A Dose-Finding Study of Birabresib (MK-8628), a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Adults With Selected Advanced Solid Tumors (MK-8628-003)

Study Overview
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Brief Summary
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Open-label, phase I, non-randomized, multicentric study of single-agent birabresib (MK-8628) (formerly known as OTX015) administered according to two distinct regimens to participants with selected advanced tumors. The study will be performed in two parts. Dose Escalation Part: This step is designed to determine the maximum tolerated dose (MTD) in each of the two regimens, which will be evaluated in parallel. Participants will receive oral birabresib according to: Continuous Dosing Regimen: continuous, once daily for 21 consecutive days (21-day cycles). OR Days 1-7 Dosing Regimen: once daily on Days 1 to 7, repeated every 3 weeks (21-day cycles; 1 week ON/2 weeks OFF). Participants will be sequentially assigned to Continuous Dosing Regimen or Days 1-7 Dosing Regimen according to the next available place and receive birabresib at escalating doses levels (DL). Cohorts of 3 participants will be treated, and an additional 3 participants will be treated at the first indication of dose-limiting toxicity (DLT). MTD assessment will be based on the tolerability observed during the first 21 days of treatment. Expansion Part: The efficacy of birabresib in each of the five indications (i.e., Bromodomain-Nuclear Protein in Testis [BRD-NUT] midline carcinoma, triple negative breast cancer [TNBC], non-small cell lung cancer [NSCLC] harboring a rearrangement Anaplastic Lymphoma Kinase [ALK] gene/fusion protein or Kirsten Ras [KRAS] mutation, castrate-resistant prostate cancer, and pancreatic ductal carcinoma) will be assessed in terms of response (Response Evaluation Criteria in Solid Tumors v1.1 [RECIST v1.1] or Prostate Cancer Clinical Trials Working Group 2 [PCWG2]) using a selected regimen.

Official Title
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A Phase IB Trial With OTX015/MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Patients With Selected Advanced Solid Tumors

Conditions
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NUT Midline Carcinoma, Triple Negative Breast Cancer, Non-small Cell Lung Cancer With Rearranged ALK Gene/Fusion Protein or KRAS Mutation, Castrate-resistant Prostate Cancer, CRPC, Pancreatic Ductal Adenocarcinoma

Intervention / Treatment
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* Drug: Birabresib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed informed consent obtained prior to initiation of any study-specific procedures and treatment; Histologically or cytologically confirmed diagnosis of one of the following advanced or metastatic solid tumors for which standard therapy either does not exist or has proven ineffective, intolerable or inacceptable for the patient: NUT midline carcinoma (ectopic expression of NUT protein as determined by immunohistochemistry (IHC) and/or detection of BRD-NUT gene translocation as determined by fluorescence In situ hybridization [FISH]); Triple negative breast cancer defined according to American Society of Clinical Oncology (ASCO) recommendations (Hammond et al., 2010; Wolff et al., 2007); Non-small cell lung cancer harboring a rearranged ALK gene/fusion protein (FISH or IHC) or KRAS mutation (as defined by any molecular analysis); Castrate-resistant prostate cancer (CRPC); Pancreatic ductal adenocarcinoma; At least one measurable lesion as per RECIST version 1.1., except for CRPC participants who may be enrolled with objective evidence of disease as per PCWG2 criteria; Age ≥18 years at the time of informed consent; Life expectancy ≥3 months; Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤1; Adequate bone marrow reserve, renal and liver function: Absolute neutrophil count ≥1.5 x10^9/L, Platelet count ≥150 x10^9/L, Hemoglobin ≥9 g/dL, Creatinine clearance ≥30 mL/min calculated according to the Cockroft and Gault formula or Modification of Diet in Renal Disease (MDRD) formula for participants aged >65 years, Alanine aminotransferase (ALT), aspartate aminotransferase (AST) ≤3 x upper limit of normal (ULN) and total bilirubin ≤1.25 x ULN (in case of liver involvement, ALT/AST ≤5 x ULN and total bilirubin ≤2 x ULN will be allowed), Serum albumin ≥2.8 g/dL, International Normalized Ratio (INR) ≤1.5 x ULN or INR <3 for participants treated with antivitamin K; An interval of ≥3 weeks 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 initiating study treatment. Exclusion Criteria: Inability to swallow oral medications or presence of a gastrointestinal disorder (e.g. malabsorption) deemed to jeopardize intestinal absorption of birabresib; Persistent grade >1 clinically significant toxicities related to prior antineoplastic therapies (except for alopecia); stable sensory neuropathy ≤ grade 2 National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.4.0 is accepted. Known primary central nervous system (CNS) malignancy or CNS involvement; History of prior or concomitant malignancies (other than excised non-melanoma skin cancer or cured in situ cervical carcinoma) within 3 years of study entry; Other serious illness or medical conditions, such as active infection, unresolved bowel obstruction, or psychiatric disorders; Known human immunodeficiency virus (HIV) positivity; Participation in another clinical trial or treatment with any investigational drug within 30 days prior to study entry; Other concomitant anticancer treatment; Concomitant therapy with strong CYP3A4 interfering drugs; Current use of anticoagulants (e.g. warfarin, heparin) at therapeutic levels within 7 days prior to the first dose of birabresib. Low-dose (prophylactic) low molecular weight heparin (LMWH) is permitted; Pregnant or breast-feeding participants, and men and women with childbearing potential not using effective contraception while on study drug.

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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Continuous Dosing Regimen<br>Participants receive birabresib capsules once daily in a fasted state in the morning on Days 1-21 of each 21-day cycle. Starting dose for dose escalation is 80 mg. | Drug: Birabresib<br>* Birabresib 10, 20 and/or 40 mg oral capsules<br>* Other names: MK-8628;|
| Experimental: Days 1-7 Dosing Regimen<br>Participants receive birabresib capsules once daily in a fasted state in the morning on Days 1-7 of each 21-day cycle. Starting dose for dose escalation is 100 mg. | Drug: Birabresib<br>* Birabresib 10, 20 and/or 40 mg oral capsules<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 defined as any of the following toxicities that were considered by the investigator to be related to MK-8628: Hematologic toxicity: Grade 4 hematologic toxicity or febrile neutropenia, Grade 3 neutropenia with infection, Grade 3 thrombocytopenia with bleeding or lasting >7 days; Non-hematologic toxicity: Grade 3 or 4 non-hematologic toxicity (regardless of duration) unless it was not optimally managed with supportive care, Grade 3 or 4 laboratory abnormality, with or without symptoms, lasting >48 hours, Intolerable Grade 2 non-hematologic toxicity resulting in study drug discontinuation or delay >7 days with or without dose reduction, Designated alanine aminotransferase (ALT) or aspartate aminotransferase (AST) liver test abnormalities; Treatment delay >2 weeks or dose reduction requirement for initiating Cycle 2. | Up to Cycle 1 Day 21 (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 is defined as any untoward medical occurrence associated with use of study treatment in humans, whether or not considered treatment related. The number of participants who experienced at least one AE is presented. | Up to approximately 17.5 months (Up to 30 days after last dose of study treatment) | 
| 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. | Up to approximately 16.5 months | 
| Best Overall Response as Assessed in Solid Tumors by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or in Castration-resistant Prostate Cancer (CRPC) by Prostate Cancer Clinical Trials Working Group (PCWG2) Response Criteria | The best overall response was the best response recorded from the start of the study treatment until the end of treatment. RECIST 1.1 response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. | Up to approximately 16.5 months | 
| Observed Maximum Plasma Concentration (Cmax) of MK-8628 | Blood samples were obtained at specified time points for pharmacokinetic (PK) analysis of the observed Cmax of MK-8628. The observed Cmax of MK-8628 after administration is presented. | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | 
| Time to Cmax (Tmax) of MK-8628 | Blood samples were obtained at specified time points for PK analysis of the Tmax of MK-8628. The Tmax of MK-8628 after administration is presented. | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | 
| Area Under to Concentration-Time Curve From 0 to Infinity (AUC0-∞) of MK-8628 | Blood samples were obtained at specified time points for PK analysis of the AUC0-∞ of MK-8628. The AUC0-first is AUC0-∞ which is derived from the post-hoc estimate of CL/F from the population model. The AUC0-∞ of MK-8628 after administration is presented. | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | 
| Volume of Distribution at Steady State (Vdss) of MK-8628 | Blood samples were obtained at specified time points for PK analysis of the Vdss of MK-8628. The Vdss of MK-8628 after administration is presented. | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | 
| Terminal Half-Life (t1/2) of MK-8628 | Blood samples were obtained at specified time points for PK analysis of the t1/2 of MK-8628. The t1/2 of MK-8628 after administration is presented. | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose | 
| Total Plasma Clearance (CL) of MK-8628 | Blood samples were obtained at specified time points for PK analysis of the CL of MK-8628. The CL of MK-8628 after administration is presented. | Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose |