Clinical trial NCT02698176: A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006)
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: NUT Midline Carcinoma (NMC)
Triple Negative Breast Cancer (TNBC)
Non-small Cell Lung Cancer (NSCLC)
Castration-resistant Prostate Cancer (CRPC)
Keywords: OTX015
MK-8628
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-03-03
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1
timeFrame: From time of first dose up to the end of the first cycle (up to 21 days)
Secondary outcomes:
measure: Number of Participants Who Experienced at Least One Adverse Event (AE)
timeFrame: From time of first dose until the end of the 30-day follow-up (up to 25 months)
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: From time of first dose until the end of treatment (up to 24 months)
measure: Objective Response Rate (ORR)
timeFrame: Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)
measure: Duration of Response (DOR)
timeFrame: Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)
measure: Disease Control Rate (DCR)
timeFrame: Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)
measure: Observed Maximum Concentration (Cmax) of MK-8628
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
measure: Observed Minimum Concentration (Cmin) of MK-8628
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
measure: Time to Maximum Concentration (Tmax) of MK-8628
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
measure: Apparent Terminal Half-Life (t1/2) of MK-8628
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
measure: Apparent Total Body Clearance (CL/F) of MK-8628
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
measure: Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)
timeFrame: Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: