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

Metastatic Prostate Cancer Clinical Trial

— PETRANHA  

Official title:

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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05367440
• Other study ID #: D9720C00003
• Secondary ID: 2021-006289-19
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 2, 2022
• Est. completion date: August 15, 2030

Study information

• Verified date: May 2024
• Source: AstraZeneca
• Contact: AstraZeneca Clinical Study Information Center
• Phone: 1-877-240-9479
• Email: information.center[@]astrazeneca.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 172
• Est. completion date: August 15, 2030
• Est. primary completion date: August 15, 2030
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years to 130 Years

Eligibility

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:

• 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 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:

1. Strong and moderate CYP3A4 inducers/inhibitors (applies for all arms)

2. For Arm 1 (enzalutamide) patients: Strong CYP2C8 inhibitors

3. 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:

1. 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.

2. 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.

3. 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) and Arm 4 (Apalutamide): 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.

• Arm 4 (Apalutamide): (i) Moderate or severe skin conditions or diseases that could affect the skin (eg. scleroderma, lupus). (ii) Any skin or medical condition that in the Investigator's opinion could increase the risk of skin toxicity.

Related Conditions & MeSH terms

• Metastatic Prostate Cancer
• Prostatic Neoplasms

Intervention

Drug:
• AZD5305
Patients will receive an oral dose of AZD5305 once daily
• Enzalutamide
Patients will receive an oral dose of Enzalutamide once daily
• Abiraterone Acetate
Patients will receive an oral dose of Abiraterone Acetate once daily
• Darolutamide
Patients will receive an oral dose of Darolutamide twice daily
• Apalutamide
Patients will receive an oral dose of Apalutamide once daily

Locations

Country	Name	City	State
Australia	Research Site	Camperdown
Australia	Research Site	Darlinghurst
Australia	Research Site	East Melbourne
Australia	Research Site	Heidelberg
Australia	Research Site	Melbourne
Australia	Research Site	St. Leonards
Italy	Research Site	Candiolo
Italy	Research Site	Milano
Italy	Research Site	Milano
Italy	Research Site	Orbassano
Italy	Research Site	Padova
Italy	Research Site	Pavia
United Kingdom	Research Site	Cambridge
United Kingdom	Research Site	Glasgow
United Kingdom	Research Site	Hampshire
United Kingdom	Research Site	Manchester
United Kingdom	Research Site	Newcastle Upon Tyne
United Kingdom	Research Site	Plymouth
United States	Research Site	Detroit	Michigan
United States	Research Site	Detroit	Michigan
United States	Research Site	Houston	Texas
United States	Research Site	Houston	Texas
United States	Research Site	Indianapolis	Indiana
United States	Research Site	Myrtle Beach	South Carolina
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	San Diego	California
United States	Research Site	Syracuse	New York

Sponsors (2)

Lead Sponsor	Collaborator
AstraZeneca	Bayer

Countries where clinical trial is conducted

United States,  Australia,  Italy,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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]
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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]
Secondary	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]
Secondary	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]
Secondary	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]
Secondary	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]
Secondary	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]
Secondary	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]
Secondary	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
Secondary	PSA Progression-free survival	To assess the preliminary antitumour activity of AZD5305 in combination with NHA.	6, 12, 18, 24 and 30 months
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	AUC of Apalutamide	To characterize the PK (AUC) of Apalutamide 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)
Secondary	Cmax of Apalutamide	To characterize the PK (Cmax) of Apalutamide 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)
Secondary	tmax of Apalutamide	To characterize the PK (tmax) of Apalutamide 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)
Secondary	Part B: Homologous recombination repair gene mutation (HRRRm)	To investigate HRRm (including BRCA1/2) and their relationship with clinical response	From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]