Trial Outcomes & Findings for A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006) (NCT NCT02698176)

Last Updated: 2021-01-27

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE1

Target enrollment

13 participants

Primary outcome timeframe

From time of first dose up to the end of the first cycle (up to 21 days)

Results posted on

2021-01-27

Participant Flow

This was a dose-escalating study in participants with advanced or metastatic non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), castration-resistant prostate cancer (CRPC), or nuclear protein in testis (NUT) midline carcinoma (NMC) for which standard therapy does not exist, proven ineffective, intolerable, or unacceptable.

Participants with CRPC, NMC, and TNBC, as defined in the entry criteria, were enrolled; no participants with NSCLC were enrolled. All participants had a Eastern Cooperative Oncology Group (ECOG) Performance Status score of ≤1 and 76.9% of participants had 2 or more prior lines of therapy. No participants were enrolled in Part B of the study.

Participant milestones

Participant milestones
Measure	MK-8628 20 mg CRPC Cohort-Part A Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg orally (PO), twice a day (BID), in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.
Overall Study STARTED	9	3	1
Overall Study COMPLETED	0	0	0
Overall Study NOT COMPLETED	9	3	1

Reasons for withdrawal

Reasons for withdrawal
Measure	MK-8628 20 mg CRPC Cohort-Part A Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg orally (PO), twice a day (BID), in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.
Overall Study Progressive disease	4	3	1
Overall Study Adverse Event	2	0	0
Overall Study Clinical progression	3	0	0

Baseline Characteristics

A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MK-8628 20 mg CRPC Cohort-Part A n=9 Participants Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A n=3 Participants Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A n=1 Participants Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	Total n=13 Participants Total of all reporting groups
Age, Continuous	71.2 Years n=5 Participants	42.7 Years n=7 Participants	66.0 Years n=5 Participants	64.2 Years n=4 Participants
Sex: Female, Male Female	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants
Sex: Female, Male Male	9 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	11 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	1 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	12 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: From time of first dose up to the end of the first cycle (up to 21 days)

Population: Participants in Part A of the study that received at least 85% of the planned MK-8628 20 mg dose (18 days) or experienced a DLT during the first 21-day cycle.

Outcome measures

Outcome measures
Measure	MK-8628 20 mg CRPC Cohort-Part A n=9 Participants Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A n=3 Participants Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A n=1 Participants Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	NMC Cohort-Part B Participants (up to 30) in Part B were to receive MK-8628 at one dose level below the dose that was currently being administered in the escalation portion of Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A was established, participants in Part B were to receive MK-8628 at the RP2D. Participants were to continue receiving MK-8628 at an assigned/adjusted dose level for continuous cycles up to 24 months.
Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1	2 Participants	1 Participants	0 Participants	—

SECONDARY outcome

Timeframe: From time of first dose until the end of the 30-day follow-up (up to 25 months)

Population: Participants in Part A of the study that received at least 1 dose of MK-8628 20 mg. No participants were enrolled in Part B of the study.

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.

Outcome measures

Outcome measures
Measure	MK-8628 20 mg CRPC Cohort-Part A n=9 Participants Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A n=3 Participants Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A n=1 Participants Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	NMC Cohort-Part B Participants (up to 30) in Part B were to receive MK-8628 at one dose level below the dose that was currently being administered in the escalation portion of Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A was established, participants in Part B were to receive MK-8628 at the RP2D. Participants were to continue receiving MK-8628 at an assigned/adjusted dose level for continuous cycles up to 24 months.
Number of Participants Who Experienced at Least One Adverse Event (AE)	9 Participants	3 Participants	1 Participants	—

SECONDARY outcome

Timeframe: From time of first dose until the end of treatment (up to 24 months)

Population: Participants in Part A of the study that received at least 1 dose of MK-8628 20 mg. No participants were enrolled in Part B of the study.

The number of participants who discontinued study treatment due to an AE is presented.

Outcome measures

Outcome measures
Measure	MK-8628 20 mg CRPC Cohort-Part A n=9 Participants Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A n=3 Participants Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A n=1 Participants Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	NMC Cohort-Part B Participants (up to 30) in Part B were to receive MK-8628 at one dose level below the dose that was currently being administered in the escalation portion of Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A was established, participants in Part B were to receive MK-8628 at the RP2D. Participants were to continue receiving MK-8628 at an assigned/adjusted dose level for continuous cycles up to 24 months.
Number of Participants Who Discontinued Study Treatment Due to an AE	2 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)

Population: Participants in Part A of the study who received at least one dose of MK-8628 20 mg. No participants were enrolled in Part B of the study.

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.

Outcome measures

Outcome measures
Measure	MK-8628 20 mg CRPC Cohort-Part A n=9 Participants Participants in the CRPC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg NMC Cohort-Part A n=3 Participants Participants in the NMC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	MK-8628 20 mg TNBC Cohort-Part A n=1 Participants Participants in the TNBC cohort in Part A of the study received MK-8628 20 mg PO, BID, in a fasted state for 21 consecutive days per cycle. Participants received MK-8628 in continuous cycles up to 24 months.	NMC Cohort-Part B Participants (up to 30) in Part B were to receive MK-8628 at one dose level below the dose that was currently being administered in the escalation portion of Part A of the study. Once the recommended Phase 2 dose (RP2D) from Part A was established, participants in Part B were to receive MK-8628 at the RP2D. Participants were to continue receiving MK-8628 at an assigned/adjusted dose level for continuous cycles up to 24 months.
Objective Response Rate (ORR)	0 Participants	0 Participants	0 Participants	—

SECONDARY outcome

Timeframe: Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)

Population: Participants in Part A of the study who received at least one dose of MK-8628 20 mg. No participants were enrolled in Part B of the study. Since no participants experienced a CR or PR, DOR could not be calculated.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Assessed every 6 weeks from time of first dose until disease progression (up to 24 months)

Population: Participants in Part A of the study who received at least one dose of MK-8628 20 mg. No participants were enrolled in Part B of the study.

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.