Symptoms and General Pathology

All Conditions

Neoplasms

Rare Diseases

Recurrence

Glioblastoma

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Participants received 80 mg of oral birabresib administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.

Participants received 120 mg of oral birabresib administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.

Participants received 160 mg of oral birabresib administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.

Administered orally in a fasted state once daily.

Birabresib

Medical Director

A study of single-agent birabresib (MK-8628) (formerly known as OTX015) in recurrent GBM after standard front-line therapy failure.

The first phase of the study (dose escalation) will determine the maximum tolerated dose (MTD). MTD assessment will be based using dose-limiting toxicities (DLTs) observed during the first 28 days of treatment.

The second phase of the study (expansion cohort) will assess efficacy as measured by the progression-free survival rate at 6 months (PFS-6) as determined by an independent central review committee.

A Dose-finding Study of Birabresib (MK-8628) in Participants With Recurrent Glioblastoma Multiforme (MK-8628-002)

A Phase IIa Trial With Dose Optimization of OTX015, a Small Molecule Inhibitor of the Bromodomain and Extra-terminal (BET) Proteins, in Recurrent Glioblastoma Multiforme (GBM) Patients

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Progression-free survival was the time from the start of study treatment to the date of clinical or radiographic evidence of progressive disease according to Response Assessment in Neuro-Oncology (RANO) 2010 criteria or death. Progression, as assessed by RANO 2010, was defined as a ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. PFS at 6 months was measured as the percentage of participants who were alive and progression-free at Month 6. PFS at 6 months was calculated for all participants who were actively enrolled in the study at the 6-month time point.

ORR was defined as the number of participants in the analysis population who experienced a Complete Response (CR: complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically) or a Partial Response (PR: ≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically) and was assessed using RANO 2010.

DOR was the time from the first documented CR (complete disappearance of all enhancing measurable and non-measurable disease sustained for at least 4 weeks; no new lesions; no corticosteroids; and stable or improved clinically)or PR (≥50% decrease compared with baseline in the sum of products of perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no new lesions; stable or reduced corticosteroid dose; and stable or improved clinically), as assessed by RANO 2010, until documentation of disease progression, or the date of the last tumor assessment (if there was no documented progression), or the last tumor assessment before the start of further antitumor therapy. DOR was calculated for all participants who experienced a CR or PR.

OS was the time from the start of study treatment to the date of death. Participants were to be censored at their last contact if they were still alive at the cut-off date. OS was calculated for all participants who did not discontinue from the study due to disease progression.

Progression-free survival was the time from the start of study treatment to the date of clinical or radiographic evidence of progressive disease according to RANO 2010 criteria or death. Progression, as assessed by RANO 2010, was defined as a ≥25% increase in sum of the products of perpendicular diameters of enhancing lesions; any new lesion; or clinical deterioration. PFS was measured as the number of participants who were alive and progression-free for up to 6 months.

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.

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. Any worsening of a preexisting condition temporally associated with the use of the product was also an AE. The number of participants who experienced ≥1 Grade 3-5 AE per National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version 4.03 criteria is presented. Grade 3 was classified as severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; or limiting self-care; Grade 4 was classified as potentially life-threatening or disabling; and Grade 5 was an AE resulting in death.

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

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 lasting \>7 days, or intolerable Grade 2 non-hematologic toxicity resulting in study treatment discontinuation or delay \>7 days with or without dose reduction.

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 and Cmax was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Cmax of MK-8628 after oral administration is presented.

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 and Tmax was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Tmax of MK-8628 after oral administration is presented.

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 and t1/2 was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The t1/2 of MK-8628 after oral administration is presented.

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 and Cl/F was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Cl/F of MK-8628 after oral administration is presented.

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 and Vz/F was calculated using the nonlinear mixed-effects modelling software program Monolix version 4.3.2s. The Vz/F of MK-8628 after oral administration is presented.

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. A single Cmin value for MK-8628 was estimated using dose and steady-state predose concentrations of MK-8628 on Days 29 and 57. The Cmin of MK-8628 after oral administration is presented.

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-∞ was estimated indirectly using the dose and CL/F values. The AUC 0-∞ of MK-8628 after oral administration is presented.

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

The Safety Population consisted of all participants who received at least one dose of study treatment.

Participants received 80 mg of oral MK-8628 administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.

MK-8628 80 mg

Participants received 120 mg of oral MK-8628 administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.

MK-8628 120 mg

Participants received 160 mg of oral MK-8628 administered once daily (in a fasted state) every day in a 28-day cycle for up to 6 cycles.

MK-8628 160 mg

Total

Age, Continuous

Sex: Female, Male

Race and Ethnicity were not collected from any participant.

Race and Ethnicity Not Collected

All participants who received at least one dose of study treatment

This study was terminated 31-Aug-2015 because no clinical activity was detected. The study was not terminated due to safety reasons.

Senior Vice President, Global Clinical Development

All participants who received at least 2 complete cycles (8 weeks) of treatment and had a baseline assessment and 1 on-study magnetic resonance imaging (MRI). Since no participants reached the 6-month time point in the study, PFS at 6 months could not be calculated.

Progression-free Survival (PFS) at 6 Months

All participants who received at least 2 complete cycles (8 weeks) of treatment and had a baseline assessment and 1 on-study MRI or had discontinued early due to disease progression.

Objective Response Rate (ORR)

All participants who received at least 2 complete cycles (8 weeks) of treatment and had a baseline assessment and 1 on-study MRI or had discontinued early due to disease progression. Since no participants experienced a CR or PR, DOR could not be calculated.

Duration of Response (DOR)

All participants who received at least 2 complete cycles (8 weeks) of treatment and had a baseline assessment and 1 on-study MRI or had discontinued early due to disease progression. Since all participants discontinued the study due to disease progression, OS could not be calculated.

Overall Survival (OS)

Progression-free Survival

All participants who received at least one dose of study treatment.

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

Number of Participants Who Experienced at Least One Toxicity Grade 3-5 AE

Number of Participants Who Discontinued Study Treatment Due to an AE

All participants who received at least 21 days of the planned dose of study drug during the first 28-day cycle or experienced a DLT.

Number of Participants Who Experienced a Dose Limiting Toxicity (DLT) During Cycle 1

All participants who received MK-8628 and had blood samples drawn for PK analyses.

Observed Maximum Concentration (Cmax) of MK-8628

Time to Maximum Concentration (Tmax) of MK-8628

Apparent Terminal Half-Life (t1/2) of MK-8628

Apparent Total Body Clearance (Cl/F) of MK-8628

Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628

All participants who received MK-8628 and had predose blood samples drawn on Days 29 and 57 for steady state MK-8628 concentration. Participants in the 160 mg dose group were not analyzed for Cmin because they discontinued before Day 29.

Observed Minimum Concentration (Cmin) of MK-8628

Area Under the Concentration-time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)

Overall Study

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Lung Neoplasms

Carcinoma, Non-Small-Cell Lung

Carcinoma

Prostatic Neoplasms

Breast Neoplasms

Triple Negative Breast Neoplasms

Breast Diseases

Skin Diseases

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.

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.

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.

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.

Administered as an oral capsule in a fasted state

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.

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

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Merck Sharp & Dohme LLC

The safety population consisted of all participants who received at least one dose of study treatment.

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 CRPC 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 NMC 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.

MK-8628 20 mg TNBC Cohort-Part A

Race (NIH/OMB)

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.

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.

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.

NMC Cohort-Part B

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.

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.

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.

Disease Control Rate (DCR)

Total number of participants from all 3 cohorts (CRPC+NMC+TNBC) in Part A of the study that received at least 1 dose of MK-8628 20 mg PO, BID, in a fasted state.

MK-8628 20 mg PK Cohort

Total number of participants from all 3 cohorts (CRPC+NMC+TNBC) in Part A of the study that received at least 1 dose of MK-8628 20 mg and had data available for the PK parameter being analyzed.

Apparent Total Body Clearance (CL/F) of MK-8628

MK-8628 20 mg DLT Cohort

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Dose-finding Study of Birabresib (MK-8628) in Participants With Recurrent Glioblastoma Multiforme (MK-8628-002)	NCT02296476	Glioblastoma Mu...	Birabresib	18 Years -	Oncoethix GmbH, a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Advanced Solid Tumors (MK-8628-006)	NCT02698176	NUT Midline Car... Triple Negative... Non-small Cell ... Castration-resi...	Birabresib	18 Years -	Merck Sharp & Dohme LLC

Spots Global Cancer Trial Database for birabresib

Every month we try and update this database with for birabresib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for birabresib

Every month we try and update this database with for birabresib cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for birabresib cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.