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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Myelodysplastic Syndromes, Myeloproliferative Chronic Myelomonocytic Leukemia

Intervention / Treatment
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* Drug: Cladribine
* Drug: Cytarabine
* Drug: Venetoclax
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >/= 18 years. 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). Eastern Cooperative Oncology Group (ECOG) performance status of </= 2 Creatinine clearance > 30 ml/min no end/stage renal disease (using Cockcroft-Gault) Adequate hepatic function with total bilirubin 2x ULN, AST or ALT 2.5 xULN unless deemed to be due to underlying disease involvement. Willing to adhere to and comply with all prohibitions and restrictions specified in the protocol. 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. 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: Uncontrolled infection not adequately responding to appropriate antibiotics New York Heart Association (NYHA) Class III or IV congestive heart failure or LVEF <50% by echocardiogram or multigated acquisition (MUGA) scan. History of myocardial infarction within the last 6 months or unstable/uncontrolled angina pectoris or history of severe and/or uncontrolled ventricular arrhythmias. Female patients who are pregnant or lactating. 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. Female patients with reproductive potential who do not have a negative urine or blood beta-human chorionic gonadotropin (beta HCG) pregnancy test at screening. Patients receiving any other concurrent investigational agent or chemotherapy, radiotherapy, or immunotherapy. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: cladribine, cytarabine, venetoclax, and azacitidine<br>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<br>* Given by Vein (IV)<br>* Other names: 2-CdA;Drug: Cytarabine<br>* Given under the skin; subcutaneous injection (SQ)<br>* Other names: Cytosine arabinosine hydrochloride;Drug: Venetoclax<br>* Given by PO<br>* Other names: GDC-0199;Drug: Azacitidine<br>* Given by IV or subcutaneous injection (SQ)<br>* Other names: Ladakamycin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To establish the overall survival (OS). |  | through study completion, an average of 1 year |