Clinical trial NCT04495179: A Study of AZD4635 With Durvalumab and With Cabazitaxel and Durvalumab in Patients With mCRPC.
Official title: 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: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Progressive Metastatic Castrate-Resistant Prostate Cancer
Keywords: Prostate Cancer
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Parexel
First posted: 2020-07-31
Enrollment: 30
Sex: MALE
Minimum age (years): 18
Maximum age (years): 150
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: From first dose to first documented progression or death from any cause (whichever comes first) (approximately 1 year)
Secondary outcomes:
measure: 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
timeFrame: From first dose to first documented progression or death from any cause (whichever comes first), up to two years
measure: 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
timeFrame: Arm A and B: Every 90 days from the last dose of study drug up to 2 years
measure: Number of Participants With Objective Response in Subjects With MCRPC Who Received AZD4635 Plus Durvalumab Plus Cabazitaxel
timeFrame: From first dose to first documented progression or death from any cause (whichever comes first), up to two years
measure: Number of Participants With Prostate-specifin Antigen (PSA50) Response in Subjects With MCRPC Who Received AZD4635 Plus Durvalumab Plus Cabazitaxel
timeFrame: 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)
measure: Change From Baseline in Worst Pain in the Daily Activities Scales of the Brief Pain Inventory - Short Form (BPI-SF)
timeFrame: 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)
measure: Change From Baseline in Average Pain in the Daily Activities Scales of the Brief Pain Inventory - Short Form (BPI-SF)
timeFrame: 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)
measure: Change From Baseline in Pain Interference in the Daily Activities Scales of the Brief Pain Inventory - Short Form (BPI-SF)
timeFrame: 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)
measure: Number of Participants Who Progressed Based on BPI-SF Item 3
timeFrame: 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)
measure: 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
timeFrame: 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)
measure: Maximum Observed Plasma Concentration (Cmax)
timeFrame: 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)
measure: Terminal Half-life (t1/2λz)
timeFrame: 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)
measure: Area Under the Plasma Concentration Time Curve From Zero to the Time of the Last Measurable Concentration (AUClast)
timeFrame: 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)
measure: Area Under the Plasma Concentration Time Curve From Zero to 24 Hours [AUC(0-24)]
timeFrame: 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)
measure: Area Under the Plasma Concentration Time Curve From Zero Extrapolated to Infinity (AUCinf)
timeFrame: 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)
measure: Apparent Volume of Distribution During the Terminal Phase (Vz/F)
timeFrame: 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)
measure: Number of Subjects With Serious and Non-serious Adverse Events
timeFrame: 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)
Other outcomes:
Locations:
city: Sacramento
country: United States
facility: Research Site
state: California
city: Tampa
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Winston-Salem
country: United States
facility: Research Site
state: North Carolina
city: Brasschaat
country: Belgium
facility: Research Site
city: Gent
country: Belgium
facility: Research Site
city: Bordeaux
country: France
facility: Research Site
city: Villejuif
country: France
facility: Research Site
city: Goyang-si
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Seoul
country: Korea, Republic of
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Barcelona
country: Spain
facility: Research Site
city: Hospitalet deLlobregat
country: Spain
facility: Research Site
city: Madrid
country: Spain
facility: Research Site
Study officials:
affiliation: Dana-Farber Cancer Institute
name: Christopher J Sweeney, MBBS
role: PRINCIPAL_INVESTIGATOR
References: