A Phase I, Open-label, Multi-centre Study to Assess the Safety, Tolerability, and Pharmacokinetics of Capivasertib (AZD5363) in Combination With Novel Agents in Patients With Metastatic Castration Resistant Prostate Cancer
Overview
- Phase
- Phase 1
- Intervention
- Capivasertib
- Conditions
- Prostate Cancer
- Sponsor
- AstraZeneca
- Enrollment
- 27
- Locations
- 1
- Primary Endpoint
- Number of patients with dose limiting toxicity (DLT) for Part A1
- Status
- Completed
- Last Updated
- 3 years ago
Overview
Brief Summary
This is a Phase Ib, open-label, multi-centre study to determine the safety, tolerability and pharmacokinetics (PK) of capivasertib when given in combination with novel agents (enzalutamide or abiraterone) to inform the selection of capivasertib dose regimens for each combination for further clinical evaluation when given to patients with metastatic castration resistant prostate cancer (CRPC). The study design allows an exploration of different doses with intensive safety monitoring to ensure the safety of the patients.
Detailed Description
The study will be conducted on multiple centers (≤10) in USA and Spain. The study design allows an exploration of different doses with intensive safety monitoring to ensure the safety of the patients. The two planned combination treatments during Part A of this study are: Part A1: Capivasertib and enzalutamide Part A2: Capivasertib and abiraterone Part B will include any optional dose expansion cohorts based on Safety Review Committee (SRC) review of data from Part A of this study. The study will include up to approximately 87 evaluable patients, divided among the 4 study parts as follows: Part A1: Up to approximately 36 patients (up to four dose levels with up to approximately 9 patients per dose level). Part B1: Up to approximately 12 patients. Part A2: Up to approximately 27 patients (up to three dose levels with up to approximately 9 patients per dose level). Part B2: Up to approximately 12 patients.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol prior to any mandatory study-specific procedures, sampling, and analyses.
- •Males aged 18 years and older at the time of signing the ICF.
- •Patients with documented evidence of metastatic CRPC who have had at least one line of systemic therapy for metastatic CRPC (either chemotherapy or an novel hormonal agents \[NHA\]) or for whom no alternative approved therapy is available.
- •World Health Organization (WHO) performance status 0 to 2 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks, as assessed at day
- •Patients must be able to swallow and retain oral medication.
- •Agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures, and agreement to refrain from donating sperm.
- •Sterilisation (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate).
- •Patients should use barrier contraception (ie, condoms) from the time of screening until 16 weeks after discontinuation of study treatment. It is not known whether the preclinical changes seen in the male animal reproductive organs, after treatment with capivasertib, will be fully reversible or will permanently affect the ability to produce healthy sperm following treatment. Therefore, if patients wish to father children they should be advised to arrange for collection of sperm samples prior to the start of study treatment.
Exclusion Criteria
- •Previous enrolment in the present study.
- •Prior enzalutamide therapy in the last 8 weeks.
- •Treatment with any of the following:
- •Nitrosourea or mitomycin C within 6 weeks of the first dose of study treatment.
- •Any investigational agents or study drugs from a previous clinical study within 30 days of the first dose of study treatment.
- •Any other chemotherapy, immunotherapy, immunosuppressant medication (other than corticosteroids) or anti-cancer agents within 3 weeks of the first dose of study treatment, except hormonal therapy with luteinising hormone-releasing hormone (LHRH) analogues for medical castration in patients with prostate cancer, which are permitted.
- •Potent inhibitors or inducers or substrates of CYP3A4 within 2 weeks before the first dose of study treatment (3 weeks for St. John's wort) or sensitive substrates of CYP3A4, CYP2C9 and/or CYP2D6 with a narrow therapeutic window within 1 week prior to the first dose of study treatment.
- •Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study treatment.
- •Radiotherapy with a wide field of radiation within 4 weeks of the first dose of study treatment.
- •Clinically significant abnormalities of glucose metabolism as defined by any of the following:
Arms & Interventions
Part A1: Capivasertib + enzalutamide
From day 1 to day 28 of this study treatment, patients will continuously enroll on a starting dose of capivasertib in combination with 160 mg enzalutamide.
Intervention: Capivasertib
Part A1: Capivasertib + enzalutamide
From day 1 to day 28 of this study treatment, patients will continuously enroll on a starting dose of capivasertib in combination with 160 mg enzalutamide.
Intervention: Enzalutamide
Part A1: Capivasertib dose level 1 + enzalutamide
On day 29 of the treatment, patients will escalate the capivasertib dose to dose level+1 along with 160 mg enzalutamide.
Intervention: Capivasertib
Part A1: Capivasertib dose level 1 + enzalutamide
On day 29 of the treatment, patients will escalate the capivasertib dose to dose level+1 along with 160 mg enzalutamide.
Intervention: Enzalutamide
Part A1: Capivasertib dose level 2 + enzalutamide
On day 29 of the treatment, patients will escalate the capivasertib dose to dose level+2 along with 160 mg enzalutamide.
Intervention: Capivasertib
Part A1: Capivasertib dose level 2 + enzalutamide
On day 29 of the treatment, patients will escalate the capivasertib dose to dose level+2 along with 160 mg enzalutamide.
Intervention: Enzalutamide
Part A2: Capivasertib + abiraterone
Patients will continuously enroll on a starting dose of capivasertib in combination with 1000 mg abiraterone.
Intervention: Capivasertib
Part A2: Capivasertib + abiraterone
Patients will continuously enroll on a starting dose of capivasertib in combination with 1000 mg abiraterone.
Intervention: Abiraterone
Part B1: Capivasertib + enzalutamide
This optional expansion will treat patients at the recommended dose regimen of capivasertib and enzalutamide.
Intervention: Capivasertib
Part B1: Capivasertib + enzalutamide
This optional expansion will treat patients at the recommended dose regimen of capivasertib and enzalutamide.
Intervention: Enzalutamide
Part B2: Capivasertib + abiraterone
This optional expansion will treat patients at the recommended dose regimen of capivasertib and abiraterone.
Intervention: Capivasertib
Part B2: Capivasertib + abiraterone
This optional expansion will treat patients at the recommended dose regimen of capivasertib and abiraterone.
Intervention: Abiraterone
Outcomes
Primary Outcomes
Number of patients with dose limiting toxicity (DLT) for Part A1
Time Frame: Day 1 to day 56 for Part A1
A DLT is defined as an AE that occurs from the first dose of study treatment up to and including the last day of the DLT period (day 1 to day 56 for Part A1) that is assessed as unrelated to the disease, intercurrent illness, or concomitant medications and that, despite optimal therapeutic interventions, meets any of the criteria defined in the protocol.
Number of patients with DLT for Part A2
Time Frame: Day 1 to day 28 for Part A2
A DLT is defined as an AE that occurs from the first dose of study treatment up to and including the last day of the DLT period (day 1 to day 28 for Part A2) that is assessed as unrelated to the disease, intercurrent illness, or concomitant medications and that, despite optimal therapeutic interventions, meets any of the criteria defined in the protocol.
Number of patients with adverse events
Time Frame: For each treatment combination, from screening (Day -28 to -1) either for up to 1.5 years or up to 30 days follow-up period after discontinuation
To investigate the safety and tolerability of capivasertib when given in combination with novel agents (enzalutamide and abiraterone) to patients with metastatic CRPC.
Secondary Outcomes
- Radiographic progression free survival (rPFS) for efficacy analyses of capivasertib for each treatment combination(From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination)
- Area under curve (AUC) for capivasertib to characterize pharmacokinetics (PK) for each treatment combination(For capivasertib and enzalutamide combination, full sampling on day 25 and on day 53; for capivasertib and abiraterone combination, full sampling on day 25.)
- Maximum plasma concentration (Cmax) for capivasertib to characterize PK for each treatment combination(For capivasertib and enzalutamide combination, full sampling on day 25 and on day 53; for capivasertib and abiraterone combination, full sampling on day 25.)
- Soft tissue objective response rate (ORR) and radiological ORR for efficacy analyses of capivasertib for each treatment combination(From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination)
- Duration of response (DoR) for efficacy analyses of capivasertib for each treatment combination(From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination)
- Percentage change in tumour size for efficacy analyses of capivasertib for each treatment combination(From screening (-28 Day) to every 8 weeks after cycle 1 day 1 for the first 24 weeks and every 12 weeks thereafter up to 1.5 years for each treatment combination)