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

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)

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

Study Overview

• Status: Completed
• Conditions: Progressive Metastatic Castrate-Resistant Prostate Cancer
• Intervention / Treatment: Drug: AZD4635; Drug: Durvalumab; Drug: Cabazitaxel

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.

As of November 2020, the Sponsor stopped enrolment in Arm A following decisions at the program level, not related to any safety issues. Ongoing participants in Arm A may continue treatment as planned.

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• Belgium
  • Brasschaat, Belgium, 2930
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
• France
  • Bordeaux, France, 33076
    • Research Site
  • Villejuif, France, 94805
    • Research Site
• Korea, Republic of
  • Goyang-si, Korea, Republic of, 10408
    • Research Site
  • Seoul, Korea, Republic of, 06351
    • Research Site
  • Seoul, Korea, Republic of, 06591
    • Research Site
• Spain
  • Barcelona, Spain, 8035
    • Research Site
  • Barcelona, Spain, 08041
    • Research Site
  • Hospitalet deLlobregat, Spain, 08907
    • Research Site
  • Madrid, Spain, 28034
    • Research Site
• United States
  • California
    • Sacramento, California, United States, 95817
      • Research Site
  • Florida
    • Tampa, Florida, United States, 33612
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30318
      • Research Site
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Research Site
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 150 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

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

7. 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

8. 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

9. 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

10. 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 <40 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: AZD4635 + durvalumab; AZD4635 plus durvalumab (Arm A) will consist of 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.	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.
Experimental: Arm B: AZD4635 + durvalumab + cabazitaxel; AZD4635 plus durvalumab plus cabazitaxel (Arm B) will consist of 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).	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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiographic Progression Free Survival (rPFS) in Each Arm Separately to Determine the Efficacy of AZD4635 Plus Durvalumab and of AZD4635 Plus Durvalumab Plus Cabazitaxel in Patients With Metastatic Castrate-resistant Prostate Cancer (mCRPC)	rPFS was defined as the time from first dose to radiographic progression, assessed by the Investigator per RECIST 1.1 (soft tissue) and PCWG3 (Prostate Cancer Working Group 3) criteria [bone] or death from any cause, whichever occurred first.	From first dose to first documented progression or death from any cause (whichever comes first) (approximately 1 year)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
rPFS by Adenosine (ADO) Signalling Gene Expression in High and Low Subgroups to Determine the Efficacy of AZD4635 Plus Durvalumab Plus Cabazitaxel in Participants With mCRPC	rPFS was 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 occurred first.	From first dose to first documented progression or death from any cause (whichever comes first), up to two years
Overall Survival (OS) in Each Arm Separately to Determine the Efficacy of AZD4635 Plus Durvalumab and of AZD4635 Plus Durvalumab Plus Cabazitaxel in Participants With mCRPC	OS was defined as the time from first dose until death due to any cause regardless of whether the participant withdrew from study treatment or received another anti-cancer therapy.	Arm A and B: Every 90 days from the last dose of study drug up to 2 years
Number of Participants With Objective Response in Subjects With MCRPC Who Received AZD4635 Plus Durvalumab Plus Cabazitaxel	Confirmed ORR was 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 was based on a subset of all treated participants with measurable disease at baseline per the site Investigator.	From first dose to first documented progression or death from any cause (whichever comes first), up to two years
Number of Participants With Prostate-specifin Antigen (PSA50) Response in Subjects With MCRPC Who Received AZD4635 Plus Durvalumab Plus Cabazitaxel	Confirmed PSA50 response is defined as the proportion of participants who achieved a ≥50% decrease in PSA from baseline to the lowest post-baseline PSA, confirmed by a consecutive PSA at least 3 weeks later and was based on PSA evaluable participants (dosed participants with an abnormal baseline PSA [≥1 ng/mL]).	Arm A: Screening, Day 1 of each cycle up to 11 months (Each cycle was 28 days in length); Arm B: Screening, Day 1 of each cycle up to 11 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Change From Baseline in Worst Pain in the Daily Activities Scales of the Brief Pain Inventory - Short Form (BPI-SF)	"Worst pain" and "Average pain" are 'single question' scores from the BPI short form and may take any value from 0 to 10 (worst outcome). "Interference Pain" is the total score of 7 sub-scores, where each value may take any value from 0 to 10 (worst outcome). The range of the "Interference Score" can be from 0 to 70.	Arm A: Screening, Day 1 of each cycle up to 9 months (Each cycle was 28 days in length); Arm B: Screening, Day 1 of each cycle up to 9 months (Each cycle was 21 days in length)
Change From Baseline in Average Pain in the Daily Activities Scales of the Brief Pain Inventory - Short Form (BPI-SF)	"Worst pain" and "Average pain" are 'single question' scores from the BPI short form and may take any value from 0 to 10 (worst outcome). "Interference Pain" is the total score of 7 sub-scores, where each value may take any value from 0 to 10 (worst outcome). The range of the "Interference Score" can be from 0 to 70.	Arm A: Screening, Day 1 of each cycle up to 9 months (Each cycle was 28 days in length); Arm B: Screening, Day 1 of each cycle up to 9 months (Each cycle was 21 days in length)
Change From Baseline in Pain Interference in the Daily Activities Scales of the Brief Pain Inventory - Short Form (BPI-SF)	"Worst pain" and "Average pain" are 'single question' scores from the BPI short form and may take any value from 0 to 10 (worst outcome). "Interference Pain" is the total score of 7 sub-scores, where each value may take any value from 0 to 10 (worst outcome). The range of the "Interference Score" can be from 0 to 70.	Arm A: Screening, Day 1 of each cycle up to 9 months (Each cycle was 28 days in length); Arm B: Screening, Day 1 of each cycle up to 9 months (Each cycle was 21 days in length)
Number of Participants Who Progressed Based on BPI-SF Item 3	Pain progression was assessed using BPI-SF.	Arm A: Screening, Day 1 of each cycle up to 12 months (Each cycle was 28 days in length); Arm B: Screening, Day 1 of each cycle up to 12 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Change From Baseline in the FACT Advanced Prostate Symptom Indext-6 (FAPSI-6), as Derived From 6 Items, the FAPSI-8 From 8 Items Within the FACT-P and the Prostate Cancer Symptoms (PCS), From the 12 Items in the Prostrate-specific Module of the FACT-P	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. FAPSI-6 is defined as a symptom score made up of 6 items from within the FACT-P (pain [n = 3], fatigue [n = 1], weight loss [n = 1], and concerns about the condition getting worse [n = 1]). Each question in the FACT-P questionnaires has a choice of 5 responses, "Not at all", "A little bit", "Somewhat", "Quite a bit" and "Very much". The scores range from 0 ("Not at all") to 4 ("Very much") for positively phrased questions. Negatively phrased questions have a reverse scoring, from 0 ("Very much") to 4 ("Not at all"). This results in a consistent approach, where higher scores indicate a better quality of life.	Arm A: Screening, Day 1 of each cycle up to 9 months (Each cycle was 28 days in length); Arm B: Screening, Day 1 of each cycle up to 9 months (Each cycle was 21 days in length)
Maximum Observed Plasma Concentration (Cmax)	Investigate the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.	Arm A:Cycle 1 to 3, and Cycle 4 onwards, and 90-day follow-up (FU) visit up to 14 months [Each cycle was 28 days in length];Arm B: Cycle 1 to 7 and Cycle 11 onwards, and 90-day FU up to 14 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Terminal Half-life (t1/2λz)	Investigated the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.	Arm A:Cycle 1 to 3, and Cycle 4 onwards, and 90-day follow-up (FU) visit up to 14 months [Each cycle was 28 days in length];Arm B: Cycle 1 to 7 and Cycle 11 onwards, and 90-day FU up to 14 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Area Under the Plasma Concentration Time Curve From Zero to the Time of the Last Measurable Concentration (AUClast)	Investigated the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.	Arm A:Cycle 1 to 3, and Cycle 4 onwards, and 90-day follow-up (FU) visit up to 14 months [Each cycle was 28 days in length];Arm B: Cycle 1 to 7 and Cycle 11 onwards, and 90-day FU up to 14 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Area Under the Plasma Concentration Time Curve From Zero to 24 Hours [AUC(0-24)]	Investigated the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.	Arm A:Cycle 1 to 3, and Cycle 4 onwards, and 90-day follow-up (FU) visit up to 14 months [Each cycle was 28 days in length];Arm B: Cycle 1 to 7 and Cycle 11 onwards, and 90-day FU up to 14 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Area Under the Plasma Concentration Time Curve From Zero Extrapolated to Infinity (AUCinf)	Investigated the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.	Arm A:Cycle 1 to 3, and Cycle 4 onwards, and 90-day follow-up (FU) visit up to 14 months [Each cycle was 28 days in length];Arm B: Cycle 1 to 7 and Cycle 11 onwards, and 90-day FU up to 14 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Apparent Volume of Distribution During the Terminal Phase (Vz/F)	Investigated the PK of AZD4635 when given in combination with durvalumab, and when given in combination with durvalumab plus cabazitaxel.	Arm A:Cycle 1 to 3, and Cycle 4 onwards, and 90-day follow-up (FU) visit up to 14 months [Each cycle was 28 days in length];Arm B: Cycle 1 to 7 and Cycle 11 onwards, and 90-day FU up to 14 months (Cycle 1 to Cycle 10 = 21 days, Cycle 11 onwards = 28 days)
Number of Subjects With Serious and Non-serious Adverse Events	Safety and tolerability of each treatment regimen were assessed in participants with mCRPC.	Arm A: From Screening up to 14 months (Each cycle was 28 days in length); Arm B: From Screening up to 14 months (Cycle 1 to Cycle 10 was 21 days in length, and Cycle 11 onwards was 28 days in length)

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Parexel
• Investigators: Principal Investigator: Christopher J Sweeney, MBBS, Dana-Farber Cancer Institute

Publications and helpful links

Helpful Links

• Related Info
• Related Info
• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): August 4, 2020
• Primary Completion (Actual): November 1, 2021
• Study Completion (Actual): August 8, 2022

Study Registration Dates

• First Submitted: July 23, 2020
• First Submitted That Met QC Criteria: July 30, 2020
• First Posted (Actual): July 31, 2020

Study Record Updates

• Last Update Posted (Actual): August 9, 2023
• Last Update Submitted That Met QC Criteria: July 21, 2023
• Last Verified: July 1, 2023

More Information

Terms related to this study

• Keywords: Prostate Cancer
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Prostatic Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Durvalumab
• Other Study ID Numbers: D8731C00002; 2020-000209-10 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All request will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool . Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No