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. Patient must be ≥18 years of age at the time of signing the ICF
3. Patients must have prostate cancer with histological or cytological confirmation
4. Patients must have previously received and progressed on standard-of-care therapy(ies)
5. Patients 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 patients 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 patients are enrolled and investigators are aware of
this requirement at all times.
7. Patients 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 patients
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: Patients 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 patients must
not donate or bank sperm for 24 weeks after treatment.
Inclusion Criteria for Modules 1, 2, and 3:
1. Patients must have metastatic castrate resistant prostate cancer with histological or
cytological confirmation. Patient may have bone-only metastatic disease.
2. Patients 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. Patients must have previously received and progressed on ≥2 lines of approved systemic
therapy for mCRPC, including a second generation hormonal agent (e.g., abiraterone,
enzalutamide, or apalutamide)
4. Patients 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 Patients 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. Patients 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 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. Patients 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. Patients 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, patient 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. Patients with a past or resolved HBV infection (defined as the
presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible.
Patients 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. Patient is receiving medications or other products known to be sensitive breast cancer
resistance protein (BCRP) or organic anion transporter 1 (OAT1) substrates or potent
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. Patients 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: Patients 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. Patients
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 patient should not
participate in the study if the patient is unlikely to comply with study procedures,
restrictions and requirements.
28. Participation in another clinical interventional study or if patient 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.
Exclusion Criteria for Module 3:
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. 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)
4. Known history of allergy or reaction to any component of oleclumab formulation or
history of anaphylaxis to any human gammaglobulin therapy
5. History of venous thrombosis within the past 3 months
