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

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

Detailed Description
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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.

Official Title
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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)

Conditions
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Progressive Metastatic Castrate-Resistant Prostate Cancer

Intervention / Treatment
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* Drug: AZD4635
* Drug: Durvalumab
* Drug: Cabazitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed adenocarcinoma of the prostate. Known castrate-resistant disease. Evidence of disease progression ≤6 months. Body weight >30 kg at screening. Willingness to adhere to the study treatment-specific contraception requirements. Adequate bone marrow reserve and organ function. 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 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 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 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: Active brain metastases or leptomeningeal metastases. There must be no requirement for immunosuppressive doses of systemic corticosteroids for at least 2 weeks prior to study enrollment. 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. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases. Creatinine clearance <40 mL/min (calculated by Cockcroft-Gault equation). Prior exposure to immune-mediated therapy including. Ongoing treatment with warfarin (Coumadin). Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study intervention.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 150 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: AZD4635 + durvalumab<br>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<br>* Subjects will receive AZD4635 orally daily<br>Drug: Durvalumab<br>* Subjects will receive intravenous durvalumab every 4 weeks for Arm A and every 3 weeks for Arm B.<br>|
| Experimental: Arm B: AZD4635 + durvalumab + cabazitaxel<br>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<br>* Subjects will receive AZD4635 orally daily<br>Drug: Durvalumab<br>* Subjects will receive intravenous durvalumab every 4 weeks for Arm A and every 3 weeks for Arm B.<br>Drug: Cabazitaxel<br>* Subjects will receive intravenous cabazitaxel every 3 weeks<br>|

What is the study measuring?
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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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prostate Cancer