MK-0482 for Acute Myeloid & Chronic Myelomonocytic Leukemias

No longer recruiting at 4 trial locations

Overseen By Toll Free Number

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Merck Sharp & Dohme Corp.

Must not be taking: Monoclonal antibodies, Immunosuppressants

Disqualifiers: CNS leukemia, HIV, Hepatitis, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment called MK-0482 for individuals with relapsed or hard-to-treat acute myeloid leukemia (AML) or chronic myelomonocytic leukemia (CMML). The main goal is to assess the treatment's safety and tolerability and determine the best dose for future studies. The trial consists of two parts: the first tests different doses, and the second uses the optimal dose to evaluate effectiveness. Individuals with AML with specific cell types or CMML who have not responded to other treatments might be suitable candidates for this trial. As a Phase 1 trial, this research aims to understand how the treatment works in people, offering participants the opportunity to be among the first to receive this new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have received systemic anticancer therapy, radiotherapy, or surgery within 2 weeks before starting the study treatment, and you must not be on chronic systemic steroid therapy exceeding 10 mg daily of prednisone equivalent within 7 days prior to the first dose.

Is there any evidence suggesting that MK-0482 is likely to be safe for humans?

Research shows that MK-0482 remains in the early testing stages to assess its safety and tolerability. Currently, limited information exists on how people react to it. Previous studies have examined the drug's mechanism and how the body processes it, helping to determine the optimal dose for future research. As MK-0482 is in early testing, researchers focus on identifying side effects and ensuring safety. Side effects can occur, and researchers monitor them closely. If MK-0482 was tested for other conditions, some safety information might be available from those trials, but responses can vary by condition. Staying in touch with the trial team is crucial for the most accurate updates. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about MK-0482 because it represents a novel approach to treating acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). Unlike traditional chemotherapy, which broadly attacks rapidly dividing cells, MK-0482 may target specific pathways involved in the growth of leukemic cells, potentially leading to more effective and less toxic treatments. This drug is administered through an intravenous infusion, which allows for precise dosing and could improve absorption compared to oral medications. The range of doses being tested, from 7.5 mg to 750 mg every three weeks, allows researchers to fine-tune its effectiveness and safety profile, offering hope for a more personalized treatment strategy.

What evidence suggests that MK-0482 might be an effective treatment for acute myeloid and chronic myelomonocytic leukemias?

Researchers are investigating MK-0482 as a potential treatment for acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). This trial will test various dosages of MK-0482, an antibody therapy, to assess its effectiveness. Although public results are not yet available, antibody therapies typically work by targeting specific proteins on cancer cells, aiding the immune system in attacking the cancer. This method has shown promise in other studies. Early results from similar treatments suggest that MK-0482 might be effective, but further research is necessary to confirm its effects on these types of leukemia. ^{1 2 3 4 5}

Who Is on the Research Team?

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory Acute Myeloid Leukemia (AML) or Chronic Myelomonocytic Leukemia (CMML). Participants must have previously treated AML or CMML that's active again or not responding to treatment. Exclusions include those with CNS leukemia, recent serious heart issues, uncontrolled infections, severe leukemia complications, certain psychiatric disorders, pregnancy/breastfeeding, recent other clinical trials participation, immunodeficiency on steroids/immunosuppressants within 7 days before the study drug administration.

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 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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Single participants are enrolled sequentially into escalating dose levels to evaluate dose-limiting toxicity (DLT)

Up to 21 days per cycle

1 visit per cycle (in-person)

Dose Expansion

Participants with R/R AML are enrolled at the recommended Phase 2 dose (RP2D) to further evaluate safety and efficacy

Up to 24 months

1 visit every 3 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to approximately 10 months

What Are the Treatments Tested in This Trial?

Interventions

• MK-0482

Trial Overview MK-0482 is being tested in this study. The first part of the trial will determine the safest dose by gradually increasing it among participants. The second part will focus on how well MK-0482 works at this determined safe dose specifically for people with relapsed/refractory AML.

How Is the Trial Designed?

Group I: MK-0482 750 mg Q3W Experimental Treatment 1 Intervention

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).

Group II: MK-0482 75 mg Q3W Experimental Treatment 1 Intervention

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).

Group III: MK-0482 7.5 mg Q3W Experimental Treatment 1 Intervention

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).

Group IV: MK-0482 25 mg Q3W Experimental Treatment 1 Intervention

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).

Group V: MK-0482 225 mg Q3W Experimental Treatment 1 Intervention

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).

Who Is Running the Clinical Trial?

Merck Sharp & Dohme Corp.

Lead Sponsor

Trials

2,287

Recruited

4,582,000+

Chirfi Guindo

Merck Sharp & Dohme Corp.

Chief Medical Officer

Engineering degree from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme Corp.

Chief Executive Officer since 2021

J.D. from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Merck Sharp & Dohme LLC

Lead Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

MK-0457 is a small-molecule Aurora kinase inhibitor that effectively blocks cell growth and induces apoptosis in various human tumors, including those with resistant mutations like T315I.

The drug shows promise in treating difficult cases of chronic myeloid leukemia (CML), acute lymphoblastic leukemia (ALL), and other hematological malignancies, with ongoing phase II clinical trials exploring its therapeutic potential.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Research progress on aurora kinase inhibitor MK-0457 in therapy for some hematological malignancies -- review]. Liang, YQ., Chen, BA., Chen, YL.[2022]

In preclinical studies, the AKT inhibitor MK-2206 effectively inhibited growth and induced cell death in AML cell lines and primary samples, suggesting potential as a treatment.

However, in a phase II trial with 19 patients, MK-2206 showed limited clinical efficacy, with only 1 out of 18 evaluable patients responding, leading to early termination of the study due to insufficient antileukemia activity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. Konopleva, MY., Walter, RB., Faderl, SH., et al.[2021]

The study evaluated MK-8242 in 26 subjects with refractory/recurrent acute myeloid leukemia (AML), finding that a 7on/14off dosing regimen (210mg or 300mg BID) had a more favorable safety profile compared to the 7on/7off regimen, with no dose-limiting toxicities observed in the higher doses.

Efficacy was demonstrated with responses including one partial response and one complete response in patients, suggesting that MK-8242, an HDM2 inhibitor, warrants further investigation for treating AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of the human double minute 2 inhibitor (MK-8242) in patients with refractory/recurrent acute myelogenous leukemia (AML). Ravandi, F., Gojo, I., Patnaik, MM., et al.[2018]

In a Phase I/II study involving 77 patients with refractory hematologic malignancies, MK-0457 demonstrated significant activity, particularly in patients with the resistant T315I BCR-ABL mutation, achieving hematologic responses in 44% of those with chronic myelogenous leukemia.

The maximum tolerated doses were established at 40 mg/m²/h for a 5-day infusion and 144 mg/m²/h for continuous infusion, with drug-related adverse events primarily including transient mucositis and alopecia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MK-0457, an Aurora kinase and BCR-ABL inhibitor, is active in patients with BCR-ABL T315I leukemia. Giles, FJ., Swords, RT., Nagler, A., et al.[2022]

Chronic myelomonocytic leukemia (CMML) has a poor prognosis with a median overall survival of about 2 years and a significant risk of transforming into acute myeloid leukemia (15-20% over 5 years), highlighting the need for better understanding and treatment options.

Current treatment options are limited, with only two FDA-approved drugs (5-azacitidine and decitabine) and allogeneic hematopoietic stem cell transplantation being the only curative approach, which carries high risks of complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Advances in chronic myelomonocytic leukemia and future prospects: Lessons learned from precision genomics. Mangaonkar, AA., Patnaik, MM.[2021]

A retrospective study of 54 patients with chronic myelomonocytic leukemia (CMML) and secondary acute myeloid leukemia (sAML) showed that a treatment regimen combining cladribine, low-dose cytarabine, and hypomethylating agents (CLAD/LDAC/HMA) resulted in a 33% overall response rate in CMML, with higher efficacy in patients who had not previously failed hypomethylating agents (50% response).

The median overall survival was significantly better for HMA-naive patients, with 14.4 months for HMA-naive CMML compared to only 8.8 months for those who had experienced HMA failure, indicating that CLAD/LDAC/HMA regimens may be particularly beneficial for newly diagnosed patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective study of cladribine and low-dose cytarabine-based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia. Bazinet, A., Darbaniyan, F., Kadia, TM., et al.[2023]

MK-0457 (VX-680) is a promising aurora kinase inhibitor that has shown clinical responses in three patients with T315I BCR-ABL mutated chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphocytic leukemia (ALL), indicating its potential effectiveness against this resistant mutation.

The treatment with MK-0457 was well-tolerated, as the doses used did not lead to significant adverse events, suggesting a favorable safety profile while achieving down-regulation of CrkL phosphorylation in leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MK-0457, a novel kinase inhibitor, is active in patients with chronic myeloid leukemia or acute lymphocytic leukemia with the T315I BCR-ABL mutation. Giles, FJ., Cortes, J., Jones, D., et al.[2023]

Chronic myelomonocytic leukemia (CMML) has a poor prognosis with a median overall survival of only 2-3 years, and current treatments like hypomethylating agents do not significantly change the disease's natural course.

New therapeutic strategies, including combination therapies with novel agents such as sotatercept and ruxolitinib, are being explored in clinical trials, highlighting the need for innovative approaches to effectively target CMML and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increasing recognition and emerging therapies argue for dedicated clinical trials in chronic myelomonocytic leukemia. Renneville, A., Patnaik, MM., Chan, O., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT05038800

A Study to Evaluate MK-0482 for Relapsed/Refractory ... The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended Phase 2 dose (RP2D) of MK-0482.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2022-00937

A Study to Evaluate MK-0482 for Relapsed/Refractory ... The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and recommended Phase 2 dose (RP2D) of MK-0482.

3. delta.larvol.com delta.larvol.com/Products/?ProductId=b7659278-2640-41e3-a60d-7c8b2c82e4b4

MK-0482 / Merck (MSD) ... MK-0482 Monotherapy in Relapsed/Refractory Acute Myeloid Leukemia and Chronic Myelomonocytic Leukemia ... data • Acute Myelogenous Leukemia • Acute ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10031751/

Antibody Therapies for the Treatment of Acute Myeloid ... Clinical efficacy data has not yet been publicly released, but pre-clinical studies of IO-202 have demonstrated that the antibody is efficacious in hLILRB4- ...

5. synapse.patsnap.com synapse.patsnap.com/drug/913e381e3ab54731a1e4e0847c328ef8

MK-0482 - Drug Targets, Indications, Patents Gone from the company's phase 1 pipeline is MK-0482, which was in development for non-small cell lung cancer as recently as the third quarter.