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

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05365035
• Other study ID #: 2021-1116
• Secondary ID: NCI-2022-03803
• Status: Recruiting
• Phase: Phase 2
• Start date: September 23, 2022
• Est. completion date: February 1, 2025

Study information

• Verified date: June 2024
• Source: M.D. Anderson Cancer Center
• Contact: Guillermo Bravo, MD
• Phone: (713) 794-3604
• Email: gmontalban1[@]mdanderson.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 60
• Est. completion date: February 1, 2025
• Est. primary completion date: February 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

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. 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.

9. 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.

Related Conditions & MeSH terms

• Anemia, Refractory, with Excess of Blasts
• Leukemia
• Leukemia, Myelomonocytic, Acute
• Leukemia, Myelomonocytic, Chronic
• Leukemia, Myelomonocytic, Juvenile
• Myelodysplastic Syndromes
• Preleukemia
• Syndrome

Intervention

Drug:
• Cladribine
Given by Vein (IV)
• Cytarabine
Given under the skin; subcutaneous injection (SQ)
• Venetoclax
Given by PO
• Azacitidine
Given by IV or subcutaneous injection (SQ)

Locations

Country	Name	City	State
United States	M D Anderson Cancer Center	Houston	Texas

Sponsors (1)

Lead Sponsor	Collaborator
M.D. Anderson Cancer Center

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To establish the overall survival (OS).		through study completion, an average of 1 year

External Links

•   M D Anderson Cancer Center