MK-0482 for Acute Myeloid & Chronic Myelomonocytic Leukemias

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

13 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing MK-0482, a new drug for blood cancers, in patients whose cancer has come back or did not respond to previous treatments. The study aims to find out if the drug is safe, how it interacts with the body, and the best dose to use.

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.

What safety data exists for MK-0482 in humans?

There is no specific safety data available for MK-0482, but similar treatments like MK-0457 have been studied in patients with leukemia, showing some adverse events like temporary mouth sores and hair loss, but no significant toxicity at certain doses. ^{1 2 3 4 5}

What makes the drug MK-0482 unique for treating acute myeloid and chronic myelomonocytic leukemias?

MK-0482 is unique because it targets specific genetic mutations and pathways involved in these leukemias, potentially offering a more personalized treatment approach compared to standard therapies like hypomethylating agents and stem cell transplantation, which do not significantly alter the disease course. ^{1 6 7 8 9}

Research Team

Medical Director

Principal Investigator

Merck Sharp & Dohme LLC

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Preclinical and early clinical evaluation of the oral AKT inhibitor, MK-2206, for the treatment of acute myelogenous leukemia. [2021]

2. United States 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. [2023]

3. China pubmed.ncbi.nlm.nih.gov

[Research progress on aurora kinase inhibitor MK-0457 in therapy for some hematological malignancies -- review]. [2022]

4. England 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). [2018]

5. England pubmed.ncbi.nlm.nih.gov

MK-0457, an Aurora kinase and BCR-ABL inhibitor, is active in patients with BCR-ABL T315I leukemia. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Targeted deep sequencing improves outcome stratification in chronic myelomonocytic leukemia with low risk cytogenetic features. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

Advances in chronic myelomonocytic leukemia and future prospects: Lessons learned from precision genomics. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Increasing recognition and emerging therapies argue for dedicated clinical trials in chronic myelomonocytic leukemia. [2023]

9. United States 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. [2023]