A Multi-arm, Open-label Phase I/IIa Study to Assess the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of AZD5305 in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer (PETRANHA)
Overview
- Phase
- Phase 1
- Intervention
- AZD5305
- Conditions
- Metastatic Prostate Cancer
- Sponsor
- AstraZeneca
- Enrollment
- 174
- Locations
- 1
- Primary Endpoint
- Number of patients with Adverse Events and Serious Adverse Events
- Status
- Active, not recruiting
- Last Updated
- 4 months ago
Overview
Brief Summary
This study will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of AZD5305 when given in combination with new hormonal agents (NHAs) in patients with Metastatic Prostate Cancer.
Detailed Description
The study consists of 2 parts, Part A and Part B. Part A consists of the dose escalation cohorts and will include patients with metastatic castration resistant prostate cancer (mCRPC) or metastatic castration-sensitive prostate cancer (mCSPC); Part B consists of dose expansion cohorts and will include patients with mCSPC only. Part A comprises 4 individual arms each evaluating the safety, tolerability, and preliminary efficacy of AZD5305 in combination with a specific new hormonal agent (NHA). Part B comprises up to 4 individual arms (arms to be opened at Sponsor's discretion) each investigating the preliminary efficacy and aims to further build on the safety data for the combination of AZD5305 with a specific NHA. Approximately 783 patients will be enrolled and screened to ensure the required number of evaluable patients in each part and arm are enrolled. For Part A, 356 patients may be screened to obtain up to approximately 308 patients that can be assigned to study treatments across all study arms (1 to 4). For Part B dose expansion cohorts, up to 427 patients may be screened to obtain up to approximately 360 patients that can be assigned to study treatments across all study arms (1 to 4). Study treatment administration will continue until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Investigators
Eligibility Criteria
Inclusion Criteria
- •For whole study:
- •Age ≥ 18 at the time of screening.
- •Histologically confirmed diagnosis of metastatic prostate cancer.
- •Candidate for treatment with enzalutamide, abiraterone acetate, darolutamide or apalutamide with documented current evidence of metastatic prostate cancer.
- •Surgically or medically castrated.
- •Adequate organ and marrow function.
- •Eastern Cooperative Oncology Group Performance Status (ECOG PS): 0-1 with no deterioration over the previous 2 weeks.
- •Life expectancy ≥ 16 weeks.
- •Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to approximately 6 months after the last dose of study treatment .
- •For Patients Recruited Specifically to tumour Pharmacodynamic Cohorts:
Exclusion Criteria
- •For Part A mCRPC patients only:
- •Any previous treatment with a new hormonal agent (NHA), poly (adenosine diphosphateribose) polymerase inhibitor (PARPi), Lutetium prostate-specific membrane antigen (Lu-PSMA), platinum chemotherapy
- •Patients recruited to the PDc cohorts should not have received a prior use of new hormonal agents (NHA).
- •For Part A and Part B mCSPC Patients:
- •Any previous treatment with a PARPi, platinum, NHA, Immuno-oncology (IO), radiopharmaceutical therapy, or prior treatment with docetaxel in mCSPC setting.
- •Concomitant use of medications or herbal supplements known to be:
- •Strong and moderate CYP3A4 inducers/inhibitors (applies for all arms)
- •For Arm 1 (enzalutamide) patients: Strong CYP2C8 inhibitors
- •For Arm 3 (darolutamide) patients: Strong P-glycoprotein inducers
- •Concomitant use of drugs that are known to prolong or shorten QT and have a known risk of Torsades de Pointes.
Arms & Interventions
Arm 1 (AZD5305 in combination with enzalutamide)
Patients will receive an oral dose of AZD5305 and Enzalutamide once daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: AZD5305
Arm 1 (AZD5305 in combination with enzalutamide)
Patients will receive an oral dose of AZD5305 and Enzalutamide once daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: Enzalutamide
Arm 2 (AZD5305 in combination with abiraterone acetate)
Patients will receive an oral dose of AZD5305 and Abiraterone Acetate once daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: AZD5305
Arm 2 (AZD5305 in combination with abiraterone acetate)
Patients will receive an oral dose of AZD5305 and Abiraterone Acetate once daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: Abiraterone Acetate
Arm 3 (AZD5305 in combination with darolutamide)
Patients will receive an oral dose of AZD5305 once daily and Darolutamide twice daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: AZD5305
Arm 3 (AZD5305 in combination with darolutamide)
Patients will receive an oral dose of AZD5305 once daily and Darolutamide twice daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: Darolutamide
Arm 4 (AZD5305 in combination with apalutamide)
Patients will receive an oral dose of AZD5305 and Apalutamide once daily until disease progression, initiation of alternative anticancer therapy, unacceptable toxicity, withdrawal of consent, or other reasons to discontinue study treatment occur.
Intervention: Apalutamide
Outcomes
Primary Outcomes
Number of patients with Adverse Events and Serious Adverse Events
Time Frame: Up to post treatment follow-up (28 days after last dose) [assessed up to 2.3 years]
Number of patients with adverse events and with serious adverse events including abnormal clinical observations, abnormal ECG parameters, abnormal laboratory assessments and abnormal vital signs that changed from baseline will be assessed.
Part A: Number of patients with Dose Limiting Toxicities (DLTs)
Time Frame: For Arm 1: 35 days, For Arm 2 and 3: 28 days
To assess the safety and tolerability of AZD5305 when given in combination with NHA.
Secondary Outcomes
- AUC of AZD5305(Arm 1: At Cycle 1 Day 1, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8, and Cycle 3 Day 1; Arm 2 and 3: At Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Each Cycle is of 28 days))
- tmax of AZD5305(Arm 1: At Cycle 1 Day 1, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8, and Cycle 3 Day 1; Arm 2 and 3: At Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Each Cycle is of 28 days))
- Duration of response (DoR)(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])
- Time to maximum concentration (tmax) of AZD5305(At the end of Cycle 0 (Cycle 0 is of 7 days))
- Cmax of AZD5305(Arm 1: At Cycle 1 Day 1, Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8, and Cycle 3 Day 1; Arm 2 and 3: At Cycle 1 Day 1, Cycle 1 Day 15 and Cycle 2 Day 1 (Each Cycle is of 28 days))
- Objective response rate (ORR)(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])
- AUC of Enzalutamide(At Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8 and Cycle 3 Day 1 (Each Cycle is of 28 days))
- Area Under the concentration Curve (AUC) of AZD5305(At the end of Cycle 0 (Cycle 0 is of 7 days))
- Time to response (TTR)(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])
- Number of patients with ≥ 90% prostate-specific antigen (PSA) decrease from baseline(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])
- Cmax of Enzalutamide(At Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8 and Cycle 3 Day 1 (Each Cycle is of 28 days))
- tmax of Enzalutamide(At Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8 and Cycle 3 Day 1 (Each Cycle is of 28 days))
- Maximum plasma concentration (Cmax) of AZD5305(At the end of Cycle 0 (Cycle 0 is of 7 days))
- Percentage change in tumour size(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])
- Part B: Number of patients with undetectable PSA (< 0.2 ng/mL)(3, 6, 9 and 12 months)
- Radiographic progression-free survival (rPFS)(From Screening (Day -28), 12 months, 24 months and up to confirmed disease progression [assessed up to 2.3 years])
- AUC of Apalutamide(At Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8 and Cycle 3 Day 1 (Each Cycle is of 28 days))
- Number of patients with ≥ 50% prostate-specific antigen (PSA) decrease from baseline(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])
- PSA Progression-free survival(6, 12, 18, 24 and 30 months)
- Cmax of Apalutamide(At Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8 and Cycle 3 Day 1 (Each Cycle is of 28 days))
- tmax of Apalutamide(At Cycle 1 Day 22, Cycle 2 Day 1, Cycle 2 Day 2, Cycle 2 Day 8 and Cycle 3 Day 1 (Each Cycle is of 28 days))
- Part B: Homologous recombination repair gene mutation (HRRRm)(From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years])