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

Phase 1

Terminated

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

Interventions: Biological: MK-0482

Registration Number: NCT05038800

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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.

Detailed Description: In Part 1, single participants will be enrolled sequentially into escalating dose levels. Progression from one dose level to the next higher dose level will be based on the evaluation of dose-limiting toxicity (DLT). Once a preliminary RP2D is identified in Part 1, approximately 10 to 15 additional participants with R/R AML will be enrolled at the RP2D for Part 2.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 13

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
MK-0482 7.5 mg Q3W	MK-0482	Participants will receive 7.5 mg of MK-0482 via intravenous (IV) infusion on Day 1 of each 21-day cycle (every 3 weeks \[Q3W\]) for up to 35 cycles (approximately 24 months).
MK-0482 25 mg Q3W	MK-0482	Participants will receive 25 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
MK-0482 75 mg Q3W	MK-0482	Participants will receive 75 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
MK-0482 225 mg Q3W	MK-0482	Participants will receive 225 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).
MK-0482 750 mg Q3W	MK-0482	Participants will receive 750 mg of MK-0482 via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 cycles (approximately 24 months).

Primary Outcome Measures

Name	Time	Method
Percentage of Participants Who Experienced a Dose-Limiting Toxicity (DLT)	Cycle 1 (up to 21 days)	DLTs were defined as any of the following assessed as treatment-related by investigator (with pre-specified exceptions): Grade (Gr) 4 non-hematologic toxicity; Gr 3 non-hematologic toxicity; Gr 3 or Gr 4 non-hematologic laboratory value if: clinically significant medical intervention was required to treat the participant, the abnormality led to hospitalization, the abnormality persisted for \>1 week, electrolyte imbalances that lasted \>48 hours despite optimal therapy, or the abnormality resulted in a drug-induced liver injury; Gr 4 neutropenia and/or thrombocytopenia lasting \>14 days; \>2 week-delay in starting Cycle 2 due to treatment-related toxicity; treatment-related toxicity resulting in treatment discontinuation during DLT evaluation period; missing \>25% of MK-0482 dose during DLT evaluation period resulting from treatment-related adverse event (AE); or Gr 5 toxicity. The percentage of participants that experienced a DLT was reported for each arm.
Number of Participants Who Experience at Least One Adverse Event (AE)	Up to approximately 10 months	An AE was 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 experienced at least one AE was reported for each arm.
Number of Participants Who Discontinued Study Treatment Due to an AE	Up to approximately 4 months	An AE was 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 discontinued study treatment due to an AE was reported for each arm.

Secondary Outcome Measures

Name	Time	Method
Maximum Concentration (Cmax) of MK-0482	Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.	Cmax was defined as the maximum concentration of MK-0482 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Cmax of MK-0482.
Minimum Concentration (Cmin) of MK-0482	Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.	Cmin (or Ctrough) was defined as the lowest concentration of MK-0482 reached during a dosing interval (time interval between administration of two doses). Blood samples were collected pre-dose and post-dose at designated timepoints to determine Cmin of MK-0482.
Area Under the Plasma Concentration-Time Curve From Time Zero to 21 Days (AUC0-21) of MK-0482	Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.	AUC0-21 was defined as the area under the plasma concentration-time curve from time zero to 21 days. Blood samples were collected pre-dose and post-dose at designated timepoints to determine AUC0-21 of MK-0482.
Time to Maximum Concentration (Tmax) of MK-0482	Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.	Tmax was defined as the time to maximum concentration of MK-0482 observed in plasma. Blood samples were collected pre-dose and post-dose at designated timepoints to determine Tmax of MK-0482.
Plasma Elimination Terminal Half-life (t½) of MK-0482	Cycle 1: Pre-dose and Days 1, 2, 4, 8, and 15 post-dose. Cycle=21 days.	t½ was defined as the time required to divide the MK-0482 plasma concentration by two after reaching pseudo-equilibrium. Blood samples were collected pre-dose and post-dose at designated timepoints to determine t½ of MK-0482.
Complete Remission (CR) Rate	Up to approximately 10 months	CR Rate was assessed by the investigator per 2017 European Leukemia Net (ELN) Response Criteria for Acute Myeloid Leukemia (AML) and was 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); and platelet count ≥100 × 10\^9/L (100,000/µL). The percentage of participants with CR (CR Rate) was reported for each arm.
Composite CR Rate	Up to approximately 10 months	Composite CR rate was assessed by the investigator per 2017 ELN Response Criteria for AML and was defined as CR plus CR with incomplete recovery (CRi). CR was 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); and platelet count ≥100 × 10\^9/L (100,000/µL). CRi was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (\<100 × 10\^9/L \[100,000/µL\]). The percentage of participants with Composite CR (Composite CR Rate) was reported for each arm.
Objective Response Rate (ORR)	Up to approximately 10 months	ORR was assessed by the investigator per 2017 ELN Response Criteria for AML and was defined as the combined percentage of participants with CR, CRi, and partial remission (PR). CR was 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 was defined as all CR criteria except for residual neutropenia (\<1.0 × 10\^9/L \[1000/µL\]) or thrombocytopenia (\<100 × 10\^9/L \[100,000/µL\]). PR was 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%). ORR was reported for each arm.

Trial Locations

Locations (5): Hadassah Medical Center ( Site 0100)
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Jerusalem, Israel
Sheba Medical Center-Hemato Oncology ( Site 0101)
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Ramat Gan, Israel
University of Texas MD Anderson Cancer Center ( Site 0004)
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Houston, Texas, United States
Roswell Park Cancer Institute ( Site 0006)
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Buffalo, New York, United States
Hospital Universitario de Salamanca - Complejo Asistencial U-Servicio de Hematologia ( Site 0301)
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Salamanca, Spain