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)

NCT02259114 | Completed Phase 1 Results FDA Drug

• 4 other identifiers: 8628-003OTX015_1082014-002680-15MK-8628-003
• Study Type: interventional
• Target: 47
• Locations: 0 countries
• Sites: N/A

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (9)

• Number of Participants Who Experienced at Least One Adverse Event (AE)

  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

  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

  Up to approximately 16.5 months

• Observed Maximum Plasma Concentration (Cmax) of MK-8628

  Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

• Time to Cmax (Tmax) of MK-8628

  Cycle 1 Day1: Predose; 0.25, 1, 2, 3 and 7 hours postdose

Study Arms (2)

Continuous Dosing Regimen

EXPERIMENTAL

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

Days 1-7 Dosing Regimen

EXPERIMENTAL

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

Interventions

Birabresib DRUG

Birabresib 10, 20 and/or 40 mg oral capsules

Also known as: OTX105, MK-8628

Continuous Dosing Regimen; Days 1-7 Dosing Regimen

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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,

You may not qualify if:

• 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.

Sponsors & Collaborators

• Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA): lead

Related Publications (2)

• Lewin J, Soria JC, Stathis A, Delord JP, Peters S, Awada A, Aftimos PG, Bekradda M, Rezai K, Zeng Z, Hussain A, Perez S, Siu LL, Massard C. Phase Ib Trial With Birabresib, a Small-Molecule Inhibitor of Bromodomain and Extraterminal Proteins, in Patients With Selected Advanced Solid Tumors. J Clin Oncol. 2018 Oct 20;36(30):3007-3014. doi: 10.1200/JCO.2018.78.2292. Epub 2018 May 7.

  PMID: 29733771 BACKGROUND

• Vazquez R, Riveiro ME, Astorgues-Xerri L, Odore E, Rezai K, Erba E, Panini N, Rinaldi A, Kwee I, Beltrame L, Bekradda M, Cvitkovic E, Bertoni F, Frapolli R, D'Incalci M. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017 Jan 31;8(5):7598-7613. doi: 10.18632/oncotarget.13814.

  PMID: 27935867 DERIVED

MeSH Terms

Conditions

Triple Negative Breast Neoplasms

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 3, 2014
• First Posted: October 8, 2014
• Study Start: October 23, 2014
• Primary Completion: March 3, 2017
• Study Completion: March 3, 2017
• Last Updated: January 26, 2021
• Results First Posted: October 1, 2018

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will share