A Study to Evaluate MK-0482 for Relapsed/Refractory Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic Leukemia (CMML) (MK-0482-002)

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended Phase 2 dose (RP2D) of MK-0482. There are 2 parts of this study. Part 1 is a dose escalation which will follow an accelerated titration design (ATD) for participants with relapsed/refractory (R/R) AML or CMML. Part 2 is a dose expansion for participants with R/R AML.

Official Title
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A Phase 1b Study to Evaluate the Safety, Tolerability, and Pharmacokinetics/Pharmacodynamics of MK-0482 in Participants With Relapsed or Refractory Acute Myeloid Leukemia or Chronic Myelomonocytic Leukemia

Conditions
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Relapsed or Refractory Acute Myeloid Leukemia, Relapsed or Refractory Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Biological: MK-0482


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Has confirmed diagnosis of AML with myelomonocytic or monoblastic/monocytic differentiation per World Health Organization (WHO) 2016 criteria and with confirmed refractory or relapsed disease (i.e., ≥5% blast in bone marrow or in peripheral blood) after treatment with available therapies known to benefit participant's AML subtypes or has a known diagnosis of CMML per WHO criteria [2017] with confirmed refractory or released disease after treatment with available therapies known to be active for CMML. Exclusion Criteria: Has active central nervous system (CNS) leukemia. Has isolated extramedullary disease, i.e., no leukemic involvement in bone marrow or peripheral blood. Has diagnosis of acute promyelocytic leukemia or participants with known Philadelphia chromosome positive (Ph+) AML. Has received previous allogeneic stem cell transplant or organ transplant within 60 days of the start of study treatment. Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 1 year. Has a history of any of the following cardiovascular conditions within 6 months of screening: myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, coronary artery bypass graft, or pulmonary embolism; has New York Heart Association (NYHA) Class III or IV congestive heart failure. Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAB) and or any components of the study intervention, MK-0482. Has an active uncontrolled infection requiring directed therapy. Has immediately life-threatening, severe complications of leukemia such as uncontrolled bleeding, pneumonia with hypoxia or shock, or disseminated intravascular coagulation. Has known human immunodeficiency virus (HIV) and/or hepatitis B or C infections, or is known to be positive for HBsAg/ Hepatitis B virus (HBV) Deoxyribonucleic acid (DNA) or hepatitis C antibody or Ribonucleic acid (RNA). Has known psychiatric or substance abuse disorders (verbally reported) that would interfere with the participant's ability to cooperate with the requirements of the study. Is pregnant or breast feeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention. Has received systemic anticancer therapy, radiotherapy, or surgery within 2 weeks before the start of study treatment. Has received hematopoietic cytokines (Granulocyte Colony Stimulating Factor (G-CSF), Granulocyte Macrophage (GM)-CSF, or erythropoietin) within 2 weeks prior to start of study treatment. Has received a live or live attenuated vaccine within 30 days before the first dose of study medication. Is currently participating and receiving study intervention in a study of an investigational agent or has participated and received study intervention in a study of an investigational agent or has used an investigational device within 14 days of administration of MK-0482. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study medication.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-0482<br>Participants will receive MK-0482 monotherapy administered in escalating doses as an intravenous (IV) infusion on Day 1 of each 21-day cycle for up to 35 cycles. | Biological: MK-0482<br>* IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) | DLTs are defined as any of the following assessed as treatment (Tx)-related by investigator: Grade (Gr) 4 non-hematologic toxicity (T); Gr 3 non-hematologic T; Gr 3 or Gr 4 non-hematologic T lasting >7 days; Gr 4 neutropenia or thrombocytopenia lasting >14 days; >2 week-delay in starting Cycle 2 due to Tx-related T; Tx related T resulting in Tx discontinuation during DLT evaluation period; missing >25% of the MK-0482 during DLT evaluation period resulting from Tx-related AE; or Gr5 toxicity. | Cycle 1 (up to 21 days) | 
| Number of Participants Who Experience at Least One Adverse Event (AE) | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who experience at least one AE will be presented. | Up to approximately 27 months | 
| Number of Participants Who Discontinue Study Treatment Due to an AE | An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants who discontinue study treatment due to an AE will be presented. | Up to approximately 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration (Cmax) | Cmax is the maximum concentration of the drug observed in plasma. Blood samples will be collected pre-dose and post-dose at designated timepoints to determine Cmax of MK-0482. | Pre- and post-dose: Day 1 of Cycles 1, 2, 3, 4, 6, 8 and every 4 Cycles thereafter up to 35 Cycles (through study completion, an average of 2 years). Post-dose: Cycle 1 on Days 2, 4, 8, 15, and Cycles 2 and 3 on Day 8. Each Cycle=21 days. | 
| Trough Plasma Concentration (Ctrough) | Ctrough is the lowest concentration reached by a drug before the next dose is administered. Blood samples will be collected pre-dose and post-dose at designated timepoints to determine Ctrough of MK-0482. | Pre- and post-dose: Day 1 of Cycles 1, 2, 3, 4, 6, 8 and every 4 Cycles thereafter up to 35 Cycles (through study completion, an average of 2 years). Post-dose: Cycle 1 on Days 2, 4, 8, 15, and Cycles 2 and 3 on Day 8. Each Cycle=21 days. | 
| Complete Remission (CR) Rate | CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥1.0 × 10^9/L (1000/µL); platelet count ≥100 × 10^9/L (100,000/µL). | Up to approximately 24 months | 
| Composite CR Rate | Composite CR rate is defined as CR + CR with incomplete recovery (CRi). CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 10^9/L (1000/µL); platelet count ≥100 × 10^9/L (100,000/µL). CRi is defined as all CR criteria except for residual neutropenia (<1.0 × 10^9/L [1000/µL]) or thrombocytopenia (<100 × 10^9/L [100,000/µL]). | Up to approximately 24 months | 
| Objective Response Rate (ORR) | Objective response: CR + CRi + partial remission (PR) ORR is defined as the percentage of participants who have a complete response (CR: CR is defined as bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count (ANC) ≥1.0 × 10^9/L (1000/µL); platelet count ≥100 × 10^9/L (100,000/µL)) and CR with incomplete hematologic recovery (CRi: CRi is defined as all CR criteria except for residual neutropenia (<1.0 × 10^9/L [1000/µL]) or thrombocytopenia (<100 × 10^9/L [100,000/µL]) and partial response (PR: PR is defined as all hematologic criteria of CR; decrease of bone marrow blast percentage to 5% to 25%; and decrease of pre-treatment bone marrow blast percentage by at least 50%). | Up to approximately 24 months |