A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Hematologic Malignancies (MK-8628-005)

Phase 1TerminatedNCT02698189

Merck Sharp & Dohme LLC9 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

AML Including AML de Novo and AML Secondary to MDS DLBCL

Interventions

Birabresib Dose 20 mgDRUG

Administered as an oral capsule twice a day for 21 consecutive days per cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

Percentage of Participants With a Dose Limiting Toxicity (DLT)

DLT was any of the following drug related (DR) investigator-assessed adverse events: pancytopenia with hypocellular bone marrow and no marrow blasts lasting for ≥6 weeks; Grade (G)4 hematologic toxicity lasting ≥7 days except thrombocytopenia; G4 thrombocytopenia; G3 thrombocytopenia with bleeding; G3 or 4 febrile or infection-related neutropenia; G4 nonhematologic (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; increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, or international normalization ratio indicative of significant liver impairment; 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.

Time frame: From time of first dose up to the end of Cycle 1 (21-day cycle): up to 21 days

Secondary Outcomes

Percentage of Participants Who Experienced At Least One Adverse Event (AE)

An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The percentage of all participants who experienced at least one AE is presented. Per protocol, these results are based on a data cutoff date of 09-May-2018.

Time frame: From time of first dose until the end of follow-up (up to 8 months)

Percentage of Participants Who Discontinued Study Treatment Due to an AE

An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The percentage of all participants who discontinued study treatment due to an AE is presented. Per protocol, these results are based on a data cutoff date of 09-May-2018.

Data from ClinicalTrials.gov

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Time frame: From time of first dose until the end of treatment (up to 7 months)

Objective Response Rate (ORR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)

ORR was defined as the percentage of the participants who had complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the AML cohort were assessed using bone marrow aspiration and hematologic criteria and response was evaluated based on European LeukemiaNet (Döhner et al, Blood, 2010). The criteria for complete response included: bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0 × 10\^9/Liter; platelet count \>100 × 10\^9/Liter; and independence of red cell transfusions. The criteria for partial response included: decrease of bone marrow blast percentage to 5% to 25%; decrease of pretreatment bone marrow blast percentage by at least 50%; and all hematologic criteria associated with CR. The percentage of participants who achieved CR or PR is presented.

Time frame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)

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)

ORR was defined as the percentage of the participants who had complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the DLBCL cohort were assessed using computed tomography (CT) and positron emission tomography (PET)-CT and response was evaluated based on the Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014). The criteria for CR included complete metabolic (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤5 cm in longest transverse diameter of a lesion) and no new lesions. The criteria for PR included: partial metabolic (moderate/high FDG uptake) and radiologic response (≥50% decrease in sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \>50% in length beyond normal). The percentage of participants who achieved CR or PR is presented.

Time frame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)

Duration of Response (DOR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)

DOR was defined as the time from complete response (CR) or partial response (PR) to documented disease progression or death as assessed by investigator review. Participants in the AML cohort were assessed using bone marrow aspiration and hematologic criteria and response was evaluated based on European LeukemiaNet (Döhner et al, Blood, 2010). The criteria for complete response included: bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0 × 10\^9/Liter; platelet count \>100 × 10\^9/Liter; and independence of red cell transfusions. The criteria for partial response included: decrease of bone marrow blast percentage to 5% to 25%; decrease of pretreatment bone marrow blast percentage by at least 50%; and all hematologic criteria associated with CR.

Time frame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)

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)

DOR was defined as the time from complete response (CR) or partial response (PR) to documented disease progression or death as assessed by investigator review. Participants in the DLBCL cohort were assessed using computed tomography (CT) and positron emission tomography (PET)-CT and response was evaluated based on the Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014). The criteria for CR included complete metabolic (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤5 cm in longest transverse diameter of a lesion) and no new lesions. The criteria for PR included: partial metabolic (moderate/high FDG uptake) and radiologic response (≥50% decrease in sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \>50% in length beyond normal).

Time frame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)

Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)

DCR was defined as the percentage of the participants who had stable disease, complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the AML cohort were assessed using bone marrow aspiration and hematologic criteria and response was evaluated based on European LeukemiaNet (Döhner et al, Blood, 2010). The criteria for complete response included: bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0 × 10\^9/Liter; platelet count \>100 × 10\^9/Liter; and independence of red cell transfusions. The criteria for partial response included: decrease of bone marrow blast percentage to 5% to 25%; decrease of pretreatment bone marrow blast percentage by at least 50%; and all hematologic criteria associated with CR.

Time frame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)

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)

DCR was defined as the percentage of the participants in the DLBCL cohort who had stable disease, complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the DLBCL cohort were assessed using computed tomography (CT) and positron emission tomography (PET)-CT and response was evaluated based on the Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014). The criteria for CR included complete metabolic (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤5 cm in longest transverse diameter of a lesion) and no new lesions. The criteria for PR included: partial metabolic (moderate/high FDG uptake) and radiologic response (≥50% decrease in sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \>50% in length beyond normal).

Time frame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)

Observed Maximum Concentration (Cmax) of MK-8628

Blood samples were collected to determine Cmax at the following time points: Cycle 1 (21-day cycle) Day 1 at predose and 20 minutes, 1 hour, 2.25 hours, 3.25 hours, 8 hours and 12 hours postdose; Cycle 1 (21-day cycle) at predose on Days 8 and 15; and Cycle 2 (21-day cycle) at predose on Day 1. Per protocol, Cmax for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The Cmax of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.