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

Sponsor
M.D. Anderson Cancer Center (Other)
Overall Status
Not yet recruiting
CT.gov ID
NCT05365035
Collaborator
(none)
60
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1
15.1
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Study Details

Study Description

Brief Summary

To learn if the combination of cladribine, cytarabine, venetoclax, and azacitidine can help to control higher-risk myelodysplastic syndrome (MDS) with excess blasts and/or higher-risk chronic myelomonocytic leukemia (CMML).

Detailed Description

Primary Objectives:
  • To determine the efficacy, safety and tolerability of the combination of cladribine, cytarabine and venetoclax in higher-risk MDS with excess blasts and higher-risk CMML.

  • MDS relapsed cohort (Cohort A, N=20): MDS with Int-2 or High risk IPSS and >5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine, CC-486 or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles

  • CMML relapsed cohort (Cohort B, N=10): CMML 1 or 2 with no response after 6 cycles of azacitidine, decitabine, guadecitabine, CC-486 or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles

  • MDS HMA-naïve cohort (Cohort C, N=20): MDS with Int-2 or High risk by IPSS and >10% blasts OR diagnosis

  • CMML HMA-naïve cohort (Cohort D, N=10): CMML-2; OR CMML-1 with at least one of the following high-risk features: extramedullary disease, splenomegaly of >5cm below costal margin, platelets <100x109/L, Hgb level <10g/dL, WBC >13x109/L, clonal cytogenetic abnormality (other than monosomy Y).

Secondary Objectives:
  • To assess overall survival (OS), duration of response, leukemia-free survival (LFS), and relapse-free survival (RFS).

  • To evaluate proportion of transplant-candidate patients bridged to allogeneic stem-cell transplant.

  • Correlative studies including correlation of response with disease subtype and genomic profile.

  • To evaluate changes in clonal composition and VAF of identified mutations with therapy.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
60 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Anticipated Study Start Date :
Oct 30, 2022
Anticipated Primary Completion Date :
Feb 1, 2024
Anticipated Study Completion Date :
Feb 1, 2024

Arms and Interventions

Arm Intervention/Treatment
Experimental: cladribine, cytarabine, venetoclax, and azacitidine

Participants will receive cladribine, cytarabine, and venetoclax for 2 cycles and then azacitidine and venetoclax for 2 cycles. Participants will repeat this pattern of 2 cycles each for up to a total of 18

Drug: Cladribine
Given by Vein (IV)
Other Names:
  • Leustatin®
  • 2-CdA
  • Drug: Cytarabine
    Given under the skin; subcutaneous injection (SQ)
    Other Names:
  • Ara-C
  • Cytosar®
  • DepoCyt™
  • Cytosine arabinosine hydrochloride
  • Drug: Venetoclax
    Given by PO
    Other Names:
  • ABT-199
  • GDC-0199
  • Drug: Azacitidine
    Given by IV or subcutaneous injection (SQ)
    Other Names:
  • 5-azacytidine
  • 5-aza
  • Vidaza™
  • 5-AZC
  • AZA-CR
  • Ladakamycin
  • Outcome Measures

    Primary Outcome Measures

    1. To establish the overall survival (OS). [through study completion, an average of 1 year]

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Age >/= 18 years.

    2. Diagnosis of MDS or CMML by WHO and:

    • MDS relapsed cohort (Cohort A): MDS with Int-2 or High risk IPSS and >5% blasts with no response after 6 cycles of azacitidine, decitabine, guadecitabine, CC-486 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, CC-486 or ASTX727 (decitabine/cedazuridine) or relapse or progression after any number of cycles

    • MDS HMA-naïve cohort (Cohort C): MDS with Int-2 or High risk by IPSS and >10% blasts OR diagnosis

    • 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, platelets <100x109/L, Hgb level <10g/dL, WBC >13x109/L, clonal cytogenetic abnormality (other than monosomy Y).

    1. Eastern Cooperative Oncology Group (ECOG) performance status of </= 2

    2. Creatinine clearance > 30 ml/min no end/stage renal disease (using Cockcroft-Gault)

    3. Adequate hepatic function with total bilirubin 2x ULN, AST or ALT 2.5 xULN unless deemed to be due to underlying disease involvement.

    4. Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol.

    5. Patient (or patient's legally authorized representative) 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.

    6. White blood cell (WBC) count <50,000/L. Hydroxyurea may be used to control leukocytosis prior to C1D1. Use of hydroxyurea beyond this point may be permitted as clinically indicated, on a case-by-case basis and after discussion with the PI.

    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.

    8. Patients known to be positive for hepatitis B surface antigen expression or with active hepatitis C infection (positive by polymerase chain reaction or on antiviral therapy for hepatitis C within the last 6 months). Patients with history of HIV disease are also excluded from the study.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 M D Anderson Cancer Center Houston Texas United States 77030

    Sponsors and Collaborators

    • M.D. Anderson Cancer Center

    Investigators

    • Principal Investigator: Guillermo Bravo, MD, M.D. Anderson Cancer Center

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    None provided.
    Responsible Party:
    M.D. Anderson Cancer Center
    ClinicalTrials.gov Identifier:
    NCT05365035
    Other Study ID Numbers:
    • 2021-1116
    • NCI-2022-03803
    First Posted:
    May 6, 2022
    Last Update Posted:
    May 6, 2022
    Last Verified:
    May 1, 2022

    Study Results

    No Results Posted as of May 6, 2022