A Dose Exploration Study With Birabresib (MK-8628) in Participants With Selected Hematologic Malignancies (MK-8628-005)
- Conditions
- AML Including AML de Novo and AML Secondary to MDSDLBCL
- Interventions
- Registration Number
- NCT02698189
- Lead Sponsor
- Merck Sharp & Dohme LLC
- 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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 9
- 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
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Birabresib 20 mg AML Cohort Birabresib Dose 20 mg Participants in the AML cohort received 20 mg of birabresib as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle). Birabresib 20 mg DLBCL Cohort Birabresib Dose 20 mg Participants in the DLBCL cohort received 20 mg of birabresib as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
- Primary Outcome Measures
Name Time Method Percentage of Participants With a Dose Limiting Toxicity (DLT) From time of first dose up to the end of Cycle 1 (21-day cycle): up to 21 days 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.
- Secondary Outcome Measures
Name Time Method Percentage of Participants Who Discontinued Study Treatment Due to an AE From time of first dose until the end of treatment (up to 7 months) 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.
Percentage of Participants Who Experienced At Least One Adverse Event (AE) From time of first dose until the end of follow-up (up to 8 months) 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.
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) Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months) 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.
Duration of Response (DOR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months) 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.
Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months) 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.
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) Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months) 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).
Observed Maximum Concentration (Cmax) of MK-8628 Up to 22 days post MK-8628 dose 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.
Objective Response Rate (ORR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months) 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.
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) Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months) 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).
Observed Minimum Concentration (Cmin) of MK-8628 Up to 22 days post MK-8628 dose Blood samples were collected to determine Cmin 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, Cmin for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The Cmin of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
Area Under the Concentration-Time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞) Up to 22 days post MK-8628 dose Blood samples were collected to determine AUC 0-∞ 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, AUC 0-∞ for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The AUC 0-∞ of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
Apparent Terminal Half-life (t1/2) for MK-8628 Up to 22 days post MK-8628 dose Blood samples were collected to determine t1/2 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, t1/2 for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The t1/2 of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
Apparent Total Body Clearance (CL/F) of MK-8628 Up to 22 days post MK-8628 dose Blood samples were collected to determine CL/F 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, CL/F for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The CL/F of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628 Up to 22 days post MK-8628 dose Blood samples were collected to determine Vz/F 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, Vz/F for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The Vz/F of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
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) Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 3 hours postdose on Day 1 of Cycle 1 (21-day cycle) Fold change from baseline (predose on Day 1 of Cycle 1 \[21-day cycle\]) in normalized gene expression ratios (nGER) for 49 target genes was measured to assess target engagement of BET proteins predose and 3 hours postdose using quantitative polymerase chain reaction (qPCR). Data were normalized by the delta-delta cycle threshold (Ct) method using housekeeping genes. Fold change from baseline was calculated as nGER at 3 hours postdose Day 1/baseline in logarithmic scale with a base of 2 (Log2 scale). Per protocol, target genes were assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The fold change in nGER for each target gene is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose. A two-fold increase in gene expression indicated a +1 Log2 fold change. Conversely, a two-fold decrease in gene expression indicated a -1 Log2 fold change.
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) Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 8 hours postdose on Day 1 of Cycle 1 (21-day cycle) Fold change from baseline (predose on Day 1 of Cycle 1 \[21-day cycle\]) in normalized gene expression ratios (nGER) for 49 target genes was measured to assess target engagement of BET proteins predose and 8 hours postdose using quantitative polymerase chain reaction (qPCR). Data were normalized by the delta-delta cycle threshold (Ct) method using housekeeping genes. Fold change from baseline was calculated as nGER at 8 hours postdose Day 1/baseline in logarithmic scale with a base of 2 (Log2 scale). Per protocol, target genes were assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The fold change in nGER for each target gene is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose. A two-fold increase in gene expression indicated a +1 Log2 fold change. Conversely, a two-fold decrease in gene expression indicated a -1 Log2 fold change.
Time to Maximum Concentration (Tmax) of MK-8628 Up to 22 days post MK-8628 dose Blood samples were collected to determine Tmax 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, Tmax for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The Tmax of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
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) Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 12 hours postdose on Day 1 of Cycle 1 (21-day cycle) Fold change from baseline (predose on Day 1 of Cycle 1 \[21-day cycle\]) in normalized gene expression ratios (nGER) for 49 target genes was measured to assess target engagement of BET proteins predose and 12 hours postdose using quantitative polymerase chain reaction (qPCR). Data were normalized by the delta-delta cycle threshold (Ct) method using housekeeping genes. Fold change from baseline was calculated as nGER at 12 hours postdose Day 1/baseline in logarithmic scale with a base of 2 (Log2 scale). Per protocol, target genes were assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The fold change in nGER for each target gene is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose. A two-fold increase in gene expression indicated a +1 Log2 fold change. Conversely, a two-fold decrease in gene expression indicated a -1 Log2 fold change.
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) Baseline (predose on Day 1 of Cycle 1) and predose on Day 8 of Cycle 1 (21-day cycle) Fold change from baseline (predose on Day 1 of Cycle 1 \[21-day cycle\]) in normalized gene expression ratios (nGER) for 49 target genes was measured to assess target engagement of BET proteins predose on Day 1 and predose on Day 8 of Cycle 1 (21-day cycle) using quantitative polymerase chain reaction (qPCR). Data were normalized by the delta-delta cycle threshold (Ct) method using housekeeping genes. Fold change from baseline was calculated as nGER at predose Day 8/baseline in logarithmic scale with a base of 2 (Log2 scale). Per protocol, target genes were assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The fold change in nGER for each target gene is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose. A two-fold increase in gene expression indicated a +1 Log2 fold change. Conversely, a two-fold decrease in gene expression indicated a -1 Log2 fold change.