Evaluating Navitoclax After Failure of Standard Treatments of Azacitidine or Decitabine and Venetoclax in Patients With Aggressive Myelodysplastic Syndrome

Myelodysplastic Syndrome Clinical Trial

Official title: A Phase Ib/II Study Evaluating Navitoclax After Failure of Hypomethylating Agent and Venetoclax for Treatment of Relapsed or Refractory High-Risk Myelodysplastic Syndrome

Status Recruiting

Clinical Trial Summary

This phase Ib/II trial tests the safety, side effects, and best dose of navitoclax in combination with venetoclax and decitabine in treating patients with higher risk myelodysplastic syndrome (MDS) that has come back after initial treatment or was not responsive to initial treatment. This study will also look at the effectiveness of the treatment combination and patient's quality of life while on these medications. Navitoclax is an oral drug that works as an inhibitor of the BCL-2 family of proteins, which are often overly expressed in a wide variety of cancers and are linked to tumor drug resistance. This drug blocks some of the enzymes that keep cancer cells from dying. Venetoclax is an oral drug that works as an inhibitor of BCL-2 proteins that works very similarly to navitoclax by blocking the action of a certain proteins in the body that helps cancer cells survive which helps to kill cancer cells. Decitabine is an intravenous drug. It is a hypomethylating agent which means it interferes with deoxyribonucleic acid (DNA) methylation. DNA methylation is a major factor that regulates gene expression in cells, and an increase in DNA methylation can block the genes that regulate cell division and growth. When these genes are blocked the overall result allows or promotes cancer as there is no control over cell growth. Decitabine stops cells from making DNA and may kill cancer cells. Participation in this trial may improve the understanding of both chemotherapy response in MDS and mechanisms of resistance to current therapies.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. To determine the safety profile leading to a recommended phase II dose (RP2D) of navitoclax in combination with venetoclax and decitabine. (Phase I) II. To evaluate the efficacy of combination therapy navitoclax, venetoclax and decitabine in patients with relapsed or refractory high-risk MDS after failure of hypomethylating agent and venetoclax. (Phase II)

SECONDARY OBJECTIVE:

I. To further evaluate the safety profile navitoclax in combination with venetoclax and decitabine. (Phase II)

EXPLORATORY OBJECTIVES:

I. To determine relative expression levels of anti-apoptotic BCL-2 family members at baseline and after triplet therapy by intracellular flow cytometry to determine predictive value for response.

II. To compare single cell gene expression at baseline and after triplet therapy.

OUTLINE: This is a phase Ib, dose-escalation study of navitoclax followed by a phase II study.

NAVITOCLAX, VENETOCLAX, & DECITABINE:

CYCLE 1: Patients receive navitoclax orally (PO) once daily (QD) on days 3-16 in combination with venetoclax PO QD on days 1-16, and decitabine intravenously (IV) on days 3-7. This cycle continues for 30 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow biopsy at baseline and day 30, and collection of blood samples at baseline and on days 1 and 15 of cycle.

CYCLE 2 AND BEYOND: Patients receive navitoclax PO QD on days 1-14 of each cycle in combination with venetoclax PO QD on days 1-14 of each cycle, and decitabine IV on days 1-5 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. After 6 cycles, patients who achieve a complete response (CR) or marrow complete response (mCR) continue on treatment in the absence of disease progression or unacceptable toxicity. After 6 cycles, patients who have hematologic improvement but who do not attain CR or mCR may continue treatment at the discretion of their treating physician in conjunction with the principal investigator (PI). Patients also undergo bone marrow biopsy on day 28 of cycles 2 and 4 and at end of treatment, as well as collection of blood samples on day 1 of each cycle and at the end of treatment.

After completion of study treatment, patients are followed every 3 months for 12 months. For survival follow-up, patients are followed for 2 years from enrollment of the last patient. ;

Related Conditions & MeSH terms

• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Preleukemia
• Recurrent Myelodysplastic Syndrome
• Refractory Myelodysplastic Syndrome
• Syndrome

• NCT number: NCT05564650
• Study type: Interventional
• Source: Thomas Jefferson University
• Contact: Gina Keiffer, MD
• Phone: 215-503-0432
• Email: gina.keiffer@jefferson.edu
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 12, 2023
• Completion date: July 2025