Azacitidine, Venetoclax, and Trametinib for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Higher-Risk Myelodysplastic Syndrome

NCT04487106 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 2020-0506NCI-2020-05350
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

This phase II trial investigates how well azacitidine, venetoclax, and trametinib work in treating patients with acute myeloid leukemia or higher-risk myelodysplastic syndrome that has come back (relapsed) or has not responded to treatment (refractory). Chemotherapy drugs, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Venetoclax and trametinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. The goal of this study is learn if the combination of azacitidine, venetoclax, and trametinib can help to control acute myeloid leukemia or myelodysplastic syndrome.

Conditions

Recurrent Acute Myeloid Leukemia; Recurrent Chronic Myelomonocytic Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Chronic Myelomonocytic Leukemia; Refractory Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (1)

• Participants With a Response

  Overall response is defined as the number of participants achieving Complete Remission (CR) or Complete Remission without recovery of counts (CRi) CR is Normalization of the peripheral blood and bone marrow with \</= to 5 % blasts with a granulocyte count of 1 x 10\^9/L or greater and a platelet count of 100 x 10\^9/L and complete resolution of all extramedullary disease. CRi is Peripheral blood and marrow results as for CR, but with incomplete recover of counts (platelets \< 100 x 10\^9/L or neutrophils \< 1 x 10\^9/L).

  Up to 2.5 years

Secondary Outcomes (5)

• Minimal Residual Disease Negativity

  Up to time of relapse, assessed up to 2.5 years

• Relapse-free Survival

  From documented CR/CRi until relapse or death, assessed until study completion

• Event-free Survival

  From the first day of treatment until any treatment failure (lack of response within 6 cycles of treatment, relapse, or death), assessed until study completion

• Overall Survival

  From the first day of treatment to time of death from any cause, assessed until study completion

• Number of Participants Proceeding to Hematopoietic Stem Cell Transplantation

  Up to 2.5 years

Study Arms (2)

Cohort A (Newly Diagnosed AML Patients)

EXPERIMENTAL

INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine; Drug: Trametinib; Drug: Venetoclax

Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)

EXPERIMENTAL

INDUCTION (CYCLE 1): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-28, and trametinib PO QD on days 1-28 in the absence of disease progression or unacceptable toxicity. CONSOLIDATION (CYCLES 2-24): Patients receive azacitidine IV over 30-60 minutes or SC on days 1-7, venetoclax PO QD on days 1-21, and trametinib PO QD on days 1-28. Treatment repeats every 28 days for up to 23 cycles in the absence of disease progression or unacceptable toxicity.

Drug: Azacitidine; Drug: Trametinib; Drug: Venetoclax

Interventions

Azacitidine DRUG

Given IV or SC

Also known as: 5 AZC, 5-AC, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Cohort A (Newly Diagnosed AML Patients); Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Cohort A (Newly Diagnosed AML Patients); Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Cohort A (Newly Diagnosed AML Patients); Cohort B (Relapsed/Refractory AML or higher-risk MDS or CMML Patients)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis:
• Cohort A (frontline): Newly diagnosed AML
• Cohort B (relapsed/refractory): Relapsed/refractory AML or relapsed/refractory MDS or chronic myelomonocytic leukemia (CMML) that is intermediate-2 or high-risk by the International Prognostic Scoring System with \>= 10% blasts harboring a Ras pathway-activating mutation. Eligible mutations include: activating mutations of KIT, HRAS/NRAS/KRAS, BRAF, CBL or PTPN11 or loss of function mutation of NF1. Other mutations not listed here that are anticipated to activate Ras signaling may be considered for enrollment after discussion with the principal investigator (PI)
• Performance status =\< 2 (Eastern Cooperative Oncology Group \[ECOG\] scale)
• Total serum bilirubin =\< 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) =\< 3 x ULN, unless due to the underlying leukemia approved by the PI
• Creatinine clearance \>= 30 mL/min
• Ability to swallow
• Signed informed consent

You may not qualify if:

• Patients suitable for and willing to receive intensive induction chemotherapy (cohort A only)
• Active serious infection not controlled by oral or intravenous antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment)
• Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI
• Consumed strong inducer of CYP3A or p-glycoprotein within 3 days of study enrollment. Agents include but are not limited to: carbamazepine, phenytoin, rifampin, and St. John's wart
• Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry, unless full recovery from side effects has occurred or patient has rapidly progressive disease judged to be life-threatening by the investigator. Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for cytoreduction) permitted
• Pregnant women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception throughout the study period and for at least 6 months after the last dose of study drugs. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 12 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control throughout the study period and for at least 4 months after the last dose of study drugs. Lactating women (or those planning to breastfeed) should not breastfeed during treatment of trametinib and for at least 2 months after the last dose of trametinib

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Links

• M D Anderson Cancer Center

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes

Interventions

Azacitidine; trametinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides

Results Point of Contact

• Title: Nichols Short MD/Associate Professor
• Organization: The University of Texas MD Anderson Cancer Center

NShort@mdanderson.org

713-563-4485

Study Officials

• Nicholas Short

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 21, 2020
• First Posted: July 27, 2020
• Study Start: July 21, 2020
• Primary Completion: February 9, 2023
• Study Completion: January 25, 2024
• Last Updated: April 22, 2025
• Results First Posted: April 22, 2025

Record last verified: 2025-04

Locations

US (1)