An Open-label, Phase II Study of AZD4635 in Patients with Prostate Cancer

Exclusion Criteria

• for all Participants in all Modules:
• 1. History or presence of another primary invasive malignancy except for: malignancy treated with curative intent and with no known active disease ≥2 years before the first dose of study drug and of low potential risk for recurrence; adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease; adequately treated carcinoma in situ without evidence of disease; localized non-invasive primary carcinoma under surveillance
• 2. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant small bowel resection that would preclude adequate absorption of AZD4635.
• 3. Previously untreated brain metastases. Participants who have received radiation or surgery for brain metastases are eligible if therapy was completed at least 21 days previously and there is no evidence of central nervous system (CNS) disease progression or mild neurologic symptoms.
• 4. With the exception of alopecia, lymphopenia, and hypothyroidism, any unresolved toxicities from prior therapy greater than National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v5.0) Grade 1 at the time of starting study treatment
• 5. Participants with prior ≥ Grade 3, serious, or life threatening immune-mediated reactions following prior anti-PD-1, anti-PD-L1, or other immuno-oncology therapies.
• 6. Prior history of myocardial infarction, transient ischemic attack, or stroke in the last 3 months
• 7. Participants must have normotensive or well controlled blood pressure (<150/90), with or without current antihypertensive treatment. If there is a diagnosis or history of hypertension, participant must have adequately controlled blood pressure on antihypertensive medications, as demonstrated by 2 blood pressure measurements taken in the clinical setting by a medical professional within 1 week prior to enrollment. Patients on a hypertensive medication must be willing and able to measure and record blood pressure readings twice-daily for a minimum of 3 weeks.
• 8. As judged by the Investigator or Medical Monitor, any evidence of severe or uncontrolled systemic diseases, including active bleeding diatheses, or active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice), hepatitis B virus [known positive HBV surface antigen (HBsAg) result], hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies), or active hepatitis A. Participants with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Participants positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. Screening for chronic conditions is not required.
• 9. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis, Crohn's disease], diverticulitis, celiac disease, systemic lupus erythematous, Wegener's syndrome, myasthenia gravis, Grave's disease, rheumatoid arthritis, hypophysitis, uveitis, autoimmune pneumonitis, autoimmune nephritis or nephropathy, etc.) within the past 3 years prior to the start of treatment. The following are exceptions to this criterion: a) vitiligo or alopecia, b) hypothyroidism (e.g., following Hashimoto's disease) stable on hormone replacement, c) psoriasis or eczema not requiring systemic therapy for disease control, d) celiac disease controlled by diet alone.
• 10. Prior/concomitant therapy with AZD4635 or any other A2AR antagonist.
• 11. Ongoing corticosteroid use, at doses above physiologic replacement therapy. The following are exceptions to this criterion: a) use of intranasal, inhaled, topical orticosteroids, local steroid injections (e.g. intra-articular injections), b) steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication) are permitted, c) systemic corticosteroids at physiologic doses below 10 mg/day of prednisone or equivalent.
• 12. The following intervals between the end of the prior treatment and first dose of study drug must be observed: a) anticancer therapy: ≥21 days or 5 half-lives (whichever is shorter) of the first dose of study drug. At least 7 days must have elapsed between the last dose of such agent and the first dose of study drug. (Exception: androgen-deprivation therapy is required to maintain castrate levels of testosterone (˂50 ng/dL), b) concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.
• 13. Major surgery (as defined by the Medical Monitor, excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
• 14. Minor surgical procedures (as defined by the Medical Monitor) within 7 days of the first dose of study treatment.
• 15. Participant is receiving medications or other products known to be sensitive breast cancer resistance protein (BCRP) or organic anion transporter polypeptide 1 (OATP1B1), OATP1B3, organic anionic transporter 1 (OAT1), organic cation transporter 1 (OCT1), OCT2, multidrug and toxin extrusion protein 1 (MATE1) and P glycoprotein (P-gp) substrates or potent or moderate inhibitors/inducers of CYP1A2, which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of AZD4635.
• 16. Concomitant medications with another A1R antagonist that would increase risk of seizure (e.g., theophylline, aminophylline).
• 17. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment
• 18. Ongoing treatment with Coumadin
• 19. Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug
• 20. Herbal preparations/medications are not allowed throughout the study, including but not limited to: St. John’s wort, kava, ephedra (ma huang), ginkgo biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Participants should stop using these herbal medications 7 days prior to the first dose of AZD4635. Exceptions may be agreed upon, but the circumstances must be reviewed by the Medical Monitor in advance.
• 21. Radiotherapy with a wide field of radiation within 4 weeks or radiotherapy with a limited field of radiation for palliation within 2 weeks, of the first dose of study treatment.
• 22. Enrollment into another therapeutic clinical trial. (Exception: Participants are allowed to participate in investigational imaging or non-interventional studies.)
• 23. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or class to AZD4635.
• 24. Any of the following cardiac criteria:
• ● Mean resting corrected QT interval (QTcF) >470 msec obtained from 3 ECGs
• ● Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECGs, e.g., complete left bundle branch block, third degree heart block
• ● Any concomitant medication with known QT interval prolongation. Participants receiving a medication(s) known to prolong the QT interval may be discussed with the Medical Monitor or Sponsor for study approval.
• ● Ejection fraction <55% or the lower limit of normal of the institutional standard
• 25. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values:
• ● Absolute neutrophil count <1.5 x 10⁹/L
• ● Platelet count <100 x 10⁹/L
• ● Hemoglobin <9.0 g/dL
• ● Alanine aminotransferase (ALT) >2.5 times the upper limit of normal (ULN) if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
• ● Aspartate aminotransferase (AST) >2.5 times ULN if no demonstrable liver metastases or >5 times ULN in the presence of liver metastases
• ● Total bilirubin (TBL) >1.5 times ULN
• ● Creatinine >1.5 times ULN concurrent with creatinine clearance <50 mL/min (measured or calculated by Cockcroft and Gault equation); confirmation of creatinine
• clearance is only required when creatinine is >1.5 times ULN.
• 26. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff and its representatives and/or staff at the study site).
• 27. Judgment by the Investigator or Medical Monitor that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions and
• requirements.
• 28. Participation in another clinical interventional study or if participant has already received at least one dose of study drug in the present study
• Exclusion Criteria for Module 1:
• 1. Prior exposure to immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, and anti-PD-L2 antibodies, excluding therapeutic anticancer vaccines.
• 2. History of active primary immunodeficiency.
• 3. Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis testing in line with local practice)
• Exclusion Criteria for Module 2:
• 1. Prior receipt of any immune-mediated therapy including, but not limited to, other anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies and agents targeting CD73, CD39, or
• adenosine receptors, excluding therapeutic anticancer vaccines.
• 2. Known history of allergy or reaction to any component of oleclumab formulation or history of anaphylaxis to any human gammaglobulin therapy.
• 3. History of venous thrombosis within the past 3 months.