Regorafenib in Combination With Venetoclax and Azacitidine for the Treatment of Patients With Relapsed or Refractory Acute Myeloid Leukemia

Refractory Acute Myeloid Leukemia Clinical Trial

Official title: A Phase 1b Study of the Multi-Kinase Inhibitor Regorafenib in Combination With the BCL-2 Inhibitor Venetoclax Plus Azacitidine in Patients With Relapsed/Refractory Acute Myeloid Leukemia

Status Not yet recruiting

Clinical Trial Summary

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

Clinical Trial Description

PRIMARY OBJECTIVES:

I. Evaluate the safety and tolerability of the multikinase inhibitor regorafenib in combination with the BCL2 inhibitor/BH3-mimetic venetoclax plus the hypomethylating agent azacitidine in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML).

II. Determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of regorafenib when co- administered with venetoclax and azacitidine.

SECONDARY OBJECTIVES:

I. Evaluate the anti-leukemic activity, as assessed by overall response rate (ORR: complete remission [CR] + CR with incomplete hematologic recovery [CRi] + CR with partial hematologic recovery [CRh] + partial remission [PR]) within the first 28 days (cycle 1).

II. Evaluate the anti-leukemic activity, as assessed by complete remission (CR+CRi+CRh), overall response (ORR: CR+CRi+CRh+PR) and minimal residual disease (MRD)- rate and duration over the study period.

III. Estimate overall survival (OS), progression-free survival (PFS) and duration of response (DOR) rate at 6 months and 1 year.

EXPLORATORY OBJECTIVES:

I. Determine biomarkers that may be predictive of regorafenib activity in this combination.

II. To evaluate expression levels of VEGF, phosphatidylinositol-glycan (PIG), and soluble (s)VEGFR2 pre and post-treatment.

III. To evaluate changes in angiogenesis and inflammation pre and post treatment by gene expression.

IV. To characterize gene expression changes, including genes involved in the RAS/MAPK pathway, by ribonucleic acid (RNA) sequencing pre and post treatment with regorafenib when co-administered with venetoclax and azacitidine.

V. To evaluate changes in the gene mutation status of leukemic cells before and after treatment with regorafenib, azacitidine, and venetoclax.

VI. Evaluate changes to phosphorylated (phospho)-ERK after treatment with combination therapy.

OUTLINE: This is a dose-escalation study of regorafenib in combination with venetoclax and azacitidine followed by a dose-expansion study.

Patients receive regorafenib orally (PO) once daily (QD) on days 1-21 of each cycle, venetoclax PO QD on days 1-21 of each cycle, and azacitidine intravenously (IV) over 10-40 minutes on days 1-7 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration during screening and on study as well as blood sample collection on study.

After completion of study treatment, patients are followed up at 30 days then every 3 months for up to 1 year. ;

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute
• Myelodysplastic Syndromes
• Preleukemia
• Recurrence
• Recurrent Acute Myeloid Leukemia
• Recurrent Myelodysplastic Syndrome
• Refractory Acute Myeloid Leukemia
• Refractory Myelodysplastic Syndrome
• Syndrome

• NCT number: NCT06454409
• Study type: Interventional
• Source: City of Hope Medical Center
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: March 20, 2025
• Completion date: February 17, 2027