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

NCT06454409 | Suspended Phase 1 DMC FDA Drug

• 3 other identifiers: 23713NCI-2024-04611P30CA033572
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Myelodysplastic Syndrome/Acute Myeloid Leukemia; Recurrent Acute Myeloid Leukemia; Recurrent Myelodysplastic Syndrome; Refractory Acute Myeloid Leukemia; Refractory Myelodysplastic Syndrome

Outcome Measures

Primary Outcomes (2)

• Dose-limiting toxicity (DLT)

  DLT will be defined as any toxicities classified as at least possibly related to the study treatment, that occur during cycle 1 and will be used for dose escalation/de-escalation/expansion decisions. Toxicity will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0.

  Up to completion of cycle 1 (28 days)

• Incidence of adverse events (AEs)

  AEs will be graded according to the NCI CTCAE v 5.0 and reported by type, frequency, severity, attribution, time course, and duration.

  Up to 30 days after last dose of study drug

Secondary Outcomes (8)

• Complete remission (CR) rate

  Up to 1 year

• Overall response rate (ORR)

  Up to 1 year

• Minimal residual disease (MRD)

  Up to 1 year

• Time to CR

  At first dose of study drug to up to 1 year

• Time to first response

  At first dose of study drug to first documented response up to 1 year

Study Arms (1)

Treatment (regorafenib, venetoclax, azacitidine)

EXPERIMENTAL

Patients receive regorafenib PO QD on days 1-21 of each cycle, venetoclax PO QD on days 1-21 of each cycle, and azacitidine 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.

Drug: Azacitidine; Procedure: Biospecimen Collection; Procedure: Bone Marrow Aspiration; Drug: Regorafenib; Drug: Venetoclax

Interventions

Azacitidine DRUG

Given IV

Also known as: 5 AZC, 5-AC, 5-Azacitidine, 5-Azacytidine, 5-AZC, Azacytidine, Azacytidine, 5-, Ladakamycin, Mylosar, U-18496, Vidaza

Treatment (regorafenib, venetoclax, azacitidine)

Biospecimen Collection PROCEDURE

Undergo blood sample collection

Also known as: Biological Sample Collection, Biospecimen Collected, Specimen Collection

Treatment (regorafenib, venetoclax, azacitidine)

Bone Marrow Aspiration PROCEDURE

Undergo bone marrow aspiration

Treatment (regorafenib, venetoclax, azacitidine)

Regorafenib DRUG

Given PO

Also known as: BAY 73-4506, Regorafenib Anhydrous

Treatment (regorafenib, venetoclax, azacitidine)

Venetoclax DRUG

Given PO

Also known as: ABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, Venclyxto

Treatment (regorafenib, venetoclax, azacitidine)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented informed consent of the participant and/or legally authorized representative
• Age: ≥ 18 years
• Eastern Cooperative Oncology Group (ECOG) ≤ 2
• Patients with histologically confirmed AML, according to World Health Organization (WHO) criteria, with refractory/relapsed (R/R) disease who are ineligible for therapies known to be effective for treatment of their AML
• Patients with extramedullary disease may be included if they also have marrow involvement
• Patients with acute promyelocytic leukemia (APL) will not be eligible
• Patients with R/R myelodysplastic syndrome (MDS)/AML, as defined by the presence of 10 - 19% blasts, are also eligible at the discretion of the principal investigator (PI)
• Fully recovered from the acute toxic effects (except alopecia) to ≤ grade 1 to prior anti-cancer therapy
• Ability to swallow pills
• White blood cells (WBC) ≤ 25 x 10\^9/L prior to initiation of study therapy. Cytoreduction with hydroxyurea prior to treatment and/or during cycle 1 may be required (To be performed within 14 days prior to day 1 of protocol therapy)
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (To be performed within 14 days prior to day 1 of protocol therapy)
• Aspartate aminotransferase (AST) ≤ 3.0 x ULN (To be performed within 14 days prior to day 1 of protocol therapy)
• Alanine aminotransferase (ALT) ≤ 3.0 x ULN (To be performed within 14 days prior to day 1 of protocol therapy)
• Creatinine clearance of ≥ 45 mL/min per 24 hour urine test or the Cockcroft-Gault formula (To be performed within 14 days prior to day 1 of protocol therapy)
• International normalized ratio (INR) OR Prothrombin (PT) ≤ 1.5 x ULN (To be performed within 14 days prior to day 1 of protocol therapy)

You may not qualify if:

• Hematopoietic stem cell transplant within 100 days prior to day 1 of protocol therapy
• Chemotherapy, radiation therapy, biological therapy, immunotherapy within 14 days or five half-lives (whichever is shorter) prior to day 1 of protocol therapy with the following exceptions:
• Subjects will be allowed to have been on venetoclax and/or azacitidine at screening and remain on it through treatment start
• Hydroxyurea is allowed prior to treatment and through cycle 1 for control of rapidly progressing leukemia
• Strong and moderate CYP3A4 inducers and strong CYP3A inhibitors within 7 days prior to day 1 of protocol therapy
• Foods/supplements that are strong inhibitors or strong or moderate inducers of CYP3A (such as grapefruit, Seville oranges, starfruit and St. John's wort) within 3 days prior to initiation of and during study treatment
• Systemic steroid therapy \> 10 mg/day (≤ 10mg/day prednisone equivalent ok) or any other form of immunosuppressive medication within 14 days. Inhaled or topical steroids, and adrenal replacement steroid doses ≤ 10 mg daily prednisone equivalent, are permitted. Steroids given for infusion prophylaxis or infusion reactions should not count towards this maximum
• Must not have received or planning to receive live vaccine while being on study or 4 weeks before and after completion of treatment
• Evidence or history of bleeding diathesis or coagulopathy
• Subjects with thrombotic, embolic, venous, or arterial events, such as cerebrovascular accident (including transient ischemic attacks) deep vein thrombosis or pulmonary embolism within 6 months of start of study treatment within 6 months of informed consent
• Presence of a non-healing wound, non-healing ulcer, or bone fracture
• Major surgical procedure or significant traumatic injury within 28 days before start of study medication
• Pleural effusion or ascites that causes respiratory compromise ( ≥ National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI-CTCAE\] version 5.0 grade 2 dyspnea)
• Patients with blast phase chronic myeloid leukemia (CML)
• Patients with t(15;17) karyotypic abnormality or acute promyelocytic leukemia (French-American-British \[FAB\] class M3-AML)

Sponsors & Collaborators

• City of Hope Medical Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

City of Hope Medical Center

Duarte, California, 91010, United States

Location

MeSH Terms

Conditions

GATA2 Deficiency; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes

Interventions

Azacitidine; Specimen Handling; regorafenib; venetoclax

Condition Hierarchy (Ancestors)

Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Investigative Techniques

Study Officials

• Paul Koller

  City of Hope Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 6, 2024
• First Posted: June 12, 2024
• Study Start: May 21, 2025
• Primary Completion (Estimated): September 6, 2030
• Study Completion (Estimated): September 6, 2030
• Last Updated: November 19, 2025

Record last verified: 2025-11

Locations

US (1)