Clinical trial NCT05367440: Study of AZD5305 When Given in Combination With New Hormonal Agents in Patients With Metastatic Prostate Cancer
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)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Metastatic Prostate Cancer
Keywords: PETRANHA
AZD5305
New Hormonal Agents
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
Collaborators: name: Bayer
First posted: 2022-05-10
Enrollment: 190
Sex: MALE
Minimum age (years): 18
Maximum age (years): 130
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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:

• 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.

Primary outcomes:
measure: Number of patients with Adverse Events and Serious Adverse Events
timeFrame: Up to post treatment follow-up (28 days after last dose) [assessed up to 2.3 years]
measure: Part A: Number of patients with Dose Limiting Toxicities (DLTs)
timeFrame: For Arm 1: 35 days, For Arm 2 and 3: 28 days
Secondary outcomes:
measure: Area Under the concentration Curve (AUC) of AZD5305
timeFrame: At the end of Cycle 0 (Cycle 0 is of 7 days)
measure: Maximum plasma concentration (Cmax) of AZD5305
timeFrame: At the end of Cycle 0 (Cycle 0 is of 7 days)
measure: Time to maximum concentration (tmax) of AZD5305
timeFrame: At the end of Cycle 0 (Cycle 0 is of 7 days)
measure: AUC of AZD5305
timeFrame: 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)
measure: Cmax of AZD5305
timeFrame: 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)
measure: tmax of AZD5305
timeFrame: 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)
measure: Objective response rate (ORR)
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
measure: Duration of response (DoR)
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
measure: Time to response (TTR)
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
measure: Radiographic progression-free survival (rPFS)
timeFrame: From Screening (Day -28), 12 months, 24 months and up to confirmed disease progression [assessed up to 2.3 years]
measure: Percentage change in tumour size
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
measure: Number of patients with ≥ 50% prostate-specific antigen (PSA) decrease from baseline
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
measure: Number of patients with ≥ 90% prostate-specific antigen (PSA) decrease from baseline
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
measure: Part B: Number of patients with undetectable PSA (< 0.2 ng/mL)
timeFrame: 3, 6, 9 and 12 months
measure: PSA Progression-free survival
timeFrame: 6, 12, 18, 24 and 30 months
measure: AUC of Enzalutamide
timeFrame: 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)
measure: Cmax of Enzalutamide
timeFrame: 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)
measure: tmax of Enzalutamide
timeFrame: 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)
measure: AUC of Apalutamide
timeFrame: 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)
measure: Cmax of Apalutamide
timeFrame: 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)
measure: tmax of Apalutamide
timeFrame: 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)
measure: Part B: Homologous recombination repair gene mutation (HRRRm)
timeFrame: From Screening (Day -28) to confirmed disease progression [assessed up to 2.3 years]
Other outcomes:
Locations:
city: San Diego
country: United States
facility: Research Site
state: California
city: Indianapolis
country: United States
facility: Research Site
state: Indiana
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Detroit
country: United States
facility: Research Site
state: Michigan
city: Syracuse
country: United States
facility: Research Site
state: New York
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Research Site
state: South Carolina
city: Houston
country: United States
facility: Research Site
state: Texas
city: Houston
country: United States
facility: Research Site
state: Texas
city: Camperdown
country: Australia
facility: Research Site
city: Darlinghurst
country: Australia
facility: Research Site
city: East Melbourne
country: Australia
facility: Research Site
city: Heidelberg
country: Australia
facility: Research Site
city: Melbourne
country: Australia
facility: Research Site
city: St. Leonards
country: Australia
facility: Research Site
city: Candiolo
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Milano
country: Italy
facility: Research Site
city: Orbassano
country: Italy
facility: Research Site
city: Padova
country: Italy
facility: Research Site
city: Pavia
country: Italy
facility: Research Site
city: Cambridge
country: United Kingdom
facility: Research Site
city: Glasgow
country: United Kingdom
facility: Research Site
city: Hampshire
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: Research Site
city: Plymouth
country: United Kingdom
facility: Research Site
Study officials:
References: