Description:
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.
Title
- Brief Title: 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
Clinical Trial IDs
- ORG STUDY ID:
8628-006
- SECONDARY ID:
MK-8628-006
- SECONDARY ID:
2015-005488-18
- NCT ID:
NCT02698176
Conditions
- NUT Midline Carcinoma (NMC)
- Triple Negative Breast Cancer (TNBC)
- Non-small Cell Lung Cancer (NSCLC)
- Castration-resistant Prostate Cancer (CRPC)
Interventions
Drug | Synonyms | Arms |
---|
Birabresib | OTX015, MK-8628 | Birabresib 20 mg CRPC Cohort-Part A |
Purpose
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.
Trial Arms
Name | Type | Description | Interventions |
---|
Birabresib 20 mg CRPC Cohort-Part A | Experimental | 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 | 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 | 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 | 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. | |
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
Maximum Eligible Age: | N/A |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1 |
Time Frame: | From time of first dose up to the end of the first cycle (up to 21 days) |
Safety Issue: | |
Description: | 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. |
Secondary Outcome Measures
Measure: | Number of Participants Who Experienced at Least One Adverse Event (AE) |
Time Frame: | From time of first dose until the end of the 30-day follow-up (up to 25 months) |
Safety Issue: | |
Description: | 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. |
Measure: | Number of Participants Who Discontinued Study Treatment Due to an AE |
Time Frame: | From time of first dose until the end of treatment (up to 24 months) |
Safety Issue: | |
Description: | The number of participants who discontinued study treatment due to an AE is presented. |
Measure: | Objective Response Rate (ORR) |
Time Frame: | Assessed every 6 weeks from time of first dose until disease progression (up to 24 months) |
Safety Issue: | |
Description: | 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. |
Measure: | Duration of Response (DOR) |
Time Frame: | Assessed every 6 weeks from time of first dose until disease progression (up to 24 months) |
Safety Issue: | |
Description: | 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. |
Measure: | Disease Control Rate (DCR) |
Time Frame: | Assessed every 6 weeks from time of first dose until disease progression (up to 24 months) |
Safety Issue: | |
Description: | 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. |
Measure: | Observed Maximum Concentration (Cmax) of MK-8628 |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Observed Minimum Concentration (Cmin) of MK-8628 |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Time to Maximum Concentration (Tmax) of MK-8628 |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Apparent Terminal Half-Life (t1/2) of MK-8628 |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Apparent Total Body Clearance (CL/F) of MK-8628 |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628 |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Measure: | Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞) |
Time Frame: | Cycle1/Day 1: predose, 20 minutes, 1 hour, 2.25 hours (hrs), 3.25 hrs, 8 hrs, and 12 hrs postdose |
Safety Issue: | |
Description: | 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. |
Details
Phase: | Phase 1 |
Primary Purpose: | Interventional |
Overall Status: | Terminated |
Lead Sponsor: | Merck Sharp & Dohme Corp. |
Trial Keywords
Last Updated
January 27, 2021