Clinical trial NCT02698189: A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Hematologic Malignancies (MK-8628-005)
Official title: A Phase IB Trial With MK-8628, a Small Molecule Inhibitor of the Bromodomain and Extra-Terminal (BET) Proteins, in Subjects With Selected Hematologic Malignancies
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: AML Including AML de Novo and AML Secondary to MDS
DLBCL
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2016-03-03
Enrollment: 9
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a study to determine the recommended dose of birabresib (MK-8628) for further studies in participants with acute myeloid leukemia (AML) including AML de novo and AML secondary to myelodysplastic syndrome (MDS) and in participants with diffuse large B cell lymphoma (DLBCL). The recommended dose will be established by evaluating dose limiting toxicity (DLT), safety, tolerability, and early efficacy signals.


Eligibility criteria: Inclusion Criteria:

* Diagnosis of AML (AML de novo and post-MDS) or DLBCL
* AML participants must have the following malignancy criteria: measurable and evaluable disease per tumor response criteria; ≥ 5% bone marrow blasts without alternate causality; and \> 90 days since allogeneic stem cell transplantation relapse in participants relapsing after transplant
* AML participants who are Philadelphia chromosome positive must have received ≥ 2 lines of therapy, including 2 bcr-abl tyrosine-kinase (TK) inhibitors (among imatinib, nilotinib and dasatinib), or only 1 line including 1 TK inhibitor if the relapse/refractoriness is associated with the detection of a resistance mutation to these inhibitors
* AML participants \< 60 years old must be in second or further relapse or relapsing after allogeneic stem cell transplantation regardless of number of relapses
* AML participants ≥ 60 years old in first relapse with a disease-free interval \< 12 months, or further relapse. First relapse is also applicable to AML post-MDS patients who have received prior treatment for MDS, but have not received prior treatment for AML.
* DLBCL participants must have the following malignancy criteria: measurable and evaluable disease per tumor response criteria and ≥ 1 tumor mass that is ≥ 15 mm (long axis of lymph node) or ≥ 10 mm (short axis of lymph node or extranodal lesions) on spiral CT scan; failed 2 standard lines of therapy (at least one containing an anti-CD20 monoclonal antibody), or for whom such treatment is contraindicated.
* Eastern Cooperative Oncology Group (ECOG) Performance Status ≤1
* An interval of ≥3 weeks 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)
* Female participants must not be pregnant (negative urine or serum human chorionic gonadotropin test within 72 hours of study start)
* Female and male participants of reproductive potential must agree to use adequate contraception starting from the first dose of trial treatment through 90 days after the last dose of study medication

Exclusion Criteria:

* Known primary central nervous system (CNS) malignancy or symptomatic or untreated CNS metastases
* History of prior or concomitant malignancies within 3 years of study start
* Has 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 history of human immunodeficiency virus (HIV) and/or active Hepatitis B or C infections
* Has one of the following cardiac-related conditions: Congestive heart failure; angina pectoris; myocardial infarction (within 1 year of study start); uncontrolled hypertension; or uncontrolled arrhythmias
* Is receiving other concomitant anticancer treatment
* Has received high dose chemotherapy followed by autologous stem cell transplantation less than 90 days prior to first dose of study treatment
* Is receiving concomitant therapy with strong CYP3A4 or CYP2A6 inhibitors or inducers
* Is pregnant or breast-feeding
* Participation in a clinical trial involving an investigational drug within 30 days of study start
* Known additional malignancy that is progressing or requires active treatment
* Has been previously treated with a Bromodomain and Extra-terminal (BET) inhibitor
* Has acute promyelocytic leukemia, clinically uncontrolled disseminated intravascular coagulation, or peripheral cytopenia
* Has chronic graft versus host disease (GVHD) or on immunosuppressive therapy for the control of GVHD
* Has uncontrolled disease-related metabolic disorder
* Unable to swallow oral medications, or has gastrointestinal condition deemed to jeopardize intestinal absorption.

Primary outcomes:
measure: Percentage of Participants With a Dose Limiting Toxicity (DLT)
timeFrame: From time of first dose up to the end of Cycle 1 (21-day cycle): up to 21 days
Secondary outcomes:
measure: Percentage of Participants Who Experienced At Least One Adverse Event (AE)
timeFrame: From time of first dose until the end of follow-up (up to 8 months)
measure: Percentage of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: From time of first dose until the end of treatment (up to 7 months)
measure: Objective Response Rate (ORR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)
timeFrame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)
measure: Objective Response Rate (ORR) in the Diffuse Large B Cell Lymphoma (DLBCL) Cohort Per International Working Group Criteria: Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014)
timeFrame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)
measure: Duration of Response (DOR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)
timeFrame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)
measure: Duration of Response (DOR) in the Diffuse Large B Cell Lymphoma (DLBCL) Cohort Per International Working Group Criteria: Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014)
timeFrame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)
measure: Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)
timeFrame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)
measure: Disease Control Rate (DCR) in the Diffuse Large B Cell Lymphoma (DLBCL) Cohort Per International Working Group Criteria: Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014)
timeFrame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)
measure: Observed Maximum Concentration (Cmax) of MK-8628
timeFrame: Up to 22 days post MK-8628 dose
measure: Time to Maximum Concentration (Tmax) of MK-8628
timeFrame: Up to 22 days post MK-8628 dose
measure: Observed Minimum Concentration (Cmin) of MK-8628
timeFrame: Up to 22 days post MK-8628 dose
measure: Area Under the Concentration-Time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)
timeFrame: Up to 22 days post MK-8628 dose
measure: Apparent Terminal Half-life (t1/2) for MK-8628
timeFrame: Up to 22 days post MK-8628 dose
measure: Apparent Total Body Clearance (CL/F) of MK-8628
timeFrame: Up to 22 days post MK-8628 dose
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628
timeFrame: Up to 22 days post MK-8628 dose
measure: Change From Baseline in Bromodomain and Extra-Terminal Domain (BET) Protein Target Gene Expression at 3 Hours Postdose on Day 1 of Cycle 1 (21-day Cycle)
timeFrame: Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 3 hours postdose on Day 1 of Cycle 1 (21-day cycle)
measure: Change From Baseline in Bromodomain and Extra-Terminal Domain (BET) Protein Target Gene Expression at 8 Hours Postdose on Day 1 of Cycle 1 (21-day Cycle)
timeFrame: Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 8 hours postdose on Day 1 of Cycle 1 (21-day cycle)
measure: Change From Baseline in Bromodomain and Extra-Terminal Domain (BET) Protein Target Gene Expression at 12 Hours Postdose on Day 1 of Cycle 1 (21-day Cycle)
timeFrame: Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 12 hours postdose on Day 1 of Cycle 1 (21-day cycle)
measure: Change From Baseline in Bromodomain and Extra-Terminal Domain (BET) Protein Target Gene Expression at Predose on Day 8 of Cycle 1 (21-day Cycle)
timeFrame: Baseline (predose on Day 1 of Cycle 1) and predose on Day 8 of Cycle 1 (21-day cycle)
Other outcomes:
Locations:
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: