Navitoclax in Relapsed or Refractory High-Risk Myelodysplastic Syndrome

Description

This trial was intended to be a Phase 1/2 trial but the trial never moved forward to Phase 2.

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.