A Study of AZD4635 With Durvalumab and With Cabazitaxel and Durvalumab in Patients With mCRPC.

Overview

This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in participants with metastatic castration-resistant prostate cancer (mCRPC).

Full Title of Study: “A Phase II, Open-label, Study to Assess the Efficacy, Safety, and Tolerability of AZD4635 in Combination With Durvalumab and in Combination With Cabazitaxel and Durvalumab in Patients Who Have Progressive Metastatic Castrate-Resistant Prostate Cancer (AARDVARC)”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: September 16, 2022

Detailed Description

This is a Phase II, international, open-label, two-arm, non-randomised study of AZD4635 in participants with mCRPC. Participants in each arm will be stratified by the presence of measurable soft tissue metastasis (per Response Evaluation Criteria in Solid Tumours [RECIST v1.1]) or bone-only metastasis (per Prostate Cancer Working Group 3 [PCWG3 criteria]). There will be no formal comparisons between treatment arms.

AZD4635 plus durvalumab (Arm A) will consist of 80 participants with mCRPC previously treated with one or more approved new hormonal agent(s) (NHAs) and one or more taxanes or participants who are taxane ineligible.

AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80 participants mCRPC previously treated with docetaxel and one prior NHA.

Interventions

  • Drug: AZD4635
    • Subjects will receive AZD4635 orally daily
  • Drug: Durvalumab
    • Subjects will receive intravenous durvalumab every 4 weeks for Arm A and every 3 weeks for Arm B.
  • Drug: Cabazitaxel
    • Subjects will receive intravenous cabazitaxel every 3 weeks

Arms, Groups and Cohorts

  • Experimental: Arm A: AZD4635 + durvalumab
    • AZD4635 plus durvalumab (Arm A) will consist of 80 participants with mCRPC previously treated with one or more approved NHAs (eg, abiraterone acetate, enzalutamide, apalutamide and/or darolutamide), and one or more taxanes, or participants who are taxane ineligible.
  • Experimental: Arm B: AZD4635 + durvalumab + cabazitaxel
    • AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 80 participants with mCRPC previously treated with docetaxel and one prior NHA (either abiraterone acetate or enzalutamide but not both (prior apalutamide is not allowed in Arm B).

Clinical Trial Outcome Measures

Primary Measures

  • rPFS in each arm separately
    • Time Frame: From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 10 months for Arm B
    • rPFS is defined as the time from first dose to radiographic progression, assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 criteria (bone) or death from any cause, whichever occurs first.

Secondary Measures

  • rPFS by adenosine (ADO) signalling gene expression in high and low subgroups in each arm separately, and by adenosine deaminase (ADA) gene expression in high and low subgroups in each arm separately
    • Time Frame: From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 10 months for Arm B
    • rPFS is defined as the time from first dose to radiographic progression, assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 criteria (bone) or death from any cause, whichever occurs first.
  • Overall survival (OS) in each arm separately, and by ADO signalling gene expression in high and low subgroups in each arm separately, and by ADA gene expression in high and low subgroups in each arm separately
    • Time Frame: Arm A and B: Every 90 days from the last dose of study drug upto 2.2 years (expected)
    • OS is defined as the time from first dose until death due to any cause regardless of whether the participant withdraws from study treatment or receives another anti-cancer therapy.
  • Objective response rate (ORR) in each arm separately, and by ADO signalling gene expression in high and low subgroups in each arm separately, and by ADA gene expression in high and low subgroups in each arm separately
    • Time Frame: From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 10 months for Arm B
    • Confirmed ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) using overall radiographic response assessed by RECIST v1.1 and PCWG-3 criteria (bone), and will be based on a subset of all treated participants with measurable disease at baseline per the site Investigator.
  • Duration of response (DoR) in each arm separately, and by ADO signalling gene expression in high and low subgroups in each arm separately, and by ADA gene expression in high and low subgroups in each arm separately
    • Time Frame: From first dose to first documented progression or death from any cause (whichever comes first). This is expected to be an average of 5.5 months for Arm A and 10 months for Arm B
    • DoR is defined as the date of first documented response (which is subsequently confirmed) until the date of documented progression or death in the absence of disease progression.
  • Prostate-specific antigen (PSA50) response in each arm separately, and by ADO signalling gene expression in high and low subgroups in each arm separately, and by ADA gene expression in high and low subgroups in each arm separately
    • Time Frame: Arm A: Screening, Day 1 of each cycle upto 2.2 years (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 2.2 years (expected); Duration of each cycle is 28 days
    • Confirmed PSA50 response is defined as the proportion of participants achieving a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and will be based on PSA evaluable participants (dosed participants with an abnormal baseline PSA [≥1 ng/mL]).
  • Change from baseline in worst pain, general pain and pain interference in the daily activities scales of the Brief Pain Inventory – Short Form (BPI-SF) and in the worst bone pain item
    • Time Frame: Arm A: Screening, Day 1 of each cycle upto 2.2 years (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 2.2 years (expected); Duration of each cycle is 28 days
    • Worst pain, general pain and pain’s interference with daily life will be assessed during the study intervention using the BPI-SF. The BPI-SF comprises a total of 15 items measuring 2 domains: pain severity and pain interference. Items measuring pain severity (including ‘worst pain’) are rated on an 11-point numeric rating scale (NRS)[ ranging from 0=No pain to 10=Pain as bad as you can imagine.
  • Time to pain progression based on BPI-SF Item 3 "worse pain in 24-hours"
    • Time Frame: Arm A: Screening, Day 1 of each cycle upto 2.2 years (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 2.2 years (expected); Duration of each cycle is 28 days
    • Pain progression will be assessed using BPI-SF.
  • Change from baseline in the FACT Advanced Prostate Symptom Indext-8 (FAPSI-8), as derived from 8 items within the FACT-P and the Prostate Cancer Symptoms (PCS), as derived from the 12 items in the prostrate-specific module of the FACT-P
    • Time Frame: Arm A: Screening, Day 1 of each cycle upto 2.2 years (expected). Duration of each cycle is 28 days; Arm B: Screening, Day 1 of each cycle upto 2.2 years (expected); Duration of each cycle is 28 days
    • The Functional Assessment of Cancer Therapy-Prostate (FACT-P) will be used to measure health related quality of life (HRQL)in men with prostate cancer. It consists of 4 subscales (physical, emotional, functional and social/family well-being) plus a 12-item prostate-specific module, the PCS subscale, which highlights concerns specific to participants with prostate cancer.
  • Pharmacokinetic (PK) plasma concentrations for AZD4635, durvalumab and cabazitaxel
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Maximum observed plasma concentration (Cmax)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Time to reach Cmax
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Time of the last measurable concentration (tlast)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Terminal elimination rate constant (λz)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Terminal half-life (t1/2λz)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Area under the plasma concentration time curve from zero to 24 hours [AUC(0-24)], from zero to 8 hours [AUC(0-8)], from zero to the time of the last measurable concentration (AUClast), and from zero extrapolated to infinity (AUCinf)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Apparent plasma clearance (CL/F for AZD4635, CL/F for cabazitaxel)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Apparent volume of distribution during the terminal phase (Vz/F for AZD4635, Vz/F for cabazitaxel)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.
  • Mean residence time (MRT)
    • Time Frame: Arm A: Cycle 1, 2, 3, and Cycle 4 onwards, and 90-day follow-up visit (FU) upto 2.2 years (expected); Arm B: Cycle 1, 2, 3, 4, 5, 7 and Cycle 11 onwards, and 90-day FU upto 2.2 years (expected); Duration of each cycle for both arms is 28 days
    • Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.

Participating in This Clinical Trial

Inclusion Criteria

1 Histologically confirmed adenocarcinoma of the prostate. 3 Known castrate-resistant disease. 4 Evidence of disease progression ≤6 months. 5 Body weight >30 kg at screening. 6 Willingness to adhere to the study treatment-specific contraception requirements.

7 Adequate bone marrow reserve and organ function. 8 Adequate organ function for Arm A as demonstrated by all of the following laboratory values:

  • Alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) if no demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases.
  • Aspartate aminotransferase (AST) ≤2.5 × ULN if no demonstrable liver metastases or ≤5 × ULN in the presence of liver metastases
  • Total bilirubin (TBL) ≤1.5 × ULN
  • TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin 9 Participants in Arm A must have received the following prior therapy:
  • Maximum of 3 lines of therapy in the mCRPC setting
  • Prior therapy with one or more NHAs (eg, abiraterone acetate, enzalutamide, apalutamide, darolutamide) in either hormone-sensitive or hormone-refractory settings
  • Prior therapy with one or more lines of taxanes (eg, docetaxel and/or cabazitaxel)
  • Alternatively, must be taxane-ineligible
  • Prior therapy can be in either the hormone-sensitive or the hormone-refractory setting 10 Adequate organ function for Arm B as demonstrated by all of the following laboratory values:
  • AST and/or ALT ≤1.5 × ULN
  • TBL ≤ ULN
  • TBL ≤2.0 × ULN in the case of known Gilbert syndrome with normal direct bilirubin 11 Participants in Arm B must have received the following prior therapy:
  • Prior docetaxel (taxane) in either hormone-sensitive or hormone-refractory settings
  • Received no prior cytotoxic chemotherapy other than docetaxel for prostate cancer except for estramustine and except adjuvant/neo-adjuvant treatment completed >3 years ago.
  • Prior therapy with only one NHAs (eg, abiraterone acetate or enzalutamide; prior apalutamide is not permitted) for treatment of mCRPC in either hormone-sensitive or hormone-refractory settings.
  • Be suitable to receive concomitant Granulocyte-colony stimulating factor during all cycles of cabazitaxel.
  • Participants who meet inclusion criteria for Arm B will be allocated preferentially to that arm until recruitment to that arm is completed.

Exclusion Criteria

1. Active brain metastases or leptomeningeal metastases.

2. There must be no requirement for immunosuppressive doses of systemic corticosteroids for at least 2 weeks prior to study enrollment.

3. History of pneumonitis requiring corticosteroids, second malignancy that is progressing and/or received active treatment ≤3 years before the first dose of study intervention, and hypersensitivity to polysorbate-80 if allocated to cabazitaxel.

4. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases.

5. Creatinine clearance <50 mL/min (calculated by Cockcroft-Gault equation).

6. Prior exposure to immune-mediated therapy including.

7. Ongoing treatment with warfarin (Coumadin).

8. Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study intervention.

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 150 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • AstraZeneca
  • Collaborator
    • Parexel
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Christopher J Sweeney, MBBS, Principal Investigator, Dana-Farber Cancer Institute
  • Overall Contact(s)
    • AstraZeneca Clinical Study Information Center, 1-877-240-9479, information.center@astrazeneca.com

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