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
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.
• 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)
• Activated partial thromboplastin Time (aPTT) ≤ 1.5 x ULN (To be performed within 14 days prior to day 1 of protocol therapy)
• Corrected QT interval by Fredericia (QTcF) ≤ 480 ms based on Fridericia's formula. (To be performed within 14 days prior to day 1 of protocol therapy) Note: To be performed within 28 days prior to day 1 of protocol therapy
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. (To be performed within 14 days prior to day 1 of protocol therapy)
• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 4 months (males) and 7 months (females) after the last dose of protocol therapy
‣ Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)