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) - AARDVARC

Phase 1

• Conditions: Progressive Metastatic Castrate-Resistant Prostate Cancer; MedDRA version: 21.1Level: PTClassification code 10036909Term: Prostate cancer metastaticSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2020-000209-10-FR
• Lead Sponsor: AstraZeneca AB

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-06-10
• Last Update Posted: 21 December 2021

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: Male
• Target Recruitment: 160

Inclusion Criteria

1 Participant must be 18 years of age inclusive at the time of signing the informed consent.
2 Histologically confirmed adenocarcinoma of the prostate
- Disease must be metastatic and inoperable and for which there is no curative intervention available. Participants may have bone-only disease.
- Participants presenting with treatment-emergent neuroendocrine differentiation, but not primary small-cell features, are eligible.
3 Known castrate-resistant disease, defined as:
- Testosterone level in the castration range (levels <50 ng/dl) because of a previous, and ongoing, androgen-deprivation with luteinizing hormone-releasing hormone (LHRH) agonists or antagonists or bilateral orchiectomy. Participants must have developed progression of metastases following surgical castration or during medical androgen ablation therapy. Participants receiving medical castration therapy with gonadotropin-releasing hormone (GnRH) analogues should continue this treatment during this study.
4 Evidence of disease progression =6 months defined by one or more of the following:
- Progression as defined by RECIST v1.1 criteria for assessment of malignant soft tissue disease and lymph nodes
- Progression of bone lesions on bone scan from a previous or baseline assessment per PCWG3
- Rising PSA
5 Must have measurable disease:
- 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 is suitable for repeated measurement
Or
- Non-measurable disease must have measurable PSA =1.0 ng/mL as the minimum starting level for trial entry if the confirmed rise is the only indication of progression (excluding small cell carcinoma)
6 Body weight >30 kg at screening.
7 Willingness to adhere to the study treatment-specific contraception requirements: Participants 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 and/or durvalumab and/or cabazitaxel to prevent pregnancy in a female partner. Participants must not donate or bank sperm for 24 weeks after treatment.
8 Adequate bone marrow reserve and organ function as demonstrated by all of the following laboratory values:
- Absolute neutrophil count (ANC) =1.5 × 10^9/L
- Platelet count =100 × 10^9/L
- Haemoglobin =9.0 g/dL
- Creatinine =1.5 × 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 × ULN.
Additional Inclusion Criteria Specific for Arm A
9 Adequate organ function for Arm A as demonstrated by all of the following laboratory values:
- Alanine aminotransferase (ALT) =2.5 × the 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
10 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-refract

Exclusion Criteria

1 Active brain metastases or leptomeningeal metastases. Participants with brain metastases are eligible if treated and there is no evidence of progression for at least 8 weeks after treatment is completed and within 28 days prior to the first dose of study intervention.
2 There must be no requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone/equivalent) for at least 2 weeks prior to study enrollment.
3 Participant with a history of pneumonitis requiring corticosteroids.
4 History of a second malignancy that is progressing and/or received active treatment =3 years before the first dose of study intervention.
5 As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension, active bleeding diatheses, or active infection including hepatitis B, hepatitis C, and human immunodeficiency virus. Screening for chronic conditions is not required.
6 Creatinine clearance <50 mL/min (calculated by Cockcroft-Gault equation).
7 Prior exposure to immune-mediated therapy including, but not limited to anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anti-cancer vaccines.
Additional Exclusion Criteria Specific for Arm B: Medical Conditions
8 Participant with active grade =2 peripheral neuropathy
9 Participant with active grade =2 stomatitis
10 Any small-molecule, biologic, or hormonal agent from a previous treatment regimen or clinical study within 21 days or 5 half-lives (whichever is shorter) prior to the first dose of study intervention. At least 7 days must have elapsed between the last dose of such agent and the first dose of study intervention. Exception: androgen-deprivation therapy is permitted.
11 History of hypersensitivity to polysorbate-80 if allocated to cabazitaxel.
12 Nitrosourea or mitomycin C within 6 weeks of the first dose of study intervention.
13 Prescription or non-prescription drugs or other products known to be sensitive BCRP or OAT1 substrates or to be strong 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 study intervention.
14 Exclusion Criteria for Arm B: Concurrent or planned treatment with strong inhibitors or strong inducers of cytochrome P450 3A4/5 (CYP3A4/5) are excluded (a 2-week washout period is required for participants already on these treatments).
15 Herbal preparations/medications are not allowed throughout the study. These herbal medications include but are not limited to St. John’s wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, yohimbe, saw palmetto, and ginseng. Participants should stop using these herbal medications 7 days prior to the first dose of study intervention. Exceptions may be agreed, but the circumstances must be reviewed by the Medical Monitor/AZ Study Physician in advance.
16 Ongoing treatment with warfarin (Coumadin).
17 Receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
18 Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study intervention.
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 intervention.
20 AZD4635 in the present study (i.e., dosing with AZD4635 previously initiated in a different arm in this study

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified