Drug: Birabresib<br>* Administered as an oral capsule in a fasted state<br>* Other names: MK-8628;|
| Experimental: Birabresib 20 mg TNBC Cohort-Part A<br>Participants in the TNBC cohort in Part A of the study received birabresib 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received birabresib in continuous cycles up to 24 months. | Drug: Birabresib<br>* Administered as an oral capsule in a fasted state<br>* Other names: MK-8628;|
| Experimental: NMC Cohort-Part B<br>Participants (up to 30) in Part B will receive birabresib at one dose level below the dose currently being administered in Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A is established, participants in Part B will receive birabresib at the RP2D. Participants will continue receiving birabresib at an assigned/adjusted dose level for continuous cycles up to 24 months. | Drug: Birabresib<br>* Administered as an oral capsule in a fasted state<br>* Other names: MK-8628;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 | A DLT was any of the following deemed drug related (DR) by investigator: Grade (G)4 hematologic toxicity lasting ≥7 days except thrombocytopenia; G4 thrombocytopenia; G3 thrombocytopenia with bleeding; G3 or 4 febrile neutropenia. G4 non-hematologic (NH) toxicity (not laboratory); G3 NH toxicity (not laboratory), nausea, vomiting, or diarrhea lasting >3 days despite supportive care; G3 or 4 NH laboratory abnormality requiring medical intervention, hospitalization, or persisting >1 week; alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8X Upper Limit of Normal(ULN); ALT or AST >5XULN for >2 weeks; ALT or AST >3XULN and total bilirubin >2XULN or international normalization ratio >1.5; ALT or AST >3XULN with fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or eosinophilia (>5%); DR adverse event leading to discontinuation or >20% missed planned doses in Cycle 1; DR toxicity causing >2 week delay in starting Cycle 2; or G5 toxicity. | From time of first dose up to the end of the first cycle (up to 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced at Least One Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product/protocol-specified procedure, whether or not considered related to the medicinal product/protocol-specified procedure. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who experienced at least one AE is presented. | From time of first dose until the end of the 30-day follow-up (up to 25 months) | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | The number of participants who discontinued study treatment due to an AE is presented. | From time of first dose until the end of treatment (up to 24 months) | 
| Objective Response Rate (ORR) | ORR was defined as the percentage of the participants in the analysis population who had a Complete Response (CR: Disappearance of all target lesions Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions per RECIST 1.1) and lack of progression according to the guidelines for prostate cancer endpoints developed by Prostate Cancer Clinical Trials Working Group (PCWG) 2 as assessed by investigator radiologic review. The number of participants who achieved a CR or PR is presented. | Assessed every 6 weeks from time of first dose until disease progression (up to 24 months) | 
| Duration of Response (DOR) | For participants who demonstrated CR or PR, DOR was defined as the time from first documented evidence of CR or PR per RECIST 1.1 until disease progression per RECIST 1.1 and PCWG2 or death due to any cause, whichever occurred first. Per RECIST 1.1, progressive disease was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. Note: The appearance of one or more new lesions was also considered progression per RECIST 1.1. Per PCWG2, progressive disease was defined as a confirmed increase of at least two new lesions on a bone scan. DOR assessments were assessed by investigator radiologic review. The DOR for all participants who experienced a CR or PR is presented. | Assessed every 6 weeks from time of first dose until disease progression (up to 24 months) | 
| Disease Control Rate (DCR) | DCR was defined as the number of subjects with CR, PR, or stable disease (SD) as assessed by investigator radiologic review according to RECIST version 1.1 and PCWG2. CR: defined as disappearance of all target and all non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to less than <10 mm per RECIST 1.1. PR: defined as at least a 30% decrease in sum of diameters of target lesions, taking as reference the baseline sum diameters along with absence of new lesions and disease progression in non-target lesions per RECIST 1.1. SD: defined as, neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on study per RECIST 1.1 and lack of a confirmed increase of at least two new lesions on a bone scan per PCWG2. The number of participants who experienced DCR is presented. | Assessed every 6 weeks from time of first dose until disease progression (up to 24 months) | 
| Observed Maximum Concentration (Cmax) of MK-8628 | Blood samples were obtained at specified time points for the pharmacokinetic (PK) analysis of Cmax of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Cmax of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 
| Observed Minimum Concentration (Cmin) of MK-8628 | Blood samples were obtained at specified time points for the PK analysis of Cmin of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Cmin of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 
| Time to Maximum Concentration (Tmax) of MK-8628 | Blood samples were obtained at specified time points for the PK analysis of Tmax of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Tmax of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 
| Apparent Terminal Half-Life (t1/2) of MK-8628 | Blood samples were obtained at specified time points for the PK analysis of t1/2 of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The t1/2 of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 
| Apparent Total Body Clearance (CL/F) of MK-8628 | Blood samples were obtained at specified time points for the PK analysis of Cl/F of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Cl/F of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 
| Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628 | Blood samples were obtained at specified time points for the PK analysis of Vz/F of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The Vz/F of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 
| Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞) | Blood samples were obtained at specified time points for the PK analysis of AUC 0-∞ of MK-8628. MK-8628 concentrations were analyzed using ultra-performance liquid chromatography coupled with a tandem mass spectrometry. The AUC 0-∞ of MK-8628 after oral administration is presented. | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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OTX015, MK-8628