AML Including AML de Novo and AML Secondary to MDS, DLBCL
Conditions
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.
Interventions
DRUGBirabresib Dose 20 mg
Administered as an oral capsule twice a day for 21 consecutive days per cycle.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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). |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| MK-8628 20 mg AML Cohort 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). | 3 |
| MK-8628 20 mg DLBCL Cohort 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). | 6 |
| Total | 9 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 3 | 0 |
| Overall Study | Progressive disease | 0 | 5 |
| Overall Study | Study terminated by sponsor | 0 | 1 |
Baseline characteristics
| Characteristic | MK-8628 20 mg AML Cohort | Total | MK-8628 20 mg DLBCL Cohort |
|---|---|---|---|
| Age, Continuous | 54.0 Years STANDARD_DEVIATION 17.3 | 60.6 Years STANDARD_DEVIATION 17.3 | 63.8 Years STANDARD_DEVIATION 17.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 9 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Agmatinase (AGMAT) | -4.659 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.888 | -4.040 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.786 | -3.731 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.573 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Annexin A3 (ANXA3) | -2.568 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.944 | -0.455 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.163 | 0.602 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.399 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Atonal BHLH Transcription Factor 8 (ATOH8) | -6.560 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.756 | -5.194 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.283 | -4.511 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.851 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) B-Cell-Activating Factor (TNFSF13B) | 0.117 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.746 | 1.103 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.235 | 1.595 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.587 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) B-cell Lymphoma 2 (BCL2) | 0.699 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.369 | 0.552 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.039 | 0.479 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.979 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) B-cell Lymphoma Extra Large (BCL.xL) | 2.744 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.893 | 4.718 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.159 | 5.704 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.588 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Bone Marrow X-linked Kinase (BMX) | -6.109 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.357 | -3.642 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.057 | -2.408 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.113 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) C17orf87 (SCIMP) | -3.588 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.237 | -0.481 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.626 | 1.073 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.589 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Caspase Recruitment Domain Family Member 6 (CARD6) | -1.604 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.49 | -1.251 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.462 | -1.074 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.364 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) C-C Motif Chemokine Receptor 1 (CCR1) | -1.566 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.72 | 0.415 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.847 | 1.405 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.863 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) CD353 Antigen (SLAMF8) | -3.950 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.981 | -3.136 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.342 | -2.729 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.847 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Chemerin Chemokine-Like Receptor 1 (CMKLR1) | -1.967 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.997 | -1.290 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.13 | -0.952 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.111 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Choline Kinase Alpha (CHKA) | 1.255 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.67 | -0.112 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.136 | -0.795 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.453 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Class B Basic Helix-Loop-Helix Protein 41 (HES6) | -4.202 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.52 | -3.853 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.217 | -3.679 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.156 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Class E Basic Helix-Loop-Helix Protein 39 (MYC) | 1.727 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.155 | 0.573 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.047 | -0.004 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.739 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Cluster of Differentiation 163 (CD163) | -4.586 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.591 | -2.722 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.784 | -1.789 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.975 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2) | -2.934 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.399 | -2.821 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.282 | -2.765 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.228 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Deoxyribonuclease 1 Like 3 (DNASE1L3) | -5.842 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.96 | -5.186 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.564 | -4.857 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.411 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Dicarbonyl and L-xylulose Reductase (DCXR) | 0.026 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.23 | -0.209 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.231 | -0.326 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.121 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Fc Gamma Receptor Ia (FCGR1A) | -2.119 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.707 | 0.622 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.687 | 1.992 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.363 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Fibroblast Growth Factor Receptor 1 (FGFR1) | -3.202 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.427 | -3.574 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.353 | -3.761 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.669 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) G Protein-Coupled Receptor 141 (GPR141) | -2.185 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.603 | -2.076 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.511 | -2.022 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.511 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Granzyme A (GZMA) | -0.640 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.151 | 1.397 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.029 | 2.416 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.002 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Granzyme B (GZMB) | -0.175 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 3.39 | 1.647 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.323 | 2.558 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.025 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Granzyme K (GZMK) | -1.730 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.427 | -0.193 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.988 | 0.576 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.356 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) H2A Histone Family Member X (H2AFX) | -0.504 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.215 | -1.254 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.646 | -1.629 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.379 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Hepatitis A Virus Cellular Receptor 2 (HAVCR2) | -1.177 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.391 | -0.532 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.744 | -0.210 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.67 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Hepatocyte Growth Factor (HGF) | 1.880 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 3.142 | 0.095 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.131 | -0.798 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.668 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Hexamethylene Bisacetamide Inducible 1 (HEXIM1) | 0.037 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.788 | 0.548 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.579 | 0.803 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.229 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Histone Cluster 2 H2B Family Member F (HIST2H2BF) | 2.317 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.412 | 3.337 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.47 | 3.848 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.44 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Inhibitor of Nuclear Factor-kB (IKBKE) | -0.358 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.494 | -0.132 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.334 | -0.019 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.186 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Interleukin 12 Receptor Subunit Beta 2 (IL12RB2) | -3.576 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.016 | -2.920 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.596 | -2.592 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.437 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Interleukin 7 Receptor (IL7R) | -0.531 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.292 | 1.700 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.131 | 2.816 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.829 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Leukocyte Immunoglobulin Like Receptor A4 (LILRA4) | -6.838 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.271 | -4.815 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.09 | -3.803 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.63 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Lunatic Fringe (Drosophila) Homolog (LFNG) | -0.931 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.722 | 0.137 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.98 | 0.671 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.549 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Lymphocyte Activation Antigen CD30 (TNFRSF8) | -4.865 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.886 | -2.238 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.151 | -0.925 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.938 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Macrophage Receptor (MARCO) | -5.927 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.816 | -2.657 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.712 | -1.022 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.37 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Membrane Spanning 4-Domains A2 (MS4A2) | -3.308 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.486 | -4.229 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.859 | -4.689 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.515 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Nemitin (WDR47) | -1.748 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.319 | -1.501 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.268 | -1.377 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.139 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Nudix Hydrolase 12 (NUDT12) | -3.948 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 2.918 | -4.118 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.566 | -4.204 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.7 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Proliferating Cell Nuclear Antigen (PCNA) | -0.861 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.241 | -1.762 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.786 | -2.212 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.484 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Protein Tyrosine Phosphatase PTP-U2 (PTPRO) | -4.546 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1 | -3.318 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.101 | -2.704 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.426 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Serpin Family G Member 1 (SERPING1) | 0.208 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.584 | 0.645 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.26 | 0.864 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.168 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Stathmin 1 (STMN1) | 2.382 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.359 | 0.556 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.529 | -0.358 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.828 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Thyroglobulin (TG) | -4.955 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.255 | -4.465 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.806 | -4.221 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.44 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) TIFA Inhibitor (TIFAB) | -2.808 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.959 | -2.873 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.148 | -2.905 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.754 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Transmembrane Protein 150B (TMEM150B) | -5.664 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.887 | -3.291 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.859 | -2.105 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.391 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) Tuftelin 1 (TUFT1) | -6.288 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.491 | -5.014 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.28 | -4.377 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.519 |
| Log2 Transformed Normalized Gene Expression Ratios (GERs) X-C Motif Chemokine Ligand 2 (XCL2) | -2.728 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 0.852 | -1.456 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.473 | -0.820 Gene expression ratio (Log2 scale) STANDARD_DEVIATION 1.313 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 9 Participants | 6 Participants |
| Sex: Female, Male Female | 1 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 3 / 3 | 0 / 6 |
| other Total, other adverse events | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 3 / 3 | 1 / 6 |
Outcome results
Primary
Percentage of Participants With a Dose Limiting Toxicity (DLT)
DLT was any of the following drug related (DR) investigator-assessed adverse events: pancytopenia with hypocellular bone marrow and no marrow blasts lasting for ≥6 weeks; Grade (G)4 hematologic toxicity lasting ≥7 days except thrombocytopenia; G4 thrombocytopenia; G3 thrombocytopenia with bleeding; G3 or 4 febrile or infection-related neutropenia; G4 nonhematologic (NH) toxicity (not laboratory); G3 NH toxicity (not laboratory), nausea, vomiting, or diarrhea lasting \>3 days despite supportive care; G3 or 4 NH laboratory abnormality requiring medical intervention, hospitalization, or persisting \>1 week; increases in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, or international normalization ratio indicative of significant liver impairment; DR adverse event leading to discontinuation or ≥20% missed planned doses in Cycle 1; DR toxicity causing \>2 week delay in starting Cycle 2; or G5 toxicity.
Time frame: From time of first dose up to the end of Cycle 1 (21-day cycle): up to 21 days
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| MK-8628 20 mg AML Cohort | Percentage of Participants With a Dose Limiting Toxicity (DLT) | 0.00 Percentage of participants |
| MK-8628 20 mg DLBCL Cohort | Percentage of Participants With a Dose Limiting Toxicity (DLT) | 16.67 Percentage of participants |
Secondary
Apparent Terminal Half-life (t1/2) for MK-8628
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Apparent Terminal Half-life (t1/2) for MK-8628 | 7.62 hr | Standard Deviation 2.94 |
Secondary
Apparent Total Body Clearance (CL/F) of MK-8628
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Apparent Total Body Clearance (CL/F) of MK-8628 | 6.46 Liters/hr | Standard Deviation 2.7 |
Secondary
Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Apparent Volume of Distribution During the Terminal Phase (Vz/F) of MK-8628 | 65.6 Liters | Standard Deviation 24.3 |
Secondary
Area Under the Concentration-Time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞)
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Area Under the Concentration-Time Curve of MK-8628 From Time 0 to Infinity (AUC 0-∞) | 3580 hr*ng/mL | Standard Deviation 1340 |
Secondary
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)
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8628 20 mg AML Cohort | 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) | Agmatinase (AGMAT) | -0.287 Log2 scale fold change | Standard Deviation 0.248 |
| MK-8628 20 mg AML Cohort | 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) | Annexin A3 (ANXA3) | 0.020 Log2 scale fold change | Standard Deviation 0.863 |
| MK-8628 20 mg AML Cohort | 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) | Atonal BHLH Transcription Factor 8 (ATOH8) | -0.363 Log2 scale fold change | Standard Deviation 0.649 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma Extra Large (BCL.xL) | -0.071 Log2 scale fold change | Standard Deviation 0.5 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma 2 (BCL2) | -0.078 Log2 scale fold change | Standard Deviation 0.313 |
| MK-8628 20 mg AML Cohort | 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) | Bone Marrow X-linked Kinase (BMX) | 0.047 Log2 scale fold change | Standard Deviation 0.781 |
| MK-8628 20 mg AML Cohort | 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) | Caspase Recruitment Domain Family Member 6 (CARD6) | -0.052 Log2 scale fold change | Standard Deviation 0.241 |
| MK-8628 20 mg AML Cohort | 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) | C-C Motif Chemokine Receptor 1 (CCR1) | -0.108 Log2 scale fold change | Standard Deviation 0.38 |
| MK-8628 20 mg AML Cohort | 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) | Cluster of Differentiation 163 (CD163) | -0.528 Log2 scale fold change | Standard Deviation 0.734 |
| MK-8628 20 mg AML Cohort | 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) | Choline Kinase Alpha (CHKA) | -0.191 Log2 scale fold change | Standard Deviation 0.343 |
| MK-8628 20 mg AML Cohort | 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) | Chemerin Chemokine-Like Receptor 1 (CMKLR1) | -0.078 Log2 scale fold change | Standard Deviation 0.51 |
| MK-8628 20 mg AML Cohort | 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) | Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2) | 0.128 Log2 scale fold change | Standard Deviation 0.328 |
| MK-8628 20 mg AML Cohort | 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) | Dicarbonyl and L-xylulose Reductase (DCXR) | 0.511 Log2 scale fold change | Standard Deviation 0.379 |
| MK-8628 20 mg AML Cohort | 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) | Deoxyribonuclease 1 Like 3 (DNASE1L3) | -0.074 Log2 scale fold change | Standard Deviation 0.409 |
| MK-8628 20 mg AML Cohort | 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) | Fc Gamma Receptor Ia (FCGR1A) | -0.126 Log2 scale fold change | Standard Deviation 0.534 |
| MK-8628 20 mg AML Cohort | 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) | Fibroblast Growth Factor Receptor 1 (FGFR1) | 0.193 Log2 scale fold change | Standard Deviation 0.304 |
| MK-8628 20 mg AML Cohort | 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) | G Protein-Coupled Receptor 141 (GPR141) | 0.040 Log2 scale fold change | Standard Deviation 0.673 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme A (GZMA) | -0.110 Log2 scale fold change | Standard Deviation 0.841 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme B (GZMB) | -0.225 Log2 scale fold change | Standard Deviation 0.37 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme K (GZMK) | -0.034 Log2 scale fold change | Standard Deviation 0.648 |
| MK-8628 20 mg AML Cohort | 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) | H2A Histone Family Member X (H2AFX) | -0.013 Log2 scale fold change | Standard Deviation 0.169 |
| MK-8628 20 mg AML Cohort | 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) | Hepatitis A Virus Cellular Receptor 2 (HAVCR2) | -0.181 Log2 scale fold change | Standard Deviation 0.239 |
| MK-8628 20 mg AML Cohort | 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) | Class B Basic Helix-Loop-Helix Protein 41 (HES6) | 0.257 Log2 scale fold change | Standard Deviation 0.654 |
| MK-8628 20 mg AML Cohort | 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) | Hexamethylene Bisacetamide Inducible 1 (HEXIM1) | 0.308 Log2 scale fold change | Standard Deviation 0.26 |
| MK-8628 20 mg AML Cohort | 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) | Hepatocyte Growth Factor (HGF) | -0.298 Log2 scale fold change | Standard Deviation 0.241 |
| MK-8628 20 mg AML Cohort | 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) | Histone Cluster 2 H2B Family Member F (HIST2H2BF) | 0.288 Log2 scale fold change | Standard Deviation 0.451 |
| MK-8628 20 mg AML Cohort | 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) | Inhibitor of Nuclear Factor-kB (IKBKE) | -0.092 Log2 scale fold change | Standard Deviation 0.224 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 12 Receptor Subunit Beta 2 (IL12RB2) | 0.035 Log2 scale fold change | Standard Deviation 0.466 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 7 Receptor (IL7R) | 0.051 Log2 scale fold change | Standard Deviation 0.316 |
| MK-8628 20 mg AML Cohort | 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) | Lunatic Fringe (Drosophila) Homolog (LFNG) | 0.167 Log2 scale fold change | Standard Deviation 0.202 |
| MK-8628 20 mg AML Cohort | 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) | Leukocyte Immunoglobulin Like Receptor A4 (LILRA4) | -0.023 Log2 scale fold change | Standard Deviation 0.396 |
| MK-8628 20 mg AML Cohort | 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) | Macrophage Receptor (MARCO) | -0.714 Log2 scale fold change | Standard Deviation 0.507 |
| MK-8628 20 mg AML Cohort | 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) | Membrane Spanning 4-Domains A2 (MS4A2) | -0.332 Log2 scale fold change | Standard Deviation 0.658 |
| MK-8628 20 mg AML Cohort | 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) | Class E Basic Helix-Loop-Helix Protein 39 (MYC) | -0.376 Log2 scale fold change | Standard Deviation 0.528 |
| MK-8628 20 mg AML Cohort | 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) | Nudix Hydrolase 12 (NUDT12) | -0.331 Log2 scale fold change | Standard Deviation 0.579 |
| MK-8628 20 mg AML Cohort | 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) | Proliferating Cell Nuclear Antigen (PCNA) | 0.049 Log2 scale fold change | Standard Deviation 0.321 |
| MK-8628 20 mg AML Cohort | 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) | Protein Tyrosine Phosphatase PTP-U2 (PTPRO) | -0.103 Log2 scale fold change | Standard Deviation 0.691 |
| MK-8628 20 mg AML Cohort | 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) | C17orf87 (SCIMP) | -0.143 Log2 scale fold change | Standard Deviation 0.349 |
| MK-8628 20 mg AML Cohort | 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) | Serpin Family G Member 1 (SERPING1) | -0.111 Log2 scale fold change | Standard Deviation 0.931 |
| MK-8628 20 mg AML Cohort | 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) | CD353 Antigen (SLAMF8) | -0.394 Log2 scale fold change | Standard Deviation 0.381 |
| MK-8628 20 mg AML Cohort | 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) | Stathmin 1 (STMN1) | -0.014 Log2 scale fold change | Standard Deviation 0.188 |
| MK-8628 20 mg AML Cohort | 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) | Thyroglobulin (TG) | 0.792 Log2 scale fold change | Standard Deviation 0.637 |
| MK-8628 20 mg AML Cohort | 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) | TIFA Inhibitor (TIFAB) | -0.120 Log2 scale fold change | Standard Deviation 0.43 |
| MK-8628 20 mg AML Cohort | 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) | Transmembrane Protein 150B (TMEM150B) | -0.073 Log2 scale fold change | Standard Deviation 0.564 |
| MK-8628 20 mg AML Cohort | 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) | Lymphocyte Activation Antigen CD30 (TNFRSF8) | -0.447 Log2 scale fold change | Standard Deviation 0.38 |
| MK-8628 20 mg AML Cohort | 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) | B-Cell-Activating Factor (TNFSF13B) | -0.119 Log2 scale fold change | Standard Deviation 0.346 |
| MK-8628 20 mg AML Cohort | 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) | Tuftelin 1 (TUFT1) | 0.279 Log2 scale fold change | Standard Deviation 0.725 |
| MK-8628 20 mg AML Cohort | 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) | Nemitin (WDR47) | 0.117 Log2 scale fold change | Standard Deviation 0.257 |
| MK-8628 20 mg AML Cohort | 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) | X-C Motif Chemokine Ligand 2 (XCL2) | -0.051 Log2 scale fold change | Standard Deviation 0.538 |
Secondary
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)
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8628 20 mg AML Cohort | 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) | Agmatinase (AGMAT) | -0.466 Log2 scale fold change | Standard Deviation 0.266 |
| MK-8628 20 mg AML Cohort | 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) | Annexin A3 (ANXA3) | -0.182 Log2 scale fold change | Standard Deviation 0.537 |
| MK-8628 20 mg AML Cohort | 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) | Atonal BHLH Transcription Factor 8 (ATOH8) | -0.296 Log2 scale fold change | Standard Deviation 0.627 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma Extra Large (BCL.xL) | -0.219 Log2 scale fold change | Standard Deviation 0.791 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma 2 (BCL2) | -0.053 Log2 scale fold change | Standard Deviation 0.289 |
| MK-8628 20 mg AML Cohort | 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) | Bone Marrow X-linked Kinase (BMX) | -0.093 Log2 scale fold change | Standard Deviation 0.718 |
| MK-8628 20 mg AML Cohort | 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) | Caspase Recruitment Domain Family Member 6 (CARD6) | -0.245 Log2 scale fold change | Standard Deviation 0.371 |
| MK-8628 20 mg AML Cohort | 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) | C-C Motif Chemokine Receptor 1 (CCR1) | -0.246 Log2 scale fold change | Standard Deviation 0.351 |
| MK-8628 20 mg AML Cohort | 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) | Cluster of Differentiation 163 (CD163) | -0.457 Log2 scale fold change | Standard Deviation 0.594 |
| MK-8628 20 mg AML Cohort | 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) | Choline Kinase Alpha (CHKA) | 0.110 Log2 scale fold change | Standard Deviation 0.309 |
| MK-8628 20 mg AML Cohort | 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) | Chemerin Chemokine-Like Receptor 1 (CMKLR1) | -0.194 Log2 scale fold change | Standard Deviation 0.465 |
| MK-8628 20 mg AML Cohort | 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) | Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2) | 0.150 Log2 scale fold change | Standard Deviation 0.19 |
| MK-8628 20 mg AML Cohort | 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) | Dicarbonyl and L-xylulose Reductase (DCXR) | 0.300 Log2 scale fold change | Standard Deviation 0.211 |
| MK-8628 20 mg AML Cohort | 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) | Deoxyribonuclease 1 Like 3 (DNASE1L3) | -0.305 Log2 scale fold change | Standard Deviation 0.614 |
| MK-8628 20 mg AML Cohort | 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) | Fc Gamma Receptor Ia (FCGR1A) | -0.360 Log2 scale fold change | Standard Deviation 0.483 |
| MK-8628 20 mg AML Cohort | 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) | Fibroblast Growth Factor Receptor 1 (FGFR1) | 0.127 Log2 scale fold change | Standard Deviation 0.382 |
| MK-8628 20 mg AML Cohort | 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) | G Protein-Coupled Receptor 141 (GPR141) | 0.054 Log2 scale fold change | Standard Deviation 0.546 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme A (GZMA) | -0.198 Log2 scale fold change | Standard Deviation 0.768 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme B (GZMB) | -0.163 Log2 scale fold change | Standard Deviation 0.262 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme K (GZMK) | -0.127 Log2 scale fold change | Standard Deviation 0.602 |
| MK-8628 20 mg AML Cohort | 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) | H2A Histone Family Member X (H2AFX) | 0.049 Log2 scale fold change | Standard Deviation 0.161 |
| MK-8628 20 mg AML Cohort | 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) | Hepatitis A Virus Cellular Receptor 2 (HAVCR2) | -0.272 Log2 scale fold change | Standard Deviation 0.172 |
| MK-8628 20 mg AML Cohort | 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) | Class B Basic Helix-Loop-Helix Protein 41 (HES6) | 0.189 Log2 scale fold change | Standard Deviation 0.594 |
| MK-8628 20 mg AML Cohort | 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) | Hexamethylene Bisacetamide Inducible 1 (HEXIM1) | 0.315 Log2 scale fold change | Standard Deviation 0.234 |
| MK-8628 20 mg AML Cohort | 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) | Hepatocyte Growth Factor (HGF) | -0.461 Log2 scale fold change | Standard Deviation 0.234 |
| MK-8628 20 mg AML Cohort | 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) | Histone Cluster 2 H2B Family Member F (HIST2H2BF) | 0.325 Log2 scale fold change | Standard Deviation 0.346 |
| MK-8628 20 mg AML Cohort | 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) | Inhibitor of Nuclear Factor-kB (IKBKE) | -0.124 Log2 scale fold change | Standard Deviation 0.243 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 12 Receptor Subunit Beta 2 (IL12RB2) | 0.012 Log2 scale fold change | Standard Deviation 0.334 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 7 Receptor (IL7R) | 0.003 Log2 scale fold change | Standard Deviation 0.47 |
| MK-8628 20 mg AML Cohort | 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) | Lunatic Fringe (Drosophila) Homolog (LFNG) | 0.182 Log2 scale fold change | Standard Deviation 0.188 |
| MK-8628 20 mg AML Cohort | 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) | Leukocyte Immunoglobulin Like Receptor A4 (LILRA4) | -0.403 Log2 scale fold change | Standard Deviation 0.59 |
| MK-8628 20 mg AML Cohort | 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) | Macrophage Receptor (MARCO) | -0.321 Log2 scale fold change | Standard Deviation 0.417 |
| MK-8628 20 mg AML Cohort | 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) | Membrane Spanning 4-Domains A2 (MS4A2) | -0.646 Log2 scale fold change | Standard Deviation 0.85 |
| MK-8628 20 mg AML Cohort | 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) | Class E Basic Helix-Loop-Helix Protein 39 (MYC) | -0.359 Log2 scale fold change | Standard Deviation 0.406 |
| MK-8628 20 mg AML Cohort | 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) | Nudix Hydrolase 12 (NUDT12) | -0.309 Log2 scale fold change | Standard Deviation 0.671 |
| MK-8628 20 mg AML Cohort | 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) | Proliferating Cell Nuclear Antigen (PCNA) | 0.093 Log2 scale fold change | Standard Deviation 0.27 |
| MK-8628 20 mg AML Cohort | 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) | Protein Tyrosine Phosphatase PTP-U2 (PTPRO) | -0.391 Log2 scale fold change | Standard Deviation 0.488 |
| MK-8628 20 mg AML Cohort | 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) | C17orf87 (SCIMP) | -0.159 Log2 scale fold change | Standard Deviation 0.328 |
| MK-8628 20 mg AML Cohort | 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) | Serpin Family G Member 1 (SERPING1) | -0.137 Log2 scale fold change | Standard Deviation 0.579 |
| MK-8628 20 mg AML Cohort | 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) | CD353 Antigen (SLAMF8) | -0.485 Log2 scale fold change | Standard Deviation 0.434 |
| MK-8628 20 mg AML Cohort | 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) | Stathmin 1 (STMN1) | -0.054 Log2 scale fold change | Standard Deviation 0.199 |
| MK-8628 20 mg AML Cohort | 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) | Thyroglobulin (TG) | 0.485 Log2 scale fold change | Standard Deviation 0.377 |
| MK-8628 20 mg AML Cohort | 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) | TIFA Inhibitor (TIFAB) | -0.405 Log2 scale fold change | Standard Deviation 0.334 |
| MK-8628 20 mg AML Cohort | 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) | Transmembrane Protein 150B (TMEM150B) | -0.283 Log2 scale fold change | Standard Deviation 0.482 |
| MK-8628 20 mg AML Cohort | 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) | Lymphocyte Activation Antigen CD30 (TNFRSF8) | -0.522 Log2 scale fold change | Standard Deviation 0.312 |
| MK-8628 20 mg AML Cohort | 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) | B-Cell-Activating Factor (TNFSF13B) | -0.135 Log2 scale fold change | Standard Deviation 0.299 |
| MK-8628 20 mg AML Cohort | 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) | Tuftelin 1 (TUFT1) | 0.282 Log2 scale fold change | Standard Deviation 0.544 |
| MK-8628 20 mg AML Cohort | 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) | Nemitin (WDR47) | 0.144 Log2 scale fold change | Standard Deviation 0.162 |
| MK-8628 20 mg AML Cohort | 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) | X-C Motif Chemokine Ligand 2 (XCL2) | -0.365 Log2 scale fold change | Standard Deviation 0.419 |
Secondary
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)
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8628 20 mg AML Cohort | 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) | Agmatinase (AGMAT) | -0.493 Log2 scale fold change | Standard Deviation 0.322 |
| MK-8628 20 mg AML Cohort | 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) | Annexin A3 (ANXA3) | 0.111 Log2 scale fold change | Standard Deviation 0.865 |
| MK-8628 20 mg AML Cohort | 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) | Atonal BHLH Transcription Factor 8 (ATOH8) | -0.049 Log2 scale fold change | Standard Deviation 0.923 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma Extra Large (BCL.xL) | -0.169 Log2 scale fold change | Standard Deviation 0.603 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma 2 (BCL2) | -0.133 Log2 scale fold change | Standard Deviation 0.266 |
| MK-8628 20 mg AML Cohort | 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) | Bone Marrow X-linked Kinase (BMX) | -0.008 Log2 scale fold change | Standard Deviation 1.008 |
| MK-8628 20 mg AML Cohort | 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) | Caspase Recruitment Domain Family Member 6 (CARD6) | -0.091 Log2 scale fold change | Standard Deviation 0.324 |
| MK-8628 20 mg AML Cohort | 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) | C-C Motif Chemokine Receptor 1 (CCR1) | -0.257 Log2 scale fold change | Standard Deviation 0.467 |
| MK-8628 20 mg AML Cohort | 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) | Cluster of Differentiation 163 (CD163) | -0.640 Log2 scale fold change | Standard Deviation 0.994 |
| MK-8628 20 mg AML Cohort | 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) | Choline Kinase Alpha (CHKA) | -0.116 Log2 scale fold change | Standard Deviation 0.384 |
| MK-8628 20 mg AML Cohort | 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) | Chemerin Chemokine-Like Receptor 1 (CMKLR1) | -0.218 Log2 scale fold change | Standard Deviation 0.736 |
| MK-8628 20 mg AML Cohort | 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) | Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2) | 0.152 Log2 scale fold change | Standard Deviation 0.35 |
| MK-8628 20 mg AML Cohort | 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) | Dicarbonyl and L-xylulose Reductase (DCXR) | 0.536 Log2 scale fold change | Standard Deviation 0.187 |
| MK-8628 20 mg AML Cohort | 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) | Deoxyribonuclease 1 Like 3 (DNASE1L3) | -0.306 Log2 scale fold change | Standard Deviation 0.661 |
| MK-8628 20 mg AML Cohort | 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) | Fc Gamma Receptor Ia (FCGR1A) | -0.126 Log2 scale fold change | Standard Deviation 0.39 |
| MK-8628 20 mg AML Cohort | 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) | Fibroblast Growth Factor Receptor 1 (FGFR1) | 0.125 Log2 scale fold change | Standard Deviation 0.295 |
| MK-8628 20 mg AML Cohort | 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) | G Protein-Coupled Receptor 141 (GPR141) | -0.085 Log2 scale fold change | Standard Deviation 0.597 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme A (GZMA) | -0.015 Log2 scale fold change | Standard Deviation 1.103 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme B (GZMB) | -0.262 Log2 scale fold change | Standard Deviation 0.382 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme K (GZMK) | 0.001 Log2 scale fold change | Standard Deviation 0.898 |
| MK-8628 20 mg AML Cohort | 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) | H2A Histone Family Member X (H2AFX) | 0.082 Log2 scale fold change | Standard Deviation 0.156 |
| MK-8628 20 mg AML Cohort | 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) | Hepatitis A Virus Cellular Receptor 2 (HAVCR2) | -0.294 Log2 scale fold change | Standard Deviation 0.276 |
| MK-8628 20 mg AML Cohort | 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) | Class B Basic Helix-Loop-Helix Protein 41 (HES6) | 0.378 Log2 scale fold change | Standard Deviation 0.888 |
| MK-8628 20 mg AML Cohort | 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) | Hexamethylene Bisacetamide Inducible 1 (HEXIM1) | 0.345 Log2 scale fold change | Standard Deviation 0.234 |
| MK-8628 20 mg AML Cohort | 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) | Hepatocyte Growth Factor (HGF) | -0.325 Log2 scale fold change | Standard Deviation 0.228 |
| MK-8628 20 mg AML Cohort | 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) | Histone Cluster 2 H2B Family Member F (HIST2H2BF) | 0.239 Log2 scale fold change | Standard Deviation 0.372 |
| MK-8628 20 mg AML Cohort | 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) | Inhibitor of Nuclear Factor-kB (IKBKE) | -0.153 Log2 scale fold change | Standard Deviation 0.262 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 12 Receptor Subunit Beta 2 (IL12RB2) | -0.018 Log2 scale fold change | Standard Deviation 0.352 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 7 Receptor (IL7R) | 0.016 Log2 scale fold change | Standard Deviation 0.461 |
| MK-8628 20 mg AML Cohort | 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) | Lunatic Fringe (Drosophila) Homolog (LFNG) | 0.104 Log2 scale fold change | Standard Deviation 0.228 |
| MK-8628 20 mg AML Cohort | 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) | Leukocyte Immunoglobulin Like Receptor A4 (LILRA4) | -0.151 Log2 scale fold change | Standard Deviation 0.494 |
| MK-8628 20 mg AML Cohort | 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) | Macrophage Receptor (MARCO) | -0.441 Log2 scale fold change | Standard Deviation 0.777 |
| MK-8628 20 mg AML Cohort | 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) | Membrane Spanning 4-Domains A2 (MS4A2) | -0.232 Log2 scale fold change | Standard Deviation 0.786 |
| MK-8628 20 mg AML Cohort | 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) | Class E Basic Helix-Loop-Helix Protein 39 (MYC) | -0.481 Log2 scale fold change | Standard Deviation 0.611 |
| MK-8628 20 mg AML Cohort | 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) | Nudix Hydrolase 12 (NUDT12) | -0.295 Log2 scale fold change | Standard Deviation 0.587 |
| MK-8628 20 mg AML Cohort | 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) | Proliferating Cell Nuclear Antigen (PCNA) | 0.036 Log2 scale fold change | Standard Deviation 0.318 |
| MK-8628 20 mg AML Cohort | 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) | Protein Tyrosine Phosphatase PTP-U2 (PTPRO) | 0.037 Log2 scale fold change | Standard Deviation 0.632 |
| MK-8628 20 mg AML Cohort | 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) | C17orf87 (SCIMP) | -0.246 Log2 scale fold change | Standard Deviation 0.425 |
| MK-8628 20 mg AML Cohort | 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) | Serpin Family G Member 1 (SERPING1) | -0.162 Log2 scale fold change | Standard Deviation 0.922 |
| MK-8628 20 mg AML Cohort | 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) | CD353 Antigen (SLAMF8) | -0.307 Log2 scale fold change | Standard Deviation 0.297 |
| MK-8628 20 mg AML Cohort | 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) | Stathmin 1 (STMN1) | -0.091 Log2 scale fold change | Standard Deviation 0.292 |
| MK-8628 20 mg AML Cohort | 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) | Thyroglobulin (TG) | 0.347 Log2 scale fold change | Standard Deviation 0.724 |
| MK-8628 20 mg AML Cohort | 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) | TIFA Inhibitor (TIFAB) | -0.257 Log2 scale fold change | Standard Deviation 0.586 |
| MK-8628 20 mg AML Cohort | 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) | Transmembrane Protein 150B (TMEM150B) | -0.136 Log2 scale fold change | Standard Deviation 0.488 |
| MK-8628 20 mg AML Cohort | 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) | Lymphocyte Activation Antigen CD30 (TNFRSF8) | -0.830 Log2 scale fold change | Standard Deviation 0.692 |
| MK-8628 20 mg AML Cohort | 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) | B-Cell-Activating Factor (TNFSF13B) | -0.112 Log2 scale fold change | Standard Deviation 0.308 |
| MK-8628 20 mg AML Cohort | 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) | Tuftelin 1 (TUFT1) | 0.341 Log2 scale fold change | Standard Deviation 0.546 |
| MK-8628 20 mg AML Cohort | 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) | Nemitin (WDR47) | 0.164 Log2 scale fold change | Standard Deviation 0.243 |
| MK-8628 20 mg AML Cohort | 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) | X-C Motif Chemokine Ligand 2 (XCL2) | -0.190 Log2 scale fold change | Standard Deviation 0.607 |
Secondary
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)
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)
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MK-8628 20 mg AML Cohort | 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) | Agmatinase (AGMAT) | -0.759 Log2 scale fold change | Standard Deviation 0.633 |
| MK-8628 20 mg AML Cohort | 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) | Annexin A3 (ANXA3) | 0.210 Log2 scale fold change | Standard Deviation 0.917 |
| MK-8628 20 mg AML Cohort | 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) | Atonal BHLH Transcription Factor 8 (ATOH8) | -0.869 Log2 scale fold change | Standard Deviation 1.059 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma Extra Large (BCL.xL) | 0.329 Log2 scale fold change | Standard Deviation 1.964 |
| MK-8628 20 mg AML Cohort | 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) | B-cell Lymphoma 2 (BCL2) | -0.056 Log2 scale fold change | Standard Deviation 0.45 |
| MK-8628 20 mg AML Cohort | 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) | Bone Marrow X-linked Kinase (BMX) | 0.115 Log2 scale fold change | Standard Deviation 0.628 |
| MK-8628 20 mg AML Cohort | 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) | Caspase Recruitment Domain Family Member 6 (CARD6) | -0.115 Log2 scale fold change | Standard Deviation 0.38 |
| MK-8628 20 mg AML Cohort | 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) | C-C Motif Chemokine Receptor 1 (CCR1) | -0.490 Log2 scale fold change | Standard Deviation 1.185 |
| MK-8628 20 mg AML Cohort | 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) | Cluster of Differentiation 163 (CD163) | -0.442 Log2 scale fold change | Standard Deviation 0.779 |
| MK-8628 20 mg AML Cohort | 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) | Choline Kinase Alpha (CHKA) | 0.218 Log2 scale fold change | Standard Deviation 0.267 |
| MK-8628 20 mg AML Cohort | 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) | Chemerin Chemokine-Like Receptor 1 (CMKLR1) | -0.708 Log2 scale fold change | Standard Deviation 1.271 |
| MK-8628 20 mg AML Cohort | 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) | Cysteine/Serine-Rich Nuclear Protein 2 (CSRNP2) | 0.119 Log2 scale fold change | Standard Deviation 0.265 |
| MK-8628 20 mg AML Cohort | 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) | Dicarbonyl and L-xylulose Reductase (DCXR) | 0.696 Log2 scale fold change | Standard Deviation 0.397 |
| MK-8628 20 mg AML Cohort | 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) | Deoxyribonuclease 1 Like 3 (DNASE1L3) | -0.386 Log2 scale fold change | Standard Deviation 0.705 |
| MK-8628 20 mg AML Cohort | 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) | Fc Gamma Receptor Ia (FCGR1A) | -0.885 Log2 scale fold change | Standard Deviation 0.348 |
| MK-8628 20 mg AML Cohort | 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) | Fibroblast Growth Factor Receptor 1 (FGFR1) | -0.561 Log2 scale fold change | Standard Deviation 1.033 |
| MK-8628 20 mg AML Cohort | 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) | G Protein-Coupled Receptor 141 (GPR141) | -0.333 Log2 scale fold change | Standard Deviation 1.207 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme A (GZMA) | -0.572 Log2 scale fold change | Standard Deviation 0.752 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme B (GZMB) | -0.442 Log2 scale fold change | Standard Deviation 1.402 |
| MK-8628 20 mg AML Cohort | 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) | Granzyme K (GZMK) | -0.657 Log2 scale fold change | Standard Deviation 0.974 |
| MK-8628 20 mg AML Cohort | 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) | H2A Histone Family Member X (H2AFX) | 0.060 Log2 scale fold change | Standard Deviation 0.466 |
| MK-8628 20 mg AML Cohort | 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) | Hepatitis A Virus Cellular Receptor 2 (HAVCR2) | -0.722 Log2 scale fold change | Standard Deviation 0.598 |
| MK-8628 20 mg AML Cohort | 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) | Class B Basic Helix-Loop-Helix Protein 41 (HES6) | 0.364 Log2 scale fold change | Standard Deviation 1.373 |
| MK-8628 20 mg AML Cohort | 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) | Hexamethylene Bisacetamide Inducible 1 (HEXIM1) | 0.429 Log2 scale fold change | Standard Deviation 0.422 |
| MK-8628 20 mg AML Cohort | 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) | Hepatocyte Growth Factor (HGF) | -0.276 Log2 scale fold change | Standard Deviation 0.383 |
| MK-8628 20 mg AML Cohort | 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) | Histone Cluster 2 H2B Family Member F (HIST2H2BF) | 0.427 Log2 scale fold change | Standard Deviation 0.415 |
| MK-8628 20 mg AML Cohort | 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) | Inhibitor of Nuclear Factor-kB (IKBKE) | -0.166 Log2 scale fold change | Standard Deviation 0.48 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 12 Receptor Subunit Beta 2 (IL12RB2) | -0.435 Log2 scale fold change | Standard Deviation 1.351 |
| MK-8628 20 mg AML Cohort | 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) | Interleukin 7 Receptor (IL7R) | -0.301 Log2 scale fold change | Standard Deviation 0.986 |
| MK-8628 20 mg AML Cohort | 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) | Lunatic Fringe (Drosophila) Homolog (LFNG) | 0.099 Log2 scale fold change | Standard Deviation 0.668 |
| MK-8628 20 mg AML Cohort | 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) | Leukocyte Immunoglobulin Like Receptor A4 (LILRA4) | 0.104 Log2 scale fold change | Standard Deviation 1.241 |
| MK-8628 20 mg AML Cohort | 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) | Macrophage Receptor (MARCO) | -1.197 Log2 scale fold change | Standard Deviation 0.832 |
| MK-8628 20 mg AML Cohort | 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) | Membrane Spanning 4-Domains A2 (MS4A2) | 0.023 Log2 scale fold change | Standard Deviation 1.266 |
| MK-8628 20 mg AML Cohort | 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) | Class E Basic Helix-Loop-Helix Protein 39 (MYC) | -0.270 Log2 scale fold change | Standard Deviation 0.521 |
| MK-8628 20 mg AML Cohort | 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) | Nudix Hydrolase 12 (NUDT12) | -0.025 Log2 scale fold change | Standard Deviation 0.697 |
| MK-8628 20 mg AML Cohort | 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) | Proliferating Cell Nuclear Antigen (PCNA) | 0.015 Log2 scale fold change | Standard Deviation 0.572 |
| MK-8628 20 mg AML Cohort | 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) | Protein Tyrosine Phosphatase PTP-U2 (PTPRO) | -1.007 Log2 scale fold change | Standard Deviation 0.839 |
| MK-8628 20 mg AML Cohort | 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) | C17orf87 (SCIMP) | -0.360 Log2 scale fold change | Standard Deviation 1.005 |
| MK-8628 20 mg AML Cohort | 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) | Serpin Family G Member 1 (SERPING1) | -0.170 Log2 scale fold change | Standard Deviation 1.191 |
| MK-8628 20 mg AML Cohort | 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) | CD353 Antigen (SLAMF8) | -0.918 Log2 scale fold change | Standard Deviation 1.057 |
| MK-8628 20 mg AML Cohort | 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) | Stathmin 1 (STMN1) | -0.251 Log2 scale fold change | Standard Deviation 0.822 |
| MK-8628 20 mg AML Cohort | 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) | Thyroglobulin (TG) | 0.399 Log2 scale fold change | Standard Deviation 0.884 |
| MK-8628 20 mg AML Cohort | 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) | TIFA Inhibitor (TIFAB) | -0.937 Log2 scale fold change | Standard Deviation 0.444 |
| MK-8628 20 mg AML Cohort | 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) | Transmembrane Protein 150B (TMEM150B) | -0.222 Log2 scale fold change | Standard Deviation 0.28 |
| MK-8628 20 mg AML Cohort | 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) | Lymphocyte Activation Antigen CD30 (TNFRSF8) | -0.464 Log2 scale fold change | Standard Deviation 0.453 |
| MK-8628 20 mg AML Cohort | 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) | B-Cell-Activating Factor (TNFSF13B) | -0.094 Log2 scale fold change | Standard Deviation 0.445 |
| MK-8628 20 mg AML Cohort | 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) | Tuftelin 1 (TUFT1) | 0.472 Log2 scale fold change | Standard Deviation 0.798 |
| MK-8628 20 mg AML Cohort | 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) | Nemitin (WDR47) | 0.263 Log2 scale fold change | Standard Deviation 0.155 |
| MK-8628 20 mg AML Cohort | 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) | X-C Motif Chemokine Ligand 2 (XCL2) | -0.666 Log2 scale fold change | Standard Deviation 0.835 |
Secondary
Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)
DCR was defined as the percentage of the participants who had stable disease, complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the AML cohort were assessed using bone marrow aspiration and hematologic criteria and response was evaluated based on European LeukemiaNet (Döhner et al, Blood, 2010). The criteria for complete response included: bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0 × 10\^9/Liter; platelet count \>100 × 10\^9/Liter; and independence of red cell transfusions. The criteria for partial response included: decrease of bone marrow blast percentage to 5% to 25%; decrease of pretreatment bone marrow blast percentage by at least 50%; and all hematologic criteria associated with CR.
Time frame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) | Complete response | 0.0 Percentage of participants |
| MK-8628 20 mg AML Cohort | Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) | Partial response | 0.0 Percentage of participants |
| MK-8628 20 mg AML Cohort | Disease Control Rate (DCR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) | Stable disease | 0.0 Percentage of participants |
Secondary
Disease Control Rate (DCR) in the Diffuse Large B Cell Lymphoma (DLBCL) Cohort Per International Working Group Criteria: Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014)
DCR was defined as the percentage of the participants in the DLBCL cohort who had stable disease, complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the DLBCL cohort were assessed using computed tomography (CT) and positron emission tomography (PET)-CT and response was evaluated based on the Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014). The criteria for CR included complete metabolic (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤5 cm in longest transverse diameter of a lesion) and no new lesions. The criteria for PR included: partial metabolic (moderate/high FDG uptake) and radiologic response (≥50% decrease in sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \>50% in length beyond normal).
Time frame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | 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) | Complete response | 0.0 Percentage of participants |
| MK-8628 20 mg AML Cohort | 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) | Partial response | 16.7 Percentage of participants |
| MK-8628 20 mg AML Cohort | 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) | Stable disease | 0.0 Percentage of participants |
Secondary
Duration of Response (DOR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)
DOR was defined as the time from complete response (CR) or partial response (PR) to documented disease progression or death as assessed by investigator review. Participants in the AML cohort were assessed using bone marrow aspiration and hematologic criteria and response was evaluated based on European LeukemiaNet (Döhner et al, Blood, 2010). The criteria for complete response included: bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0 × 10\^9/Liter; platelet count \>100 × 10\^9/Liter; and independence of red cell transfusions. The criteria for partial response included: decrease of bone marrow blast percentage to 5% to 25%; decrease of pretreatment bone marrow blast percentage by at least 50%; and all hematologic criteria associated with CR.
Time frame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)
Population: 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.
Secondary
Duration of Response (DOR) in the Diffuse Large B Cell Lymphoma (DLBCL) Cohort Per International Working Group Criteria: Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014)
DOR was defined as the time from complete response (CR) or partial response (PR) to documented disease progression or death as assessed by investigator review. Participants in the DLBCL cohort were assessed using computed tomography (CT) and positron emission tomography (PET)-CT and response was evaluated based on the Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014). The criteria for CR included complete metabolic (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤5 cm in longest transverse diameter of a lesion) and no new lesions. The criteria for PR included: partial metabolic (moderate/high FDG uptake) and radiologic response (≥50% decrease in sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \>50% in length beyond normal).
Time frame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)
Population: 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.
Secondary
Objective Response Rate (ORR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010)
ORR was defined as the percentage of the participants who had complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the AML cohort were assessed using bone marrow aspiration and hematologic criteria and response was evaluated based on European LeukemiaNet (Döhner et al, Blood, 2010). The criteria for complete response included: bone marrow blasts \<5%; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count \>1.0 × 10\^9/Liter; platelet count \>100 × 10\^9/Liter; and independence of red cell transfusions. The criteria for partial response included: decrease of bone marrow blast percentage to 5% to 25%; decrease of pretreatment bone marrow blast percentage by at least 50%; and all hematologic criteria associated with CR. The percentage of participants who achieved CR or PR is presented.
Time frame: Every 3 weeks starting from Cycle 2 (21-day cycle) until disease progression (up to 7 months)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Objective Response Rate (ORR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) | Complete response | 0.0 Percentage of participants |
| MK-8628 20 mg AML Cohort | Objective Response Rate (ORR) in the Acute Myeloid Leukemia (AML) Cohort Per International Working Group Criteria: European LeukemiaNet (Döhner et al, Blood, 2010) | Partial response | 0.0 Percentage of participants |
Secondary
Objective Response Rate (ORR) in the Diffuse Large B Cell Lymphoma (DLBCL) Cohort Per International Working Group Criteria: Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014)
ORR was defined as the percentage of the participants who had complete response (CR) or partial response (PR) as assessed by investigator review. Participants in the DLBCL cohort were assessed using computed tomography (CT) and positron emission tomography (PET)-CT and response was evaluated based on the Lugano Classification (Cheson et al, Journal of Clinical Oncology, 2014). The criteria for CR included complete metabolic (no/minimal fluorodeoxyglucose \[FDG\] uptake) and radiologic response (target lesions regress to ≤5 cm in longest transverse diameter of a lesion) and no new lesions. The criteria for PR included: partial metabolic (moderate/high FDG uptake) and radiologic response (≥50% decrease in sum of the product of the perpendicular diameters for multiple lesions of up to 6 target measurable nodes and extranodal sites, no increase in lesions, and spleen regressed by \>50% in length beyond normal). The percentage of participants who achieved CR or PR is presented.
Time frame: Every 12 weeks starting from Cycle 5 (21-day cycle) until disease progression (up to 7 months)
Population: 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 | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | 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) | Complete response | 0.0 Percentage of participants |
| MK-8628 20 mg AML Cohort | 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) | Partial response | 16.7 Percentage of participants |
Secondary
Observed Maximum Concentration (Cmax) of MK-8628
Blood samples were collected to determine Cmax at the following time points: Cycle 1 (21-day cycle) Day 1 at predose and 20 minutes, 1 hour, 2.25 hours, 3.25 hours, 8 hours and 12 hours postdose; Cycle 1 (21-day cycle) at predose on Days 8 and 15; and Cycle 2 (21-day cycle) at predose on Day 1. Per protocol, Cmax for MK-8628 was assessed across all study participants by dose and this assessment was not related to any specific disease cohort. The Cmax of MK-8628 after oral administration is presented for participants pooled from the AML and DLBCL cohorts since both cohorts received the same dose.
Time frame: Up to 22 days post MK-8628 dose
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Observed Maximum Concentration (Cmax) of MK-8628 | 360 ng/mL | Standard Deviation 132 |
Secondary
Observed Minimum Concentration (Cmin) of MK-8628
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-8628 20 mg AML Cohort | Observed Minimum Concentration (Cmin) of MK-8628 | 134 ng/mL | Standard Deviation 77.2 |
Secondary
Percentage of Participants Who Discontinued Study Treatment Due to an AE
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The percentage of all participants who discontinued study treatment due to an AE is presented. Per protocol, these results are based on a data cutoff date of 09-May-2018.
Time frame: From time of first dose until the end of treatment (up to 7 months)
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8628 20 mg AML Cohort | Percentage of Participants Who Discontinued Study Treatment Due to an AE | 0.0 Percentage of participants |
| MK-8628 20 mg DLBCL Cohort | Percentage of Participants Who Discontinued Study Treatment Due to an AE | 0.0 Percentage of participants |
Secondary
Percentage of Participants Who Experienced At Least One Adverse Event (AE)
An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that is temporally associated with the use of study treatment, is also an AE. The percentage of all participants who experienced at least one AE is presented. Per protocol, these results are based on a data cutoff date of 09-May-2018.
Time frame: From time of first dose until the end of follow-up (up to 8 months)
Population: The analysis population consisted of all participants who received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MK-8628 20 mg AML Cohort | Percentage of Participants Who Experienced At Least One Adverse Event (AE) | 100.0 Percentage of participants |
| MK-8628 20 mg DLBCL Cohort | Percentage of Participants Who Experienced At Least One Adverse Event (AE) | 100.0 Percentage of participants |
Secondary
Time to Maximum Concentration (Tmax) of MK-8628
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
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| MK-8628 20 mg AML Cohort | Time to Maximum Concentration (Tmax) of MK-8628 | 2.25 hr |