An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer
Condition: Prostate Cancer; Metastatic Castration-Resistant Prostate Cancer (mCRPC)
MeSH terms: Prostatic Neoplasms
Intervention: AZD4635; Oleclumab; Durvalumab
Intervention description: In Module 1, participants will receive AZD4635 75 mg capsule orally QD for first 14 days and thereafter will continue to receive 75 mg orally QD Q4W.
In Module 2, participants will receive AZD4635 50 mg / 75 mg capsule orally QD Q2W of 28-day cycle for the first 4 doses and Q4W thereafter.
In both modules, participants will receive treatment until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.; In Module 2, participants will receive oleclumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q2W of 28-day cycle for the first 4 doses and Q4W thereafter until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.; In Module 1 after monotherapy of AZD4635, participants will receive durvalumab 1500 mg IV (solution for infusion after dilution, 50 mg/mL) Q4W until will derive clinical benefit as judged by the investigator or until confirmed disease progression, unacceptable toxicity, started alternative anticancer therapy, withdrawal of consent, or lost to-follow-up, whichever occurs first.
Intervention MeSH terms: Durvalumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 59.0
Sex: Male
Minimum age: 18 Years
Maximum age: 130 Years
Healthy volunteers: No
Keywords: Prostate cancer; AZD4635; oleclumab; durvalumab; MEDI9447; Adenosine 2A Receptor Antagonist; A2AR

Summary:

      This is an open-label Phase II modular study in participants with prostate cancer which will
      assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic
      agents in different treatment arms (referred to as modules).

      Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2:
      AZD4635 plus oleclumab.
    

Eligibility criteria:

        Inclusion Criteria for all Patients in all Modules:

          1. Provision of signed and dated, written informed consent form prior to any mandatory
             study specific procedures, sampling, and analyses

          2. Participant must be ≥18 years of age at the time of signing the inform consent form
             (ICF)

          3. Participants must have prostate cancer with histological or cytological confirmation

          4. Participants must have previously received and progressed on standard-of-care
             therapy(ies)

          5. Participants must be able to provide an archival tumor tissue sample. If archival
             tumor tissue is not available, then tissue from a fresh tumor biopsy is required.

          6. All participants will be required to have a site of disease that is safely accessible
             for biopsy (paired) upon enrollment unless there are sufficient paired samples for the
             analysis. Accessible lesions are defined as those which are biopsiable (at screening)
             and amenable to repeat biopsy (after 2 weeks of AZD4635 therapy), unless clinically
             contraindicated. The provision of paired biopsies will be closely monitored to ensure
             the desired number of biopsiable participants are enrolled and investigators are aware
             of this requirement at all times.

          7. Participants with measurable disease must have at least 1 documented lesion on either
             a bone scan or a computed tomography (CT)/ magnetic resonance imaging (MRI) scan that
             can be followed for response and is suitable for repeated measurement, or participants
             with non-measurable disease must have measurable PSA ≥1.0 ng/mL if the confirmed rise
             is the only indication of progression (excluding small cell carcinoma) 8 Eastern
             Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no clinical
             deterioration over the previous 2 weeks prior to the 28-day screening period and
             likely able to complete at least 12 weeks of treatment.

        9. Ability to swallow and retain oral medication. 10. Must have life expectancy of at least
        12 weeks 11. Body weight ≥ 35 kg at screening 12. Willingness to adhere to the study
        treatment-specific contraception requirements: Participants must be surgically sterile or
        using an acceptable method of contraception (defined as barrier methods in conjunction with
        spermicides) for the duration of the study (from the time they sign ICF) and for 3 months
        after the last dose of AZD4635 to prevent pregnancy in a female partner. Male participants
        must not donate or bank sperm for 24 weeks after treatment.

        Inclusion Criteria for Modules 1 and 2:

          1. Participants must have metastatic castrate resistant prostate cancer with histological
             or cytological confirmation. Participant may have bone-only metastatic disease.

          2. Participants must have had either orchiectomy or be on luteinizing hormone-releasing
             hormone (LHRH) agonist or antagonist therapy with testosterone <50 ng/dL and agree to
             stay on LHRH agonist or antagonist therapy during the study

          3. Participants must have previously received and progressed on ≥2 lines of approved
             systemic therapy for metastatic castration-resistant prostate cancer (mCRPC),
             including a second generation hormonal agent (e.g, abiraterone, enzalutamide, or
             apalutamide)

          4. Participants must have evidence of mCRPC that progressed within 6 months prior to
             screening according to one of the following:

               1. PSA progression as defined by a minimum of 2 rising PSA levels with an interval
                  of ≥1 week between each assessment, where the PSA value at screening should be ≥
                  1.0 ng/mL.

               2. Radiographic disease progression in soft tissue based on RECIST Version 1.1
                  criteria with or without PSA progression.

               3. Radiographic disease progression in bone defined as the appearance of 2 or more
                  new bone lesions on bone scan with or without PSA progression.

        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.