Clinical Trials /

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

NCT04089553

Description:

This is an open-label Phase II modular study in patients 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. The protocol may be amended to include other combinations.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: An Open-label, Phase II Study of AZD4635 in Patients With Prostate Cancer
  • Official Title: An Open-label, Multi-drug, Multi-center Phase II Combination Study of AZD4635 in Patients With Prostate Cancer

Clinical Trial IDs

  • ORG STUDY ID: D8731C00001
  • SECONDARY ID: GU 156
  • NCT ID: NCT04089553

Conditions

  • Prostate Cancer
  • Metastatic Castration-Resistant Prostate Cancer (mCRPC)

Interventions

DrugSynonymsArms
AZD4635Module 1
OleclumabMEDI9447Module 2
DurvalumabImfinziModule 1

Purpose

This is an open-label Phase II modular study in patients 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. The protocol may be amended to include other combinations.

Detailed Description

      This is an open-label Phase II modular study in patients with prostate cancer which will
      assess safety, efficacy, and tolerability of AZD4635 in combination with other therapeutic
      agents in different treatment arm (referred to as modules).

      Combinations to be studied include: 1) Module 1: AZD4635 plus durvalumab; 2) Module 2:
      AZD4635 plus oleclumab. The protocol may be amended to include other combinations.

      All patients will be allocated into a module using an Interactive Web Response System (IWRS).
      Randomization will occur when patients meet eligibility criteria for two or more modules that
      are currently recruiting. If patients only meet the criteria for only one currently
      recruiting module, they will be allocated to that module without randomization taking place.

      The primary objective of the clinical study is to evaluate the efficacy of each combination
      therapy by: 1) assessing the objective response rate (ORR) of patients with measurable
      disease [response will be determined by Response Evaluation Criteria in Solid Tumours (RECIST
      1.1)]; 2) assessing the PSA confirmed response rate of each combination therapy [PSA
      confirmed response rate is defined as the proportion of participants with a reduction in the
      PSA level of ≥50% measured from baseline to the lowest post-baseline PSA result measured
      twice, at least 3 weeks apart by the Prostate Cancer Working Group 3 criteria PCWG3).

      The primary safety endpoints include assessment of adverse events and serious adverse events,
      physical examinations, vital signs, and collection of clinical chemistry/hematology
      parameters

      In Modules 1 and 2 there will be approximately 30 evaluable patients in each module, and at
      least 20 patients will have RECIST measurable disease at baseline. If any of the required
      patients for PSA and/or ORR are not evaluable for PSA response or tumor response,
      respectively, they may be replaced at the sponsor's discretion.
    

Trial Arms

NameTypeDescriptionInterventions
Module 1ExperimentalModule 1 will investigate the safety, efficacy, and tolerability of AZD4635 in combination with durvalumab in post-standard of care therapy for metastatic castration resistant prostate cancer (mCRPC) patients. In Module 1 approximately 30 patients will be enrolled, and biopsies will be obtained from a minimum of 15 patients in order to assess tumor microenvironment at baseline and after treatment with AZD4635. Patients will receive AZD4635 75 mg PO QD monotherapy for 2 weeks (Cycle 0). Starting with Cycle 1, durvalumab 1500 mg IV Q4W will be added to continuous AZD4635 dosing.
  • AZD4635
  • Durvalumab
Module 2ExperimentalModule 2 will investigate the safety, efficacy, and tolerability of AZD4635 in combination with oleclumab in post-standard of care therapy for metastatic castration resistant prostate cancer (mCRPC) patients. In Module 2 approximately 30 patients will be enrolled, and biopsies will be obtained from a minimum of 15 patients in order to assess tumor microenvironment at baseline and after treatment with AZD4635 plus oleclumab. Patients will receive a starting dose of AZD4635 50 mg PO QD and oleclumab 1500 mg Q2W for the first 4 doses and Q4W thereafter. Administration of the first dose of oleclumab must be staggered by a minimum of 24 hours between the first 6 patients. After the first 6 patients have completed 28 days of therapy with AZD4635 and oleclumab, there will be an early review for safety/toxicity by a Safety Review Committee (SRC) with stopping rules for toxicity.
  • AZD4635
  • Oleclumab

Eligibility Criteria

        Inclusion Criteria for all Patients in all Modules.

        Patients are eligible to be included in the study only if all of the following inclusion
        criteria are met and none of the exclusion criteria apply:

          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. A minimum of 15 patients per module will be required to have a site of disease that is
             safely accessible for biopsy (paired) upon enrollment. 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 diseases 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. Body weight >35 kg at screening

        11. 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 Module 1

          1. Patients must have had either orchiectomy or be on luteinizing hormone-releasing
             hormone (LHRH) agonist or antagonist therapy with serum testosterone <50 ng/dL, and
             agree to stay on LHRH agonist or antagonist therapy during the study.

          2. 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).

          3. 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.

        Inclusion Criteria for Module 2.

          1. Patients must have had either orchiectomy or be on luteinizing hormone-releasing
             hormone (LHRH) agonist or antagonist therapy with serum testosterone <50 ng/dL, and
             agree to stay on LHRH agonist or antagonist therapy during the study.

          2. 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).

          3. 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

        Exclusion Criteria for all Patients in all Modules

        Patients must not enter the study if any of the following exclusion criteria apply:

          1. Refractory nausea and vomiting, chronic gastrointestinal diseases, or previous
             significant small bowel resection that would preclude adequate absorption of AZD4635.

          2. 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.

          3. With the exception of alopecia, lymphopenia, hypothyroidism, or 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.

          4. 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.

          5. Patients must have normotensive or well controlled blood pressure (<140/90), 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.

          6. 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.

          7. 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.

          8. Prior/concomitant therapy with AZD4635 or any other A2AR antagonist.

          9. 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.

         10. 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. (Exception: androgen-deprivation therapy is
             permitted), b) concurrent use of hormones for non-cancer-related conditions (e.g.,
             insulin for diabetes and hormone replacement therapy) is acceptable.

         11. Major surgery (as defined by the Medical Monitor, excluding placement of vascular
             access) within 4 weeks of the first dose of study treatment.

         12. Minor surgical procedures (as defined by the Medical Monitor) within 7 days of the
             first dose of study treatment.

         13. 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.

         14. Concomitant medications with another A1R antagonist that would increase risk of
             seizure (e.g., theophylline, aminophylline).

         15. Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.

         16. Ongoing treatment with Coumadin.

         17. Receipt of live attenuated vaccine within 30 days prior to the first dose of study
             drug.

         18. Herbal preparations/medications are not allowed throughout the study, including bu not
             limited to: St. John's wort, kava, ephedra (ma huang), gingko biloba,
             dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Patients should stop using
             these herbal medications 7 days prior to the first dose of AZD4635.

         19. 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.

         20. Enrollment into another therapeutic clinical trial. (Exception: Patients are allowed
             to participate in investigational imaging or non-interventional studies.)

         21. History of hypersensitivity to AZD4635 or drugs with a similar chemical structure or
             class to AZD4635.

         22. 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 factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, congenital long QT syndrome, family
                  history of long QT syndrome or unexplained sudden death under 40 years-of-age, or
                  any concomitant medication with known or possible risk of QT interval
                  prolongation.

               -  Ejection fraction <55% or the lower limit of normal of the institutional
                  standard.

         23. 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.

         24. Involvement in the planning and/or conduct of the study (applies to AstraZeneca staff
             and its representatives and/or staff at the study site).

         25. 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.

         26. 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

        Patients must not enter Module 1 of the study if any of the following exclusion criteria
        apply.

          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. Known sensitivity to acetaminophen/paracetamol, diphenhydramine or equivalent
             antihistamine, and methylprednisolone or equivalent glucocorticoid.

          4. History of venous thrombosis within the past 3 months.

          5. Prior history of myocardial infarction, transient ischemic attack, or stroke in the
             last three months.
      
Maximum Eligible Age:130 Years
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective Response Rate (ORR)
Time Frame:Up to approximately 2 years
Safety Issue:
Description:ORR is defined as the proportion of patients with measurable disease at baseline who have a confirmed response as assessed by the Response Evaluation Criteria in Solid Tumours (RECIST 1.1). Reassessment of tumors must be done by the same methods used to establish baseline tumor measurements.

Secondary Outcome Measures

Measure:Radiologic Progression Free Survival (PFS) at Six Months
Time Frame:Six months
Safety Issue:
Description:The proportion of patients alive and radiologically progression free at 6 months using assessment methods described in RECIST 1.1 (soft tissue lesions) and PCWG3 (bone lesions).
Measure:Duration of Response (DoR)
Time Frame:Throughout the study (up to approximately 2 years)
Safety Issue:
Description:Duration of Response (DoR) is defined as the time from the date of first documented response until date of documented progression or death in the absence of disease progression.
Measure:Overall Survival (OS)
Time Frame:Throughout the study (up to approximately 2 years)
Safety Issue:
Description:Overall survival is defined as the length of time from date of first dose until the date of death due to any cause.
Measure:Durvalumab Anti-Drug Antibodies (ADA)
Time Frame:Anti-drug antibodies (ADAs) to durvalumab will be assessed pre-dose Day 1 of Cycles 1, 2, 4, 7 & 90 days after the last dose. Each cycle is 28 days.
Safety Issue:
Description:The proportion of patients with the presence of anti-drug antibody (ADA) will be determined.
Measure:Oleclumab Anti-Drug Antibodies (ADA)
Time Frame:Anti-drug antibodies (ADAs) to oleclumab will be assessed pre-dose on Day 1 of Cycles 0, 1, 3, 5 & every 12 weeks thereafter, & 90 days after the last dose. Each cycle is 28 days.
Safety Issue:
Description:The proportion of patients with the presence of anti-drug antibody (ADA) will be determined.
Measure:Minimum steady state plasma concentration (Ctrough) of AZD4635.
Time Frame:Day 1 of Cycles 1, 2, 4, and 7 and 90 days after last dose (up to approximately 260 days). Each cycle is 28 days.
Safety Issue:
Description:Pre-infusion and end of infusion plasma concentrations will be determined on Day 1 of Cycles 1 and 4. Only pre-infusion concentration will be determined on Day 1 of cycles 2 and 7.
Measure:Proportion of Patients Experiencing Adverse Events
Time Frame:Throughout the study (up to approximately 2 years)
Safety Issue:
Description:Safety and tolerability will be judged by assessment of the severity and proportion of patients experiencing adverse events (AEs) and serious adverse events (SAEs), assessment of abnormalities in physical exam findings, vital signs, clinical chemistry, hematology, and coagulation parameters, and urinalysis parameters.
Measure:Proportion of Patients Experiencing Serious Adverse Events
Time Frame:Throughout the study (up to approximately 2 years)
Safety Issue:
Description:Safety and tolerability will be judged by assessment of the severity and proportion of patients experiencing adverse events (AEs) and serious adverse events (SAEs), assessment of abnormalities in physical exam findings, vital signs, clinical chemistry, hematology, and coagulation parameters, and urinalysis parameters.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • Prostate cancer
  • AZD4635
  • oleclumab
  • durvalumab
  • MEDI9447
  • Adenosine 2A Receptor Antagonist
  • A2AR

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