Study of AZD5305 When Given in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer

Study Overview
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Brief Summary
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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
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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 3 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 3 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 520 patients will be enrolled and screened to ensure the required number of evaluable patients in each part and arm are enrolled. For Part A, 300 patients may be screened to obtain up to approximately 252 patients that can be assigned to study treatments across all study arms (1 to 3). For Part B dose expansion cohorts, up to 220 patients may be screened to obtain up to approximately 180 patients that can be assigned to study treatments across all study arms (1 to 3). 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.

Official Title
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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)

Conditions
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Metastatic Prostate Cancer

Intervention / Treatment
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* Drug: AZD5305
* Drug: Enzalutamide
* Drug: Abiraterone Acetate
* Drug: Darolutamide


Participation Criteria
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Eligibility Criteria
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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, or darolutamide 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: • Patients must have at least 1 tumour suitable for paired biopsies For Part A: • Patients with Metastatic Castrate ion-Resistant Prostate Cancer (mCRPC) or Metastatic Castration Sensitive Prostate Cancer (mCSPC). For Part B: • Patients must have mCSPC (de novo or recurrent) with a baseline PSA value of ≥ 0.2 ng/mL Exclusion Criteria: For Part A mCRPC patients only: Any previous treatment with a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor, 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 PARP inhibitor, 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. Treatment with any of the following: Any investigational agents or study interventions from a previous clinical study within 5 half lives or 3 weeks (whichever is longer) of the first dose of study treatment. Any other anticancer treatment within the following time periods prior to the first dose of study treatment: (i) Cytotoxic and non-cytotoxic treatment: 3 weeks or 5 half-lives (whichever is shorter). (ii) Biological products including immuno-oncology agents: 4 weeks before enrolment. Any live virus or bacterial vaccine within 28 days of the first dose of study treatment. Any concurrent anticancer therapy or concurrent use of prohibited medications. Major surgery within 4 weeks prior to the first dose of study treatment. 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 treatment. With the exception of alopecia, and peripheral neuropathy; any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) Grade 1 at the time of study enrolment. Any history of persisting (> 2 weeks) severe pancytopenia. Spinal cord compression, or brain metastases unless asymptomatic and treated and stable. Any evidence of severe or uncontrolled systemic diseases, including, active bleeding diatheses, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Patients with any known predisposition to bleeding (eg, active peptic ulceration, recent [within 6 months] haemorrhagic stroke, proliferative diabetic retinopathy. Any clinically significant cardiac disorders including QT prolongation, abnormal electrocardiogram (ECG). Any clinically significant cardiovascular diseases including symptomatic heart failure, uncontrolled hypertension, acute coronary syndrome, cardiomyopathy, valvular heart disease, atrial fibrillation, stroke. Patients with history of myelodysplastic syndrome (MDS)/ acute myeloid leukaemia (AML). Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection. Known allergy or hypersensitivity to investigational product(s) or any of the excipients of the investigational product(s). Any condition that would interfere with evaluation of the study treatment or interpretation of patient safety or study results. Uncontrolled intercurrent illness within the last 12 months, including but not limited to, active interstitial lung disease, serious chronic gastrointestinal (GI) conditions associated with diarrhoea, or psychiatric illness/social situations History of another primary malignancy except for malignancy treated with curative intent with no known active disease within 3 years before the first dose of study treatment and of low potential risk for recurrence. Concurrent enrolment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study. Arm 1 (Enzalutamide) only: History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke, significant brain trauma). Arm 2 (Abiraterone acetate) only: (i) Active infection or other medical condition that would contraindicate the use of systemic steroids (prednisone/prednisolone). (ii) Low serum potassium (< 3.5 mmol/L). (iii) History of uncontrolled pituitary or adrenal dysfunction.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 130 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 1 (AZD5305 in combination with enzalutamide)<br>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. | Drug: AZD5305<br>* Patients will receive an oral dose of AZD5305 once daily<br>Drug: Enzalutamide<br>* Patients will receive an oral dose of Enzalutamide once daily<br>* Other names: Xtandi;|
| Experimental: Arm 2 (AZD5305 in combination with abiraterone acetate)<br>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. | Drug: AZD5305<br>* Patients will receive an oral dose of AZD5305 once daily<br>Drug: Abiraterone Acetate<br>* Patients will receive an oral dose of Abiraterone Acetate once daily<br>* Other names: Zytiga;|
| Experimental: Arm 3 (AZD5305 in combination with darolutamide)<br>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. | Drug: AZD5305<br>* Patients will receive an oral dose of AZD5305 once daily<br>Drug: Darolutamide<br>* Patients will receive an oral dose of Darolutamide twice daily<br>* Other names: Nubeqa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with Adverse Events and Serious Adverse Events | 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. | Up to post treatment follow-up (28 days after last dose) [assessed up to 2.3 years] | 
| Part A: Number of patients with Dose Limiting Toxicities (DLTs) | To assess the safety and tolerability of AZD5305 when given in combination with NHA. | For Arm 1: 35 days, For Arm 2 and 3: 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the concentration Curve (AUC) of AZD5305 | To characterise the PK (AUC) of AZD5305 at steady state after multiple dosing of AZD5305 monotherapy. | At the end of Cycle 0 (Cycle 0 is of 7 days) | 
| Maximum plasma concentration (Cmax) of AZD5305 | To characterise the PK (Cmax) of AZD5305 at steady state after multiple dosing of AZD5305 monotherapy. | At the end of Cycle 0 (Cycle 0 is of 7 days) | 
| Time to maximum concentration (tmax) of AZD5305 | To characterise the PK (tmax) of AZD5305 at steady state after multiple dosing of AZD5305 monotherapy. | At the end of Cycle 0 (Cycle 0 is of 7 days) | 
| AUC of AZD5305 | To characterise the PK (AUC) of AZD5305 following oral dose administration of AZD5305 in combination with NHA. | 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) | 
| Cmax of AZD5305 | To characterise the PK (Cmax) of AZD5305 following oral dose administration of AZD5305 in combination with NHA. | 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 | To characterise the PK (tmax) of AZD5305 following oral dose administration of AZD5305 in combination with NHA. | 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) | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. ORR will be assessed as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (soft tissue) and Prostate Cancer Clinical Trials Working Group 3 (PCWG3) and is defined as the percentage of patients who have a confirmed visit response of complete response (CR) or partial response (PR) in their soft tissue disease and no disease progression in their bone scan. | From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years] | 
| Duration of response (DoR) | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. DoR is defined as the time from the date of first documented response (which is subsequently confirmed) until date of documented progression or death in the absence of progressive disease (PD). | From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years] | 
| Time to response (TTR) | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. TTR is defined as the time from first dose until the first documentation of a subsequently confirmed objective response. | From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years] | 
| Radiographic progression-free survival (rPFS) | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. rPFS is defined as the time from start of first treatment until progression as per RECIST v1.1 (soft tissue) and PCWG3 criteria (bone) or death from any cause. | From Screening (Day -28), 12 months, 24 months and up to confirmed disease progression [assessed up to 2.3 years] | 
| Percentage change in tumour size | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. Percentage change in tumour size will be determined for patients with measurable disease at baseline. | From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years] | 
| Number of patients with ≥ 50% prostate-specific antigen (PSA) decrease from baseline | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. | 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 | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. | 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) | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. | 3, 6, 9 and 12 months | 
| PSA Progression-free survival | To assess the preliminary antitumour activity of AZD5305 in combination with NHA. | 6, 12, 18, 24 and 30 months | 
| AUC of Enzalutamide | To characterize the PK (AUC) of Enzalutamide in plasma at steady state when given orally in combination with AZD5305 | 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) | 
| Cmax of Enzalutamide | To characterize the PK (Cmax) of Enzalutamide in plasma at steady state when given orally in combination with AZD5305 | 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 | To characterize the PK (tmax) of Enzalutamide in plasma at steady state when given orally in combination with AZD5305 | 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) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AZD5305, PETRANHA, New Hormonal Agents