Study of Orally Administered CA-4948(IRAK4i) as a Monotherapy in patients with Acute Myelogenous Leukemia or Myelodysplastic Syndrome

Prior treatment

• Viral Infections: a. Known to be human immunodeficiency virus (HIV) positive or have an acquired immunodeficiency syndrome-related illness. If HIV virus is undetectable and maintained on treatment, enrollment may be allowed after discussion with the Sponsor b. Hepatitis B virus (HBV) DNA positive or hepatitis C virus (HCV) infection < 6 months prior to start of CA-4948 unless viral load is undetectable, or HCV with cirrhosis Note: testing only required in patients with history of HBV or history of HCV < 6 months prior to start of CA-4948.
• Known active central nervous system (CNS) leukemia; patients with previously treated CNS disease may participate if asymptomatic as determined by treating physician (without symptomatic active disease for at least 4 weeks prior to the first dose of treatment, and any neurologic symptoms have returned to baseline)
• Allogeneic SCT within 60 days of the first dose of CA 4948, or clinically significant graft-versus-host disease (GVHD) requiring ongoing up titration of immunosuppressive medications prior to start of CA-4948 Note: The use of a stable or tapering dose of immunosuppressive therapy post-SCT and/or topical steroids for ongoing skin GVHD is permitted with Medical Monitor approval.
• Any prior systemic anti-cancer treatment such as chemotherapy, immunomodulatory drug therapy, etc, received within 3 weeks (or 5 half-lives), whichever is shorter, or radiotherapy received 2 weeks prior to the start of CA-4948. Note: Localized radiation or surgical resection of skin cancers is allowed.
• Use of any investigational agent within 3 weeks (or 5 half-lives), whichever is shorter, prior to start of CA 4948
• Presence of an acute or chronic toxicity resulting from prior anti-cancer therapy, with the exception of alopecia that has not resolved to Grade ≤ 1, as determined by NCI-CTCAE v 4.03 within 7 days prior to start of CA-4948, unless approved by the Medical Monitor
• Major surgery, other than diagnostic surgery, < 28 days from the start of CA-4948; minor surgery < 14 days from the start of CA-4948 Note: Insertion of a vascular access device is not considered minor surgery.

Other illness

• Patients with active advanced malignant solid tumors
• History of ≥ Grade 3 rhabdomyolysis without complete recovery
• Known allergy or hypersensitivity to any component of the formulation of CA-4948 used in this study

Lab values

• Concomitant illnesses that would preclude safe participation in study, identified within approximately 28 days of C1D1, including: a. Uncontrolled or severe cardiovascular disease, including myocardial infarction or unstable angina within 6 months prior to CA-4948, New York Heart Association Class II or greater congestive heart failure, or left ventricular ejection fraction < 50% by echocardiogram or multi-gated acquisition scan, serious arrhythmias uncontrolled on treatment, clinically significant pericardial disease, cardiac amyloidosis, congenital long QT syndrome, or QTc with Fridericia’s correction (QTcF) that is unmeasurable or > 450 msec on Screening electrocardiogram (ECG) Note: for QTcF > 450 msec on the Screening ECG, the ECG may be repeated twice at least 24 hours apart; the mean QTcF from the 3 Screening ECGs must be ≤ 450 msec in order to meet eligibility for study participation. Patients with bundle branch block and/or ventricular paced rhythms should be reviewed by the Medical Monitor for potential inclusion. b. Gastrointestinal disease or disorder that could interfere with the swallowing, oral absorption, or tolerance of CA-4948. This includes major abdominal surgery and/or significant bowel resection and/or gastrointestinal diseases that could alter the assessment of PK or safety c. Any other severe, acute, or chronic medical, psychiatric or social condition, or laboratory abnormality that may increase the risk of study participation or CA-4948 administration, may interfere with the informed consent process and/or with compliance with the requirements of the study or may interfere with the interpretation of the study results and, in the Investigator's opinion, would make the patient inappropriate for entry into this study d. Systemic fungal, bacterial, viral, or other infection that is not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)

Other

• Diagnosed with acute promyelocytic leukemia (APL, M3)
• Pregnant or lactating
• Chronic myelogenous leukemia

• Males and females >=18 years of age
• Negative serum pregnancy test in women of childbearing potential (WOCP)
• WOCP and men who partner with a WOCP must agree to use highly effective contraceptive methods for the duration of the study and for 180 days after the last dose of CA-4948
• Willing and able to provide written informed consent and comply with the requirements of the study
• Biopsy requirement for AML and MDS: patients must be willing to have serial bone marrow sampling and peripheral blood sampling during the study. The diagnosis and evaluation of AML and MDS will be made by bone marrow aspiration and/or biopsy. If an aspirate is unobtainable (ie, a “dry tap”), the diagnosis is made from the core biopsy.
• Life expectancy of at least 3 months
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
• Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization 2016 classification) with the following characteristics: -Phase 1 Dose Escalation Patients that meet 1 of the following criteria: • R/R AML with FLT3 mutations who have been previously treated with a FLT3 inhibitor • R/R AML with spliceosome mutations of SF3B1 or U2AF1 • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 And • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)
• Cytomorphology based confirmed diagnosis of MDS or AML (as per the World Health Organization 2016 classification) with the following characteristics: Phase 2a Dose Expansion Patients with: • R/R AML with FLT-3 mutations who have been previously treated with a FLT3 inhibitor • R/R AML with spliceosome mutations of SF3B1 or U2AF1 • R/R hrMDS (IPSS-R score > 3.5) with spliceosome mutations of SF3B1 or U2AF1 And • Have had ≤ 2 lines of prior systemic anti-cancer treatment (see Appendix M for guidelines)
• Acceptable organ function at Screening as described below: a. Estimated creatinine clearance of ≥ 35 mL/min b. Aspartate aminotransferase or alanine aminotransferase ≤ 2 × ULN c. Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN in patients with documented Gilbert’s syndrome d. White blood cell count ≤ 25,000/µL (hydroxyurea is allowed during Screening and Cycle 1 for cytoreduction, if needed, for patients with AML per Investigator’s discretion. However, hydroxyurea must stop prior to Cycle 2)
• CPK < Grade 2
• For patients on a cholesterol lowering agent that has been associated with CPK elevations, such as statins or fibrates, the agent should be discontinued or replaced with an alternative if medically feasible. Otherwise, it should be reduced to the lowest dose that is biologically effective (ie, the lowest dose required to achieve the desired clinical effect).
• Ability to swallow and retain oral medications