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
| Registry | NCT02698176 |
|---|---|
| Status | Terminated - This study was terminated due to limited efficacy and not due to safety reasons. |
| Phase | Phase 1 |
| Study type | Interventional; non randomized, parallel, masking: none, treatment |
| Enrollment | 13 (Actual) |
| Sponsor | Merck Sharp & Dohme LLC (Industry) |
| Conditions | NUT Midline Carcinoma (NMC), Triple Negative Breast Cancer (TNBC), Non-small Cell Lung Cancer (NSCLC), Castration-resistant Prostate Cancer (CRPC) |
| Interventions | Birabresib (Drug) |
| Dates | start 2016-05-04, primary completion 2017-04-26, completion 2017-04-26, first posted 2016-03-03, last updated 2021-01-27 |
Related Papers Related Patents Related Grants Related Experts
All trials for NUT Midline Carcinoma (NMC) All trials for Triple Negative Breast Cancer (TNBC) All trials of Birabresib
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.
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.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| Birabresib 20 mg CRPC Cohort-Part A | Experimental | Drug: Birabresib | 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. |
| Birabresib 20 mg NMC Cohort-Part A | Experimental | Drug: Birabresib | 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. |
| Birabresib 20 mg TNBC Cohort-Part A | Experimental | Drug: Birabresib | 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. |
| NMC Cohort-Part B | Experimental | Drug: Birabresib | 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. |
Sex: All, ages: 18 Years to any
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
| Milestone | MK-8628 20 mg CRPC Cohort-Part A | MK-8628 20 mg NMC Cohort-Part A | MK-8628 20 mg TNBC Cohort-Part A | NMC Cohort-Part B |
|---|---|---|---|---|
| Started | 9 | 3 | 1 | 0 |
| Completed | 0 | 0 | 0 | 0 |
| Not completed | 9 | 3 | 1 | 0 |
Time frame: From time of first dose until the end of the 30-day follow-up (up to 25 months)
| Arm | Deaths | Serious adverse events | Other adverse events |
|---|---|---|---|
| MK-8628 20 mg CRPC Cohort-Part A | 0/9 (0.0%) | 3/9 (33.3%) | 9/9 (100.0%) |
| MK-8628 20 mg NMC Cohort-Part A | 0/3 (0.0%) | 2/3 (66.7%) | 3/3 (100.0%) |
| MK-8628 20 mg TNBC Cohort-Part A | 0/1 (0.0%) | 0/1 (0.0%) | 1/1 (100.0%) |
| Term | Organ system | MK-8628 20 mg CRPC Cohort-Part A | MK-8628 20 mg NMC Cohort-Part A | MK-8628 20 mg TNBC Cohort-Part A |
|---|---|---|---|---|
| Thrombocytopenia | Blood and lymphatic system disorders | 0/9 | 1/3 | 0/1 |
| Diarrhoea | Gastrointestinal disorders | 1/9 | 0/3 | 0/1 |
| Pyrexia | General disorders | 1/9 | 0/3 | 0/1 |
| Neutrophil count decreased | Investigations | 0/9 | 1/3 | 0/1 |
| Altered state of consciousness | Nervous system disorders | 0/9 | 1/3 | 0/1 |
| Cognitive disorder | Nervous system disorders | 1/9 | 0/3 | 0/1 |
| Haematuria | Renal and urinary disorders | 1/9 | 0/3 | 0/1 |
| Term | Organ system | MK-8628 20 mg CRPC Cohort-Part A | MK-8628 20 mg NMC Cohort-Part A | MK-8628 20 mg TNBC Cohort-Part A |
|---|---|---|---|---|
| Anaemia | Blood and lymphatic system disorders | 2/9 | 0/3 | 0/1 |
| Leukocytosis | Blood and lymphatic system disorders | 1/9 | 0/3 | 0/1 |
| Leukopenia | Blood and lymphatic system disorders | 0/9 | 0/3 | 1/1 |
| Thrombocytopenia | Blood and lymphatic system disorders | 2/9 | 0/3 | 0/1 |
| Atrial fibrillation | Cardiac disorders | 1/9 | 0/3 | 0/1 |
| Vertigo | Ear and labyrinth disorders | 1/9 | 0/3 | 0/1 |
| Vision blurred | Eye disorders | 1/9 | 0/3 | 0/1 |
| Abdominal pain | Gastrointestinal disorders | 3/9 | 0/3 | 0/1 |
| Abdominal pain upper | Gastrointestinal disorders | 1/9 | 0/3 | 0/1 |
| Constipation | Gastrointestinal disorders | 1/9 | 0/3 | 0/1 |
| Diarrhoea | Gastrointestinal disorders | 3/9 | 1/3 | 0/1 |
| Dyspepsia | Gastrointestinal disorders | 2/9 | 0/3 | 0/1 |
| Dysphagia | Gastrointestinal disorders | 1/9 | 0/3 | 0/1 |
| Gastrointestinal pain | Gastrointestinal disorders | 1/9 | 0/3 | 0/1 |
| Nausea | Gastrointestinal disorders | 6/9 | 1/3 | 0/1 |
| Odynophagia | Gastrointestinal disorders | 1/9 | 0/3 | 0/1 |
| Vomiting | Gastrointestinal disorders | 3/9 | 1/3 | 0/1 |
| Asthenia | General disorders | 2/9 | 1/3 | 0/1 |
| Fatigue | General disorders | 2/9 | 2/3 | 0/1 |
| Mucosal inflammation | General disorders | 0/9 | 1/3 | 0/1 |
| Oedema peripheral | General disorders | 1/9 | 0/3 | 0/1 |
| Pyrexia | General disorders | 2/9 | 0/3 | 0/1 |
| Respiratory tract infection | Infections and infestations | 1/9 | 0/3 | 0/1 |
| Rhinitis | Infections and infestations | 0/9 | 1/3 | 0/1 |
| Sepsis | Infections and infestations | 0/9 | 1/3 | 0/1 |
| Fall | Injury, poisoning and procedural complications | 1/9 | 0/3 | 0/1 |
| Alanine aminotransferase increased | Investigations | 1/9 | 0/3 | 0/1 |
| Aspartate aminotransferase increased | Investigations | 1/9 | 0/3 | 0/1 |
| Blood creatinine increased | Investigations | 1/9 | 0/3 | 0/1 |
| C-reactive protein increased | Investigations | 1/9 | 0/3 | 0/1 |
| Haemoglobin decreased | Investigations | 1/9 | 0/3 | 0/1 |
| Lymphocyte count decreased | Investigations | 0/9 | 0/3 | 1/1 |
| Platelet count decreased | Investigations | 2/9 | 0/3 | 1/1 |
| Weight decreased | Investigations | 0/9 | 1/3 | 0/1 |
| Decreased appetite | Metabolism and nutrition disorders | 2/9 | 2/3 | 0/1 |
| Dehydration | Metabolism and nutrition disorders | 1/9 | 0/3 | 0/1 |
| Hyperuricaemia | Metabolism and nutrition disorders | 0/9 | 1/3 | 0/1 |
| Hypokalaemia | Metabolism and nutrition disorders | 1/9 | 0/3 | 0/1 |
| Hyponatraemia | Metabolism and nutrition disorders | 1/9 | 0/3 | 0/1 |
| Hypophosphataemia | Metabolism and nutrition disorders | 1/9 | 0/3 | 0/1 |
| Arthralgia | Musculoskeletal and connective tissue disorders | 1/9 | 0/3 | 0/1 |
| Bone pain | Musculoskeletal and connective tissue disorders | 2/9 | 0/3 | 0/1 |
| Musculoskeletal pain | Musculoskeletal and connective tissue disorders | 1/9 | 2/3 | 0/1 |
| Myalgia | Musculoskeletal and connective tissue disorders | 1/9 | 0/3 | 0/1 |
| Dysgeusia | Nervous system disorders | 0/9 | 2/3 | 0/1 |
| Headache | Nervous system disorders | 0/9 | 1/3 | 0/1 |
| Haematuria | Renal and urinary disorders | 1/9 | 0/3 | 0/1 |
| Scrotal oedema | Reproductive system and breast disorders | 1/9 | 0/3 | 0/1 |
| Cough | Respiratory, thoracic and mediastinal disorders | 1/9 | 1/3 | 0/1 |
| Dyspnoea | Respiratory, thoracic and mediastinal disorders | 0/9 | 2/3 | 0/1 |
| Dyspnoea exertional | Respiratory, thoracic and mediastinal disorders | 1/9 | 0/3 | 0/1 |
| Oropharyngeal pain | Respiratory, thoracic and mediastinal disorders | 1/9 | 0/3 | 0/1 |
| Dry skin | Skin and subcutaneous tissue disorders | 0/9 | 2/3 | 0/1 |
| Erythema | Skin and subcutaneous tissue disorders | 0/9 | 1/3 | 0/1 |
| Rash | Skin and subcutaneous tissue disorders | 0/9 | 1/3 | 0/1 |
| Rash maculo-papular | Skin and subcutaneous tissue disorders | 1/9 | 0/3 | 0/1 |
| Hot flush | Vascular disorders | 0/9 | 1/3 | 0/1 |
| Hypertension | Vascular disorders | 0/9 | 1/3 | 0/1 |
Limitations and caveats: The study was terminated due to limited efficacy and not due to safety reasons. Due to limited PK sampling for t1/2, caution must be exercised when interpreting the results of t1/2, CL/F, and AUC 0-∞ values.
NIH grants: 2015