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

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT02698189
• Collaborator: (none)
• Enrollment: 9
• Arms: 2
• Actual Duration (Months): 63.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
AML Including AML de Novo and AML Secondary to MDS; DLBCL	Drug: Birabresib Dose 20 mg	Phase 1

Study Design

• Study Type: Interventional
• Actual Enrollment: 9 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: May 19, 2016
• Actual Primary Completion Date: Jan 18, 2018
• Actual Study Completion Date: Sep 9, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Birabresib 20 mg AML Cohort 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).	Drug: Birabresib Dose 20 mg; Administered as an oral capsule twice a day for 21 consecutive days per cycle.; Other Names: OTX015 MK-8628
Experimental: Birabresib 20 mg DLBCL Cohort 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).	Drug: Birabresib Dose 20 mg; Administered as an oral capsule twice a day for 21 consecutive days per cycle.; Other Names: OTX015 MK-8628

Outcome Measures

Primary Outcome Measures

1. 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

1. 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. These safety results are based on a 09-May-2018 data cutoff date.

2. 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)]

   The percentage of all participants who discontinued study treatment due to an AE is presented. These results are based on a 09-May-2018 data cutoff date.

3. 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.

4. 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.

5. 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.

6. 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).

7. 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.

8. 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).

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 29, 2017

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT02698189
• Other Study ID Numbers: 8628-005; 2015-005487-42; MK-8628-005
• First Posted: Mar 3, 2016
• Last Update Posted: Oct 19, 2021
• Last Verified: Sep 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Hematologic Neoplasms

Study Results

Participant Flow

Pre-assignment Detail	Enrollment to the study was discontinued early based on a decision to terminate the MK-8628 program and based on limited efficacy signals and not due to safety-related concerns. This results disclosure is based on a data cutoff date of 09-May-2018; at which time 1 participant was ongoing in the study.

Arm/Group Title	MK-8628 20 mg Acute Myeloid Leukemia (AML) Cohort	MK-8628 20 mg Diffuse Large B Cell Lymphoma (DLBCL) Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Period Title: Overall Study
STARTED	3	6
COMPLETED	0	0
NOT COMPLETED	3	6

Baseline Characteristics

Arm/Group Title	MK-8628 20 mg AML Cohort	MK-8628 20 mg DLBCL Cohort	Total
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).	Total of all reporting groups
Overall Participants	3	6	9
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	54.0 (17.3)	63.8 (17.8)	60.6 (17.3)
Sex: Female, Male (Count of Participants)
Female	1 33.3%	3 50%	4 44.4%
Male	2 66.7%	3 50%	5 55.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	3 100%	6 100%	9 100%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Log2 Transformed Normalized Gene Expression Ratios (GERs) (Gene expression ratio (Log2 scale)) [Mean (Standard Deviation) ]
Agmatinase (AGMAT)	-4.659 (0.888)	-3.731 (0.573)	-4.040 (0.786)
Annexin A3 (ANXA3)	-2.568 (1.944)	0.602 (1.399)	-0.455 (2.163)
Atonal BHLH Transcription Factor 8 (ATOH8)	-6.560 (0.756)	-4.511 (0.851)	-5.194 (1.283)
B-cell Lymphoma Extra Large (BCL.xL)	2.744 (1.893)	5.704 (1.588)	4.718 (2.159)
B-cell Lymphoma 2 (BCL2)	0.699 (1.369)	0.479 (0.979)	0.552 (1.039)
Bone Marrow X-linked Kinase (BMX)	-6.109 (0.357)	-2.408 (1.113)	-3.642 (2.057)
Caspase Recruitment Domain Family Member 6 (CARD6)	-1.604 (0.490)	-1.074 (0.364)	-1.251 (0.462)
C-C Motif Chemokine Receptor 1 (CCR1)	-1.566 (1.720)	1.405 (0.863)	0.415 (1.847)
Cluster of Differentiation 163 (CD163)	-4.586 (1.591)	-1.789 (0.975)	-2.722 (1.784)
Choline Kinase Alpha (CHKA)	1.255 (0.670)	-0.795 (0.453)	-0.112 (1.136)
Chemerin Chemokine-Like Receptor 1 (CMKLR1)	-1.967 (0.997)	-0.952 (1.111)	-1.290 (1.130)
Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2)	-2.934 (0.399)	-2.765 (0.228)	-2.821 (0.282)
Dicarbonyl and L-xylulose Reductase (DCXR)	0.026 (0.230)	-0.326 (0.121)	-0.209 (0.231)
Deoxyribonuclease 1 Like 3 (DNASE1L3)	-5.842 (1.960)	-4.857 (1.411)	-5.186 (1.564)
Fc Gamma Receptor Ia (FCGR1A)	-2.119 (2.707)	1.992 (1.363)	0.622 (2.687)
Fibroblast Growth Factor Receptor 1 (FGFR1)	-3.202 (2.427)	-3.761 (0.669)	-3.574 (1.353)
G Protein-Coupled Receptor 141 (GPR141)	-2.185 (0.603)	-2.022 (0.511)	-2.076 (0.511)
Granzyme A (GZMA)	-0.640 (2.151)	2.416 (1.002)	1.397 (2.029)
Granzyme B (GZMB)	-0.175 (3.390)	2.558 (1.025)	1.647 (2.323)
Granzyme K (GZMK)	-1.730 (2.427)	0.576 (1.356)	-0.193 (1.988)
H2A Histone Family Member X (H2AFX)	-0.504 (0.215)	-1.629 (0.379)	-1.254 (0.646)
Hepatitis A Virus Cellular Receptor 2 (HAVCR2)	-1.177 (0.391)	-0.210 (0.670)	-0.532 (0.744)
Class B Basic Helix-Loop-Helix Protein 41 (HES6)	-4.202 (1.520)	-3.679 (1.156)	-3.853 (1.217)
Hexamethylene Bisacetamide Inducible 1 (HEXIM1)	0.037 (0.788)	0.803 (0.229)	0.548 (0.579)
Hepatocyte Growth Factor (HGF)	1.880 (3.142)	-0.798 (0.668)	0.095 (2.131)
Histone Cluster 2 H2B Family Member F (HIST2H2BF)	2.317 (2.412)	3.848 (0.440)	3.337 (1.470)
Inhibitor of Nuclear Factor-kB (IKBKE)	-0.358 (0.494)	-0.019 (0.186)	-0.132 (0.334)
Interleukin 12 Receptor Subunit Beta 2 (IL12RB2)	-3.576 (2.016)	-2.592 (1.437)	-2.920 (1.596)
Interleukin 7 Receptor (IL7R)	-0.531 (2.292)	2.816 (0.829)	1.700 (2.131)
Lunatic Fringe (Drosophila) Homolog (LFNG)	-0.931 (0.722)	0.671 (0.549)	0.137 (0.980)
Leukocyte Immunoglobulin Like Receptor A4 (LILRA4)	-6.838 (1.271)	-3.803 (1.630)	-4.815 (2.090)
Macrophage Receptor (MARCO)	-5.927 (0.816)	-1.022 (1.370)	-2.657 (2.712)
Membrane Spanning 4-Domains A2 (MS4A2)	-3.308 (2.486)	-4.689 (1.515)	-4.229 (1.859)
Class E Basic Helix-Loop-Helix Protein 39 (MYC)	1.727 (0.155)	-0.004 (0.739)	0.573 (1.047)
Nudix Hydrolase 12 (NUDT12)	-3.948 (2.918)	-4.204 (0.700)	-4.118 (1.566)
Proliferating Cell Nuclear Antigen (PCNA)	-0.861 (0.241)	-2.212 (0.484)	-1.762 (0.786)
Protein Tyrosine Phosphatase PTP-U2 (PTPRO)	-4.546 (1.000)	-2.704 (0.426)	-3.318 (1.101)
C17orf87 (SCIMP)	-3.588 (2.237)	1.073 (0.589)	-0.481 (2.626)
Serpin Family G Member 1 (SERPING1)	0.208 (1.584)	0.864 (1.168)	0.645 (1.260)
CD353 Antigen (SLAMF8)	-3.950 (1.981)	-2.729 (0.847)	-3.136 (1.342)
Stathmin 1 (STMN1)	2.382 (0.359)	-0.358 (0.828)	0.556 (1.529)
Thyroglobulin (TG)	-4.955 (1.255)	-4.221 (0.440)	-4.465 (0.806)
TIFA Inhibitor (TIFAB)	-2.808 (1.959)	-2.905 (0.754)	-2.873 (1.148)
Transmembrane Protein 150B (TMEM150B)	-5.664 (0.887)	-2.105 (0.391)	-3.291 (1.859)
Lymphocyte Activation Antigen CD30 (TNFRSF8)	-4.865 (0.886)	-0.925 (0.938)	-2.238 (2.151)
B-Cell-Activating Factor (TNFSF13B)	0.117 (1.746)	1.595 (0.587)	1.103 (1.235)
Tuftelin 1 (TUFT1)	-6.288 (1.491)	-4.377 (0.519)	-5.014 (1.280)
Nemitin (WDR47)	-1.748 (0.319)	-1.377 (0.139)	-1.501 (0.268)
X-C Motif Chemokine Ligand 2 (XCL2)	-2.728 (0.852)	-0.820 (1.313)	-1.456 (1.473)

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Dose Limiting Toxicity (DLT)
Description	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

Outcome Measure Data

Analysis Population Description

The population consisted of all participants that received at least 85% of the planned dose of study drug (18 days) or experienced a DLT during Cycle 1 (21-day cycle).

Arm/Group Title	MK-8628 20 mg AML Cohort	MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	2	6
Number [Percentage of participants]	0.00 0%	1 16.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	MK-8628 20 mg AML Cohort
	Comments
	Type of Statistical Test	Other
	Comments	80% Bayesian credible interval based on a prior distribution of Beta (1, 1).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		80% 2-sided Bayesian credible interval: lower = 0.000; upper = 0.415

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	MK-8628 20 mg DLBCL Cohort
	Comments
	Type of Statistical Test	Other
	Comments	80% Bayesian credible interval based on a prior distribution of Beta (1, 1).
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Other Statistical Analysis		80% 2-sided Bayesian credible interval: lower = 0.040; upper = 0.391

2. Secondary Outcome

Title	Percentage of Participants Who Experienced At Least One Adverse Event (AE)
Description	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. These safety results are based on a 09-May-2018 data cutoff date.
Time Frame	From time of first dose until the end of follow-up (up to 8 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MK-8628 20 mg AML Cohort	MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	3	6
Number [Percentage of participants]	100.0 3333.3%	100.0 1666.7%

3. Secondary Outcome

Title	Percentage of Participants Who Discontinued Study Treatment Due to an AE
Description	The percentage of all participants who discontinued study treatment due to an AE is presented. These results are based on a 09-May-2018 data cutoff date.
Time Frame	From time of first dose until the end of treatment (up to 7 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	MK-8628 20 mg AML Cohort	MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	3	6
Number [Percentage of participants]	0.0 0%	0.0 0%

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants in the AML cohort who received at least one dose of study treatment and had data evaluable for ORR analysis.

Arm/Group Title	MK-8628 20 mg AML Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	3
Complete response	0.0 0%
Partial response	0.0 0%

5. Secondary Outcome

Title	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)
Description	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)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants in the DLBCL cohort who received at least one dose of study treatment and had data evaluable for ORR analysis.

Arm/Group Title	MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	6
Complete response	0.0 0%
Partial response	16.7 556.7%

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants in the AML cohort who received at least one dose of study treatment and had data evaluable for DOR analysis. DOR could not be calculated because no participants met criteria for analysis: CR or PR and documented disease progression or death.

Arm/Group Title	MK-8628 20 mg AML Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	0

7. Secondary Outcome

Title	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)
Description	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)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants in the DLBCL cohort who received at least one dose of study treatment and had data evaluable for DOR analysis. DOR could not be calculated because no participants met criteria for analysis: CR or PR and documented disease progression or death.

Arm/Group Title	MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	0

8. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants in the AML cohort who received at least one dose of study treatment and had data evaluable for DCR analysis.

Arm/Group Title	MK-8628 20 mg AML Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	3
Complete response	0.0 0%
Partial response	0.0 0%
Stable disease	0.0 0%

9. Secondary Outcome

Title	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)
Description	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)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of all participants in the DLBCL cohort who received at least one dose of study treatment and had data evaluable for DCR analysis.

Arm/Group Title	MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	6
Complete response	0.0 0%
Partial response	16.7 556.7%
Stable disease	0.0 0%

10. Secondary Outcome

Title	Observed Maximum Concentration (Cmax) of MK-8628
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for Cmax analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	9
Mean (Standard Deviation) [ng/mL]	360 (132)

11. Secondary Outcome

Title	Time to Maximum Concentration (Tmax) of MK-8628
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for the Tmax analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	9
Median (Full Range) [hr]	2.25

12. Secondary Outcome

Title	Observed Minimum Concentration (Cmin) of MK-8628
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for the Cmin analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	9
Mean (Standard Deviation) [ng/mL]	134 (77.2)

13. Secondary Outcome

Title	Area Under the Concentration-Time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for the AUC 0-∞ analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Mean (Standard Deviation) [hr*ng/mL]	3580 (1340)

14. Secondary Outcome

Title	Apparent Terminal Half-life (t1/2) for MK-8628
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for the t1/2 analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Mean (Standard Deviation) [hr]	7.62 (2.94)

15. Secondary Outcome

Title	Apparent Total Body Clearance (CL/F) of MK-8628
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for CL/F analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Mean (Standard Deviation) [Liters/hr]	6.46 (2.70)

16. Secondary Outcome

Title	Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628
Description	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.
Time Frame	Up to 22 days post MK-8628 dose

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received at least one dose of MK-8628 20 mg and had data available for Vz/F analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Mean (Standard Deviation) [Liters]	65.6 (24.3)

17. Secondary Outcome

Title	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)
Description	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.
Time Frame	Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 3 hours postdose on Day 1 of Cycle 1 (21-day cycle)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received one dose of MK-8628 20 mg on Day 1 of Cycle 1 (21-day cycle) and had data available for the gene expression analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	9
Agmatinase (AGMAT)	-0.466 (0.266)
Annexin A3 (ANXA3)	-0.182 (0.537)
Atonal BHLH Transcription Factor 8 (ATOH8)	-0.296 (0.627)
B-cell Lymphoma Extra Large (BCL.xL)	-0.219 (0.791)
B-cell Lymphoma 2 (BCL2)	-0.053 (0.289)
Bone Marrow X-linked Kinase (BMX)	-0.093 (0.718)
Caspase Recruitment Domain Family Member 6 (CARD6)	-0.245 (0.371)
C-C Motif Chemokine Receptor 1 (CCR1)	-0.246 (0.351)
Cluster of Differentiation 163 (CD163)	-0.457 (0.594)
Choline Kinase Alpha (CHKA)	0.110 (0.309)
Chemerin Chemokine-Like Receptor 1 (CMKLR1)	-0.194 (0.465)
Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2)	0.150 (0.190)
Dicarbonyl and L-xylulose Reductase (DCXR)	0.300 (0.211)
Deoxyribonuclease 1 Like 3 (DNASE1L3)	-0.305 (0.614)
Fc Gamma Receptor Ia (FCGR1A)	-0.360 (0.483)
Fibroblast Growth Factor Receptor 1 (FGFR1)	0.127 (0.382)
G Protein-Coupled Receptor 141 (GPR141)	0.054 (0.546)
Granzyme A (GZMA)	-0.198 (0.768)
Granzyme B (GZMB)	-0.163 (0.262)
Granzyme K (GZMK)	-0.127 (0.602)
H2A Histone Family Member X (H2AFX)	0.049 (0.161)
Hepatitis A Virus Cellular Receptor 2 (HAVCR2)	-0.272 (0.172)
Class B Basic Helix-Loop-Helix Protein 41 (HES6)	0.189 (0.594)
Hexamethylene Bisacetamide Inducible 1 (HEXIM1)	0.315 (0.234)
Hepatocyte Growth Factor (HGF)	-0.461 (0.234)
Histone Cluster 2 H2B Family Member F (HIST2H2BF)	0.325 (0.346)
Inhibitor of Nuclear Factor-kB (IKBKE)	-0.124 (0.243)
Interleukin 12 Receptor Subunit Beta 2 (IL12RB2)	0.012 (0.334)
Interleukin 7 Receptor (IL7R)	0.003 (0.470)
Lunatic Fringe (Drosophila) Homolog (LFNG)	0.182 (0.188)
Leukocyte Immunoglobulin Like Receptor A4 (LILRA4)	-0.403 (0.590)
Macrophage Receptor (MARCO)	-0.321 (0.417)
Membrane Spanning 4-Domains A2 (MS4A2)	-0.646 (0.850)
Class E Basic Helix-Loop-Helix Protein 39 (MYC)	-0.359 (0.406)
Nudix Hydrolase 12 (NUDT12)	-0.309 (0.671)
Proliferating Cell Nuclear Antigen (PCNA)	0.093 (0.270)
Protein Tyrosine Phosphatase PTP-U2 (PTPRO)	-0.391 (0.488)
C17orf87 (SCIMP)	-0.159 (0.328)
Serpin Family G Member 1 (SERPING1)	-0.137 (0.579)
CD353 Antigen (SLAMF8)	-0.485 (0.434)
Stathmin 1 (STMN1)	-0.054 (0.199)
Thyroglobulin (TG)	0.485 (0.377)
TIFA Inhibitor (TIFAB)	-0.405 (0.334)
Transmembrane Protein 150B (TMEM150B)	-0.283 (0.482)
Lymphocyte Activation Antigen CD30 (TNFRSF8)	-0.522 (0.312)
B-Cell-Activating Factor (TNFSF13B)	-0.135 (0.299)
Tuftelin 1 (TUFT1)	0.282 (0.544)
Nemitin (WDR47)	0.144 (0.162)
X-C Motif Chemokine Ligand 2 (XCL2)	-0.365 (0.419)

18. Secondary Outcome

Title	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)
Description	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 Frame	Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 8 hours postdose on Day 1 of Cycle 1 (21-day cycle)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received one dose of MK-8628 20 mg on Day 1 of Cycle 1 (21-day cycle) and had data available for the gene expression analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Agmatinase (AGMAT)	-0.493 (0.322)
Annexin A3 (ANXA3)	0.111 (0.865)
Atonal BHLH Transcription Factor 8 (ATOH8)	-0.049 (0.923)
B-cell Lymphoma Extra Large (BCL.xL)	-0.169 (0.603)
B-cell Lymphoma 2 (BCL2)	-0.133 (0.266)
Bone Marrow X-linked Kinase (BMX)	-0.008 (1.008)
Caspase Recruitment Domain Family Member 6 (CARD6)	-0.091 (0.324)
C-C Motif Chemokine Receptor 1 (CCR1)	-0.257 (0.467)
Cluster of Differentiation 163 (CD163)	-0.640 (0.994)
Choline Kinase Alpha (CHKA)	-0.116 (0.384)
Chemerin Chemokine-Like Receptor 1 (CMKLR1)	-0.218 (0.736)
Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2)	0.152 (0.350)
Dicarbonyl and L-xylulose Reductase (DCXR)	0.536 (0.187)
Deoxyribonuclease 1 Like 3 (DNASE1L3)	-0.306 (0.661)
Fc Gamma Receptor Ia (FCGR1A)	-0.126 (0.390)
Fibroblast Growth Factor Receptor 1 (FGFR1)	0.125 (0.295)
G Protein-Coupled Receptor 141 (GPR141)	-0.085 (0.597)
Granzyme A (GZMA)	-0.015 (1.103)
Granzyme B (GZMB)	-0.262 (0.382)
Granzyme K (GZMK)	0.001 (0.898)
H2A Histone Family Member X (H2AFX)	0.082 (0.156)
Hepatitis A Virus Cellular Receptor 2 (HAVCR2)	-0.294 (0.276)
Class B Basic Helix-Loop-Helix Protein 41 (HES6)	0.378 (0.888)
Hexamethylene Bisacetamide Inducible 1 (HEXIM1)	0.345 (0.234)
Hepatocyte Growth Factor (HGF)	-0.325 (0.228)
Histone Cluster 2 H2B Family Member F (HIST2H2BF)	0.239 (0.372)
Inhibitor of Nuclear Factor-kB (IKBKE)	-0.153 (0.262)
Interleukin 12 Receptor Subunit Beta 2 (IL12RB2)	-0.018 (0.352)
Interleukin 7 Receptor (IL7R)	0.016 (0.461)
Lunatic Fringe (Drosophila) Homolog (LFNG)	0.104 (0.228)
Leukocyte Immunoglobulin Like Receptor A4 (LILRA4)	-0.151 (0.494)
Macrophage Receptor (MARCO)	-0.441 (0.777)
Membrane Spanning 4-Domains A2 (MS4A2)	-0.232 (0.786)
Class E Basic Helix-Loop-Helix Protein 39 (MYC)	-0.481 (0.611)
Nudix Hydrolase 12 (NUDT12)	-0.295 (0.587)
Proliferating Cell Nuclear Antigen (PCNA)	0.036 (0.318)
Protein Tyrosine Phosphatase PTP-U2 (PTPRO)	0.037 (0.632)
C17orf87 (SCIMP)	-0.246 (0.425)
Serpin Family G Member 1 (SERPING1)	-0.162 (0.922)
CD353 Antigen (SLAMF8)	-0.307 (0.297)
Stathmin 1 (STMN1)	-0.091 (0.292)
Thyroglobulin (TG)	0.347 (0.724)
TIFA Inhibitor (TIFAB)	-0.257 (0.586)
Transmembrane Protein 150B (TMEM150B)	-0.136 (0.488)
Lymphocyte Activation Antigen CD30 (TNFRSF8)	-0.830 (0.692)
B-Cell-Activating Factor (TNFSF13B)	-0.112 (0.308)
Tuftelin 1 (TUFT1)	0.341 (0.546)
Nemitin (WDR47)	0.164 (0.243)
X-C Motif Chemokine Ligand 2 (XCL2)	-0.190 (0.607)

19. Secondary Outcome

Title	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)
Description	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.
Time Frame	Baseline (predose on Day 1 of Cycle 1 [21-day cycle]) and 12 hours postdose on Day 1 of Cycle 1 (21-day cycle)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received two doses of MK-8628 20 mg on Day 1 of Cycle 1 (21-day cycle) and had data available for the gene expression analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Agmatinase (AGMAT)	-0.287 (0.248)
Annexin A3 (ANXA3)	0.020 (0.863)
Atonal BHLH Transcription Factor 8 (ATOH8)	-0.363 (0.649)
B-cell Lymphoma Extra Large (BCL.xL)	-0.071 (0.500)
B-cell Lymphoma 2 (BCL2)	-0.078 (0.313)
Bone Marrow X-linked Kinase (BMX)	0.047 (0.781)
Caspase Recruitment Domain Family Member 6 (CARD6)	-0.052 (0.241)
C-C Motif Chemokine Receptor 1 (CCR1)	-0.108 (0.380)
Cluster of Differentiation 163 (CD163)	-0.528 (0.734)
Choline Kinase Alpha (CHKA)	-0.191 (0.343)
Chemerin Chemokine-Like Receptor 1 (CMKLR1)	-0.078 (0.510)
Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2)	0.128 (0.328)
Dicarbonyl and L-xylulose Reductase (DCXR)	0.511 (0.379)
Deoxyribonuclease 1 Like 3 (DNASE1L3)	-0.074 (0.409)
Fc Gamma Receptor Ia (FCGR1A)	-0.126 (0.534)
Fibroblast Growth Factor Receptor 1 (FGFR1)	0.193 (0.304)
G Protein-Coupled Receptor 141 (GPR141)	0.040 (0.673)
Granzyme A (GZMA)	-0.110 (0.841)
Granzyme B (GZMB)	-0.225 (0.370)
Granzyme K (GZMK)	-0.034 (0.648)
H2A Histone Family Member X (H2AFX)	-0.013 (0.169)
Hepatitis A Virus Cellular Receptor 2 (HAVCR2)	-0.181 (0.239)
Class B Basic Helix-Loop-Helix Protein 41 (HES6)	0.257 (0.654)
Hexamethylene Bisacetamide Inducible 1 (HEXIM1)	0.308 (0.260)
Hepatocyte Growth Factor (HGF)	-0.298 (0.241)
Histone Cluster 2 H2B Family Member F (HIST2H2BF)	0.288 (0.451)
Inhibitor of Nuclear Factor-kB (IKBKE)	-0.092 (0.224)
Interleukin 12 Receptor Subunit Beta 2 (IL12RB2)	0.035 (0.466)
Interleukin 7 Receptor (IL7R)	0.051 (0.316)
Lunatic Fringe (Drosophila) Homolog (LFNG)	0.167 (0.202)
Leukocyte Immunoglobulin Like Receptor A4 (LILRA4)	-0.023 (0.396)
Macrophage Receptor (MARCO)	-0.714 (0.507)
Membrane Spanning 4-Domains A2 (MS4A2)	-0.332 (0.658)
Class E Basic Helix-Loop-Helix Protein 39 (MYC)	-0.376 (0.528)
Nudix Hydrolase 12 (NUDT12)	-0.331 (0.579)
Proliferating Cell Nuclear Antigen (PCNA)	0.049 (0.321)
Protein Tyrosine Phosphatase PTP-U2 (PTPRO)	-0.103 (0.691)
C17orf87 (SCIMP)	-0.143 (0.349)
Serpin Family G Member 1 (SERPING1)	-0.111 (0.931)
CD353 Antigen (SLAMF8)	-0.394 (0.381)
Stathmin 1 (STMN1)	-0.014 (0.188)
Thyroglobulin (TG)	0.792 (0.637)
TIFA Inhibitor (TIFAB)	-0.120 (0.430)
Transmembrane Protein 150B (TMEM150B)	-0.073 (0.564)
Lymphocyte Activation Antigen CD30 (TNFRSF8)	-0.447 (0.380)
B-Cell-Activating Factor (TNFSF13B)	-0.119 (0.346)
Tuftelin 1 (TUFT1)	0.279 (0.725)
Nemitin (WDR47)	0.117 (0.257)
X-C Motif Chemokine Ligand 2 (XCL2)	-0.051 (0.538)

20. Secondary Outcome

Title	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)
Description	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.
Time Frame	Baseline (predose on Day 1 of Cycle 1) and predose on Day 8 of Cycle 1 (21-day cycle)

Outcome Measure Data

Analysis Population Description

The analysis population consisted of the total number of participants pooled from both cohorts (AML and DLBCL) who received 14 doses of MK-8628 20 mg by Day 8 of Cycle 1 (21-day cycle) and had data available for the gene expression analysis.

Arm/Group Title	MK-8628 20 mg AML+DLBCL Cohorts
Arm/Group Description	Total number of participants from both cohorts (AML and DLBCL) received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
Measure Participants	8
Agmatinase (AGMAT)	-0.759 (0.633)
Annexin A3 (ANXA3)	0.210 (0.917)
Atonal BHLH Transcription Factor 8 (ATOH8)	-0.869 (1.059)
B-cell Lymphoma Extra Large (BCL.xL)	0.329 (1.964)
B-cell Lymphoma 2 (BCL2)	-0.056 (0.450)
Bone Marrow X-linked Kinase (BMX)	0.115 (0.628)
Caspase Recruitment Domain Family Member 6 (CARD6)	-0.115 (0.380)
C-C Motif Chemokine Receptor 1 (CCR1)	-0.490 (1.185)
Cluster of Differentiation 163 (CD163)	-0.442 (0.779)
Choline Kinase Alpha (CHKA)	0.218 (0.267)
Chemerin Chemokine-Like Receptor 1 (CMKLR1)	-0.708 (1.271)
Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2)	0.119 (0.265)
Dicarbonyl and L-xylulose Reductase (DCXR)	0.696 (0.397)
Deoxyribonuclease 1 Like 3 (DNASE1L3)	-0.386 (0.705)
Fc Gamma Receptor Ia (FCGR1A)	-0.885 (0.348)
Fibroblast Growth Factor Receptor 1 (FGFR1)	-0.561 (1.033)
G Protein-Coupled Receptor 141 (GPR141)	-0.333 (1.207)
Granzyme A (GZMA)	-0.572 (0.752)
Granzyme B (GZMB)	-0.442 (1.402)
Granzyme K (GZMK)	-0.657 (0.974)
H2A Histone Family Member X (H2AFX)	0.060 (0.466)
Hepatitis A Virus Cellular Receptor 2 (HAVCR2)	-0.722 (0.598)
Class B Basic Helix-Loop-Helix Protein 41 (HES6)	0.364 (1.373)
Hexamethylene Bisacetamide Inducible 1 (HEXIM1)	0.429 (0.422)
Hepatocyte Growth Factor (HGF)	-0.276 (0.383)
Histone Cluster 2 H2B Family Member F (HIST2H2BF)	0.427 (0.415)
Inhibitor of Nuclear Factor-kB (IKBKE)	-0.166 (0.480)
Interleukin 12 Receptor Subunit Beta 2 (IL12RB2)	-0.435 (1.351)
Interleukin 7 Receptor (IL7R)	-0.301 (0.986)
Lunatic Fringe (Drosophila) Homolog (LFNG)	0.099 (0.668)
Leukocyte Immunoglobulin Like Receptor A4 (LILRA4)	0.104 (1.241)
Macrophage Receptor (MARCO)	-1.197 (0.832)
Membrane Spanning 4-Domains A2 (MS4A2)	0.023 (1.266)
Class E Basic Helix-Loop-Helix Protein 39 (MYC)	-0.270 (0.521)
Nudix Hydrolase 12 (NUDT12)	-0.025 (0.697)
Proliferating Cell Nuclear Antigen (PCNA)	0.015 (0.572)
Protein Tyrosine Phosphatase PTP-U2 (PTPRO)	-1.007 (0.839)
C17orf87 (SCIMP)	-0.360 (1.005)
Serpin Family G Member 1 (SERPING1)	-0.170 (1.191)
CD353 Antigen (SLAMF8)	-0.918 (1.057)
Stathmin 1 (STMN1)	-0.251 (0.822)
Thyroglobulin (TG)	0.399 (0.884)
TIFA Inhibitor (TIFAB)	-0.937 (0.444)
Transmembrane Protein 150B (TMEM150B)	-0.222 (0.280)
Lymphocyte Activation Antigen CD30 (TNFRSF8)	-0.464 (0.453)
B-Cell-Activating Factor (TNFSF13B)	-0.094 (0.445)
Tuftelin 1 (TUFT1)	0.472 (0.798)
Nemitin (WDR47)	0.263 (0.155)
X-C Motif Chemokine Ligand 2 (XCL2)	-0.666 (0.835)

Adverse Events

Time Frame	Safety data was collected up to 30 days after last dose of study treatment (up to approximately 8 months).
Adverse Event Reporting Description	The safety population consisted of all participants that received at least one dose of study treatment.
Arm/Group Title	MK-8628 20 mg AML Cohort		MK-8628 20 mg DLBCL Cohort
Arm/Group Description	Participants in the AML cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).		Participants in the DLBCL cohort received 20 mg of MK-8628 as an oral capsule twice a day for 21 consecutive days per cycle (21-day cycle).
All Cause Mortality
	MK-8628 20 mg AML Cohort		MK-8628 20 mg DLBCL Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		0/6 (0%)
Serious Adverse Events
	MK-8628 20 mg AML Cohort		MK-8628 20 mg DLBCL Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		1/6 (16.7%)
Blood and lymphatic system disorders
Febrile neutropenia	1/3 (33.3%)	1	0/6 (0%)	0
Leukocytosis	1/3 (33.3%)	1	0/6 (0%)	0
Hepatobiliary disorders
Hepatic function abnormal	1/3 (33.3%)	1	0/6 (0%)	0
Infections and infestations
Influenza	0/3 (0%)	0	1/6 (16.7%)	1
Pulmonary mycosis	1/3 (33.3%)	1	0/6 (0%)	0
Sepsis	1/3 (33.3%)	1	0/6 (0%)	0
Other (Not Including Serious) Adverse Events
	MK-8628 20 mg AML Cohort		MK-8628 20 mg DLBCL Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		6/6 (100%)
Blood and lymphatic system disorders
Anaemia	2/3 (66.7%)	2	2/6 (33.3%)	4
Lymphopenia	0/3 (0%)	0	1/6 (16.7%)	1
Neutropenia	1/3 (33.3%)	1	1/6 (16.7%)	2
Thrombocytopenia	2/3 (66.7%)	2	3/6 (50%)	6
Cardiac disorders
Tachycardia	2/3 (66.7%)	2	0/6 (0%)	0
Congenital, familial and genetic disorders
Factor VII deficiency	1/3 (33.3%)	1	0/6 (0%)	0
Eye disorders
Eye irritation	0/3 (0%)	0	1/6 (16.7%)	1
Vision blurred	0/3 (0%)	0	1/6 (16.7%)	1
Gastrointestinal disorders
Abdominal pain	0/3 (0%)	0	3/6 (50%)	4
Abdominal pain upper	1/3 (33.3%)	1	1/6 (16.7%)	1
Constipation	1/3 (33.3%)	1	2/6 (33.3%)	2
Diarrhoea	2/3 (66.7%)	3	3/6 (50%)	7
Dyspepsia	0/3 (0%)	0	1/6 (16.7%)	1
Mouth ulceration	0/3 (0%)	0	1/6 (16.7%)	1
Nausea	0/3 (0%)	0	1/6 (16.7%)	2
Oral pain	1/3 (33.3%)	1	1/6 (16.7%)	1
Proctalgia	1/3 (33.3%)	2	0/6 (0%)	0
Vomiting	1/3 (33.3%)	1	1/6 (16.7%)	1
General disorders
Asthenia	1/3 (33.3%)	1	1/6 (16.7%)	1
Catheter site pain	1/3 (33.3%)	1	0/6 (0%)	0
Fatigue	1/3 (33.3%)	1	2/6 (33.3%)	2
Infusion site erythema	1/3 (33.3%)	1	0/6 (0%)	0
Mucosal inflammation	0/3 (0%)	0	2/6 (33.3%)	2
Oedema peripheral	2/3 (66.7%)	2	2/6 (33.3%)	2
Pain	0/3 (0%)	0	1/6 (16.7%)	1
Peripheral swelling	1/3 (33.3%)	1	0/6 (0%)	0
Pyrexia	1/3 (33.3%)	1	2/6 (33.3%)	3
Infections and infestations
Angular cheilitis	0/3 (0%)	0	1/6 (16.7%)	1
Anorectal infection	1/3 (33.3%)	1	0/6 (0%)	0
Cellulitis	1/3 (33.3%)	1	0/6 (0%)	0
Conjunctivitis	0/3 (0%)	0	1/6 (16.7%)	2
Device related infection	1/3 (33.3%)	1	0/6 (0%)	0
Escherichia infection	1/3 (33.3%)	1	0/6 (0%)	0
Herpes zoster	0/3 (0%)	0	1/6 (16.7%)	1
Nasopharyngitis	0/3 (0%)	0	1/6 (16.7%)	1
Rhinitis	0/3 (0%)	0	1/6 (16.7%)	1
Sinusitis	0/3 (0%)	0	1/6 (16.7%)	1
Injury, poisoning and procedural complications
Wrist fracture	1/3 (33.3%)	1	0/6 (0%)	0
Investigations
Aspartate aminotransferase increased	1/3 (33.3%)	1	0/6 (0%)	0
Blood albumin decreased	1/3 (33.3%)	1	0/6 (0%)	0
Blood magnesium decreased	2/3 (66.7%)	2	0/6 (0%)	0
Blood phosphorus decreased	1/3 (33.3%)	3	0/6 (0%)	0
Blood sodium decreased	1/3 (33.3%)	1	0/6 (0%)	0
C-reactive protein increased	1/3 (33.3%)	1	0/6 (0%)	0
Electrocardiogram QT prolonged	0/3 (0%)	0	1/6 (16.7%)	1
Neutrophil count decreased	0/3 (0%)	0	1/6 (16.7%)	2
Platelet count decreased	0/3 (0%)	0	1/6 (16.7%)	1
Weight decreased	0/3 (0%)	0	1/6 (16.7%)	1
Weight increased	1/3 (33.3%)	1	0/6 (0%)	0
White blood cell count increased	2/3 (66.7%)	2	0/6 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	2/3 (66.7%)	2	0/6 (0%)	0
Dehydration	1/3 (33.3%)	1	0/6 (0%)	0
Fluid overload	1/3 (33.3%)	2	0/6 (0%)	0
Hypocalcaemia	1/3 (33.3%)	1	1/6 (16.7%)	1
Hypokalaemia	1/3 (33.3%)	2	2/6 (33.3%)	3
Hypomagnesaemia	0/3 (0%)	0	1/6 (16.7%)	1
Hyponatraemia	2/3 (66.7%)	2	1/6 (16.7%)	2
Metabolic acidosis	1/3 (33.3%)	1	0/6 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/3 (33.3%)	1	0/6 (0%)	0
Back pain	0/3 (0%)	0	2/6 (33.3%)	2
Bone pain	1/3 (33.3%)	1	1/6 (16.7%)	1
Groin pain	0/3 (0%)	0	1/6 (16.7%)	1
Limb discomfort	0/3 (0%)	0	1/6 (16.7%)	1
Muscle spasms	1/3 (33.3%)	1	1/6 (16.7%)	4
Muscular weakness	1/3 (33.3%)	1	0/6 (0%)	0
Musculoskeletal chest pain	1/3 (33.3%)	1	0/6 (0%)	0
Neck pain	0/3 (0%)	0	1/6 (16.7%)	1
Pain in extremity	1/3 (33.3%)	1	1/6 (16.7%)	1
Nervous system disorders
Dizziness	0/3 (0%)	0	1/6 (16.7%)	1
Dysgeusia	0/3 (0%)	0	1/6 (16.7%)	1
Neuralgia	0/3 (0%)	0	1/6 (16.7%)	1
Paraesthesia	0/3 (0%)	0	1/6 (16.7%)	1
Psychiatric disorders
Confusional state	1/3 (33.3%)	1	0/6 (0%)	0
Renal and urinary disorders
Acute kidney injury	1/3 (33.3%)	2	0/6 (0%)	0
Urinary incontinence	1/3 (33.3%)	1	0/6 (0%)	0
Reproductive system and breast disorders
Breast pain	0/3 (0%)	0	1/6 (16.7%)	1
Vaginal discharge	1/3 (33.3%)	1	0/6 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	2/3 (66.7%)	3	1/6 (16.7%)	1
Dyspnoea	3/3 (100%)	3	0/6 (0%)	0
Epistaxis	1/3 (33.3%)	1	0/6 (0%)	0
Nasal congestion	0/3 (0%)	0	1/6 (16.7%)	1
Tachypnoea	1/3 (33.3%)	1	0/6 (0%)	0
Skin and subcutaneous tissue disorders
Dry skin	1/3 (33.3%)	1	0/6 (0%)	0
Night sweats	1/3 (33.3%)	1	0/6 (0%)	0
Pain of skin	0/3 (0%)	0	1/6 (16.7%)	1
Petechiae	1/3 (33.3%)	1	1/6 (16.7%)	1
Pruritus	1/3 (33.3%)	1	1/6 (16.7%)	2
Rash	1/3 (33.3%)	1	2/6 (33.3%)	2
Rash maculo-papular	0/3 (0%)	0	1/6 (16.7%)	1
Vascular disorders
Haematoma	0/3 (0%)	0	1/6 (16.7%)	1
Hypotension	2/3 (66.7%)	3	0/6 (0%)	0

Limitations/Caveats

Due to limited pharmacokinetics sampling for t1/2, caution must be exercised when interpreting the results of t1/2, CL/F, and AUC 0-∞ results.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The Sponsor must have the opportunity to review all proposed abstracts, manuscripts or presentations regarding this trial 45 days prior to submission for publication/presentation. Any information identified by the Sponsor as confidential must be deleted prior to submission; this confidentiality does not include efficacy and safety results. Sponsor review can be expedited to meet publication timelines.