Combination treatment for higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia

A Phase II Study of Cladribine and Low Dose Cytarabine in Combination With Venetoclax, Alternating With Azacitidine and Venetoclax, in Patients With Higher-risk Myeloproliferative Chronic Myelomonocytic Leukemia or Higher-risk Myelodysplastic Syndromes With Excess Blasts

This study is testing a new combination of four medications to see if it can help people with higher-risk myelodysplastic syndromes and chronic myelomonocytic leukemia live longer and respond better to treatment.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: M.D. Anderson Cancer Center (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy
• Locations: 1 site (Houston, Texas)
• Trial ID: NCT05365035 on ClinicalTrials.gov

What this trial studies

This clinical trial evaluates the effectiveness and safety of a combination therapy involving cladribine, cytarabine, venetoclax, and azacitidine in patients with higher-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). The study includes different cohorts based on prior treatment responses and disease characteristics, aiming to assess overall survival, duration of response, and the potential for patients to be bridged to allogeneic stem-cell transplant. Participants will undergo a series of treatments while their disease response and genetic profiles are monitored.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18 and older with higher-risk MDS or CMML, particularly those who have not responded to previous therapies.

Not a fit: Patients with lower-risk MDS or CMML, or those who have not yet received treatment, may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could provide a new effective option for patients with higher-risk MDS and CMML who have limited treatment alternatives.

How similar studies have performed: Other studies have shown promising results with similar combination therapies in treating hematological malignancies, suggesting potential for success in this approach.

Eligibility criteria

Inclusion Criteria:

1. Age \>/= 18 years.
2. Diagnosis of MDS or CMML by WHO and:

   * MDS relapsed cohort (Cohort A): MDS with IPSS-R score \>3.5 and \>5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
   * CMML relapsed cohort (Cohort B): CMML 1 or 2 with no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
   * MDS HMA-naïve cohort (Cohort C): MDS with IPSS-R score \>3.5 and \>/= 10% blasts
   * CMML HMA-naïve cohort (Cohort D): CMML-2; OR CMML-1 with at least one of the following high-risk features: extramedullary disease, splenomegaly of \>5cm below costal margin or by sonographic volumetric assessment, platelets \<100x109/L, Hgb level \<10g/dL, WBC \>13x109/L, clonal cytogenetic abnormality (other than monosomy Y) or high risk mutations (ASXL1, RUNX1, SETBP1, BRAF, NRAS, KRAS, PTPN11, NF1, CBL).
   * MDS/MPN relapsed cohort (Cohort E): MDS/MPN-NOS, MDS/MPN with neutrophilia (atypical CML) or MDS/MPN-RS-T with \>5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles
   * MDS/MPN HMA-naïve cohort (Cohort F): MDS/MPN-NOS or MDS/MPN with neutrophilia (atypical CML) with

     * \>/=10% blasts or
     * with \>5% blasts at least one of the following high-risk features: splenomegaly \>5cm below costal margin, WBC \>13x109/L, high risk cytogenetic or molecular features (ASXL1, SETBP1, i(17q), TP53) or
     * who might not be deemed to benefit from HMA therapy due to proliferative or extramedullary disease.
3. Eastern Cooperative Oncology Group (ECOG) performance status of \</= 2
4. Creatinine clearance \> 30 ml/min no end/stage renal disease (using Cockcroft-Gault)
5. Adequate hepatic function with total bilirubin 2x ULN, AST or ALT 2.5 xULN unless deemed to be due to underlying disease involvement.
6. Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol.
7. Patient must have signed an informed consent document indicating that the patient understands the purpose of and procedures required for the study and is willing to participate in the study.
8. English and Non-English speaking patients will be allowed

Exclusion Criteria:

1. Uncontrolled infection not adequately responding to appropriate antibiotics
2. New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF \<50% by echocardiogram or multigated acquisition (MUGA) scan.
3. History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias.
4. Female patients who are pregnant or lactating.
5. Patients with reproductive potential who are unwilling to following contraception requirements (including condom use for males with sexual partners, and for females: prescription oral contraceptives \[birth control pills\], contraceptive injections, intrauterine devices \[IUD\], double-barrier method \[spermidical jelly or foam with condoms or diaphragm\], contraceptive patch, or surgical sterilization) throughout the study.
6. Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening.
7. Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy.

Where this trial is running

Houston, Texas

• M D Anderson Cancer Center — Houston, Texas, United States (Recruiting)

Study contacts

• Principal investigator: Guillermo Bravo, MD — M.D. Anderson Cancer Center
• Study coordinator: Guillermo Bravo, MD

Conditions Myelodysplastic Syndromes; Myeloproliferative Chronic Myelomonocytic Leukemia