A study of AZD2962, an IRAK4 inhibitor, in Participants with Haematologic Neoplasms

Prior treatment

• Prior treatment with IRAK inhibitors or inhibitors of the inflammasome pathway.
• Acute coronary syndrome/myocardial infarction or percutaneous coronary intervention or coronary artery bypass graft within 6 months prior to C1D1.
• Stroke or transient ischaemic attack within 6 months prior to C1D1.
• History of intracranial bleeding within 6 months prior to C1D1
• Active HIV infection. Participants on an effective anti-retroviral therapy and sustained viral load undetectable for at least 6 months prior to enrolment, are eligible after confirmation from the Sponsor. HIV viral load must be monitored while on study per institutional guidance.
• Received any antineoplastic therapy (except hydroxyurea) within 15 days prior to C1D1
• History of a prior non-haematologic neoplasm, except for adequately treated basal cell or squamous cell skin cancer, in situ cancer, or other cancer from which the patient has been disease free with no evidence of recurrence for ≥ 2 years.
• Unresolved Grade ≥ 2 toxicities from prior anticancer therapies except for alopecia, vitiligo, or endocrine disorders controlled with replacement hormone therapy.
• Active GVHD. Topical steroids for GVHD may continue indefinitely
• Received major surgery (as defined by the investigator) within 28 days prior to C1D1, or still recovering from surgery.
• Received immunosuppressive medications (including GVHD prophylaxis) within 28 days prior to C1D1, or within 15 days in the case of systemic steroids (doses exceeding 10 mg/day of prednisone or equivalent).
• Received live attenuated vaccines within 28 days prior to C1D1.
• Symptomatic heart failure (New York Heart Association Grade 2 to Grade 4), or hospitalisation for heart failure within 6 months prior to C1D1.

Other illness

• Any planned revascularisation intervention or severe valvular heart disease.
• Symptomatic and uncontrolled hypertension.
• Serologic status reflecting active hepatitis B or C infection: a. Participants with positive HBsAg will be excluded; b. Participants with anti-HBc IgG Ab positive will be excluded unless they have a negative HBV PCR result before enrolment (in this case HBV PCR will be monitored repeatedly while on study per institutional guidance); c. Participants with positive anti-HCV Ab will be excluded unless they have a negative HCV PCR result before enrolment.
• Active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of oral therapy (eg, ulcerative disease, uncontrolled nausea, vomiting, diarrhoea Grade ≥ 2, and malabsorption).
• Active major bleeding event.

Lab values

• LVEF < 50%.
• Received drugs that are known to prolong QT and with known risk of Torsades de Pointes, within 15 days (or 5 half-lives, whichever is longer) prior to C1D1.
• Any evidence of systemic disease (severe or uncontrolled), significant clinical disorder, or laboratory finding, that make undesirable the participation in the study.

Other

• Mean resting QTcF > 450 ms obtained from triplicate ECGs and averaged, recorded within 5 minutes. In the presence of bundle branch block, QTcF > 470 ms is applicable.

• Participant must be at least 18 (or older as per the legal age of consent in the applicable jurisdiction) at the time of signing the informed consent.
• Patients with R/R MDS or patients with R/R dysplastic CMML, with peripheral blasts or bone marrow blasts < 20%, and who received one or more prior lines of therapy as per standard of care (or who exhausted locally available treatments including treatments for actionable mutations). Note: Participants with dysplastic CMML are only eligible for dose escalation cohort.
• ECOG performance status of ≤ 2.
• Patients must have symptomatic disease that requires therapy and allows for objective efficacy assessments.
• Willing to provide baseline BMA (or biopsy if dry-tap).
• Must meet the following laboratory parameters: a. WBC count ≤ 10.0 x 109/L (MDS patients), or < 13.0 x 109/L (CMML patients). Note: For MDS patients, treatment with hydroxyurea is permitted to lower the WBC to reach this inclusion criterion. The WBC should be determined ≥ 24 hours after the last dose of hydroxyurea; b. ALT and AST ≤ 3 × ULN; c. Serum TBL ≤ 1.5× ULN (≤ 3 × ULN in case of documented Gilbert’s Syndrome); d. Creatinine clearance ≥ 60 mL/min calculated by Cockcroft and Gault method.