Clinical trial NCT04729114: A Safety and Dose-finding Study of PRL-02 Depot in Men With Advanced Prostate Cancer
Official title: Phase 1, Open-Label, Multicenter Study of Intramuscular PRL-02 Depot in Patients With Advanced Prostate Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Prostate Cancer
Metastatic Castration Resistant Prostate Cancer
Metastatic Castration-sensitive Prostate Cancer
Keywords: Testosterone
Testosterone suppression
metastatic castrate sensitive prostate cancer
metastatic castrate resistant prostate cancer
metastatic disease
prostate cancer
mCSPC
mCRPC
abiraterone
abiraterone decanoate
abiraterone acetate
Phase 1
Propella
ASP5541
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2021-01-28
Enrollment: 174
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Medicines that reduce the amount of testosterone in the body are commonly used to treat prostate cancer. PRL-02 depot is a potential treatment for men with advanced prostate cancer. It is given by an injection into the muscle. Men with advanced prostate cancer can take part in this study. Their cancer has come back after previous cancer treatment, or the previous cancer treatment they had didn't work.

The main aims of the study are:

* to check the safety of PRL-02 depot given with and without another medicine called enzalutamide.
* to check if the men can tolerate PRL-02 depot given with or without enzalutamide.
* to find a suitable dose of PRL-02 depot.

This study will be in 2 parts.

In the first part, different small groups of men will receive lower to higher doses of PRL-02 depot together with other medicines.

In the second part of the study, men who have previously taken a hormone therapy called abiraterone acetate or have previously taken 1 specific hormone therapy as part of their prostate cancer treatment can take part.

Men in both parts of the study will receive injections of PRL-02 depot into a muscle once every 12 weeks. They will also take dexamethasone or prednisone, or enzalutamide once a day. The other medicines they take depend on which group and which part of the study they are in.

During the study, the men will visit the clinic several times for health checks and scans.

After the final visit, men whose cancer has not become worse will continue to have health checks and scans every few months.


Eligibility criteria: Inclusion Criteria:

* Histological evidence of adenocarcinoma of the prostate
* Phase 1a Dose Escalation Groups A and B: participants must have one of the following documented conditions:

  * mCSPC (must have documentation by positive bone scan \[for bone disease\] or metastatic lesions on computed tomography \[CT\] or magnetic resonance imaging \[MRI\] scan \[for soft tissue\])
  * nmCSPC with biochemical relapse of prostate cancer
  * mCSPC with oligometastatic prostate cancer (e.g., positron emission tomography positive)
  * mCRPC (must have documentation by positive bone scan \[for bone disease\] or metastatic lesions on CT or MRI scan \[for soft tissue\])
  * NOTE: For participants in the Dose Escalation Cohorts (including backfill) at each of the dose levels up to approximately 10 participants with ARPI-naïve mCRPC who have not received prior treatment with an ARPI (e.g., abiraterone acetate, enzalutamide, apalutamide, darolutamide) will be enrolled.
* Phase 1a Dose Escalation Groups A and B: participants with mCRPC must have evidence of disease progression defined as one or more of the following:

  * Evidence of radiographic progression of disease following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per RECIST v1.1 or on a bone scan per PCWG3.
  * PSA progression defined as the following:
* PSA nadir is defined as the lowest PSA during or after the most recent treatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior to screening.
* Participants with nmCSPC and biochemical recurrence, who had a radical prostatectomy (with or without radiotherapy) as the primary treatment for prostate cancer, must have a screening PSA ≥1 ng/mL. Participants with nmCSPC and biochemical recurrence who had radiotherapy only, as primary treatment for prostate cancer, must have a screening PSA ≥2 ng/mL above the nadir.
* Phase 1b Expansion Groups D and E: participants must have mCRPC Participants in Group D must have received prior treatment with abiraterone acetate, but must not have received treatment with other ARPIs (enzalutamide, apalutamide or darolutamide). Participants in Group E must have received prior treatment with only 1 of the following ARPIs: enzalutamide, apalutamide or darolutamide. Participants in both Groups D and E must have documented evidence of progression with one or more of the following:

  * Evidence of radiographic progression of disease following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per RECIST v1.1 or on a bone scan per PCWG3. Disease spread that is limited to the regional pelvic lymph nodes does not qualify as radiographic progression.
  * PSA progression defined as the following:
  * PSA nadir is defined as the lowest PSA during or after the most recent treatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior to screening.
* Participants with mCRPC must have undergone bilateral orchiectomy or received concurrent GnRH agonist or antagonist therapy for at least 6 weeks prior to the first dose of study drug.
* Participants with mCSPC or nmCSPC with biochemical recurrence should have received \<6 months of ADT with a GnRH agonist or antagonist or have a history of bilateral orchiectomy (i.e., surgical or medical castration) within 6 months prior to Day 1. Castration therapy (i.e., medical or surgical) must have been started at least 14 days prior to Cycle 1 Day 1 and participants should have no radiographic evidence of disease progression or rising PSA levels after starting ADT and prior to Cycle 1 Day 1.
* A serum testosterone level \<50 ng/dL at screening (for mCRPC participants only)
* Adequate muscle mass for an i.m. injection
* An ECOG PS of 0 or 1
* Adequate bone marrow reserve defined as:

  * Absolute neutrophil count (ANC) ≥1500/µL
  * Platelet count ≥100,000/µL
  * Hemoglobin ≥9 gm/dL
* Adequate renal function defined as a serum creatinine ≤1.5 × upper limit of normal (ULN) for the reference laboratory or a calculated creatinine clearance ≥50 mL/min as determined by a validated algorithm for calculating creatinine clearance
* Adequate hepatic function, defined as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × ULN and total bilirubin ≤1.5 × ULN. Exception for elevated bilirubin secondary to Gilbert's disease. Confirmation of Gilbert's diagnosis requires: elevated unconjugated (indirect) bilirubin values; normal complete blood count in previous 12 months, blood smear, and reticulocyte count; normal aminotransferases and alkaline phosphatase in previous 12 months.
* Serum albumin ≥3 gm/dL and serum potassium ≥3.5 mEq/L
* Participants who are non-sterile and who are heterosexually active with a female partner of childbearing potential must be willing to use a highly effective means of contraception, such as a male condom plus spermicide, from the time of screening, throughout the total duration of the drug treatment, and until 12 weeks after the final dose of PRL-02 or enzalutamide (Group H).
* Participant is able to comply with study requirements throughout the study.

The Following Inclusion Criteria Apply to Dose Escalation Group H Only

* Participants must have one of the following documented conditions:

  * mCSPC (must have documentation of a positive PMSA-PET or positive bone scan \[for bone disease\] or metastatic lesions on CT or MRI scan \[for soft tissue\])
  * mCRPC (must have documentation of a positive PMSA-PET or positive bone scan \[for bone disease\] or metastatic lesions on CT or MRI scan \[for soft tissue\])
  * NOTE: For participants in the Dose Escalation Cohorts (including backfill) at each of the dose levels, the Sponsor may elect to enroll up to 10 participants with ARPI-naïve mCRPC who have not received prior treatment with an ARPI (e.g., abiraterone acetate, enzalutamide, apalutamide, darolutamide).
* Participants with mCRPC must have evidence of disease progression defined as one or more of the following:

  * Evidence of radiographic progression of disease following the most recent prostate cancer treatment, defined as progressive disease on CT/MRI per RECIST v1.1 or on a bone scan per PCWG3.
  * PSA progression defined as the following:
* PSA nadir is defined as the lowest PSA during or after the most recent treatment. PSA progression is defined as an increased PSA of at least 25% and ≥1 ng/mL above the nadir confirmed by at least 2 measurements with a minimum of 1 week apart, and with at least 1 of the measurements within 90 days prior to screening.
* Participant is able to swallow enzalutamide capsules whole.

Exclusion Criteria:

* Known active central nervous system (CNS) metastases. Note: Participants with CNS metastases that have been treated with surgery and/or radiation therapy, who are off pharmacologic doses of glucocorticoids, and who are neurologically stable are eligible.
* Impending bone fracture due to bone metastases
* Has a known additional malignancy beyond prostate cancer that required active treatment with the exception of any of the following:

  * Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ carcinoma of any type
  * Adequately treated Stage I cancer from which the participant is currently in remission and has been in remission for ≥2 years
  * Any other cancer from which the participant has been disease-free for ≥5 years
* Clinically significant cardiac disease, defined as any of the following:

  * Clinically significant cardiac arrhythmias including bradyarrhythmia which are poorly controlled.
  * Congenital long QT syndrome
  * QT interval corrected by Fridericia's formula (QTcF) ≥450 msec at screening (based on average of triplicate ECGs at baseline). If the QT interval corrected for heart rate intervals (QTc) is prolonged in a participant with a pacemaker or bundle branch block, the participant may be enrolled in the study if confirmed by the Medical Monitor.
  * History of clinically significant cardiac disease or congestive heart failure greater than New York Heart Association (NYHA) Class II or left ventricular ejection fraction measurement of \<50% at baseline. Participants must not have unstable angina (symptoms at rest) or new-onset angina within the last 3 months or myocardial infarction within the past 6 months \[NYHA Classification 2014\].
  * Uncontrolled hypertension, defined as systolic blood pressure (BP) \>160 mmHg or diastolic BP \>100 mmHg which has been confirmed by 2 successive measurements despite optimal medical management.
  * Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis, or pulmonary embolism within the 3 months before start of study medication (except for adequately treated catheter-related venous thrombosis occurring \>1 month before the start of study medication).
* Received an investigational drug within 4 weeks or 5 half-lives (whichever is shorter) of the first dose of study drug.
* Received chemotherapy within 2 weeks or 5 half-lives (whichever is shorter) of the first dose of study drug.

  * Additional criteria: ARPI-naïve mCRPC participants enrolled in the Dose Escalation Cohorts (including backfill) must not have received prior chemotherapy in the mCRPC setting (prior receipt of chemotherapy in the mCSPC setting is allowed, if received at least 2 weeks or 5 half-lives prior to the first dose of study drug).
* Any unresolved NCI CTCAE criteria v5.0 Grade \>2 toxicity from previous anticancer therapy at the Screening visit. Note: Participants receiving ongoing hormone replacement therapy for endocrine immune-related AEs without clinical symptoms will not be excluded.
* Has not recovered from recent major surgery or trauma
* Received a blood transfusion within 2 weeks of the first dose of study drug
* History of impaired pituitary or adrenal gland function (e.g., Addison's disease, Cushing's syndrome)
* Prior treatment with abiraterone acetate, orteronel. Exception: participants in Phase 1b Expansion Group D will have received prior abiraterone acetate, and participants in Group H may have received prior treatment with abiraterone acetate.
* Current treatment with systemic ketoconazole or any other CYP17 inhibitor. Participants who have received systemic ketoconazole or any other CYP17 inhibitor must have discontinued these agents ≥4 weeks prior to the first dose of study drug.
* Prior systemic treatment with an azole drug (e.g., fluconazole, itraconazole) within 4 weeks of first dose of study drug.
* Prior treatment with estrogens within 12 weeks of the first dose of study drug
* Need for systemic glucocorticoids greater than replacement doses; the use of topical, intraocular, inhalational, intranasal, or intra-articular glucocorticoids is permitted.
* Prior use of any herbal products that could decrease PSA levels (e.g., saw palmetto) within 4 weeks of the first dose of study drug. Participants must agree not to use such herbal products during study participation.
* Use of biotin (i.e., vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 µg \[NIH-ODS 2022\]. Note: Participants who switch from a high dose to a dose of 30 µg/day or less prior to first dose of study drug are eligible for study entry.
* Required concomitant use of strong inducers of CYP3A4, except for enzalutamide given as study drug in Group H
* Known hypersensitivity to PRL-02, abiraterone, abiraterone decanoate, prednisone, or dexamethasone or any of their excipients or components.
* Has jaundice or known current active liver disease from any cause, including hepatitis A (hepatitis A virus immunoglobulin M \[IgM\] positive), hepatitis B (hepatitis B virus surface antigen \[HBsAg\] positive, confirmed by polymerase chain reaction \[PCR\]), or hepatitis C (hepatitis C virus \[HCV\] antibody positive, confirmed by HCV ribonucleic acid)
* Hemoglobin A1c (HbA1c) \>10% in participants previously diagnosed with diabetes mellitus. HbA1c \>8% in participants whose diabetes mellitus is previously undiagnosed. (Excluded participants may be rescreened after referral and evidence of improved control of their condition).
* Uncontrolled infection with human immunodeficiency virus (HIV)+. Exception: participants with well-controlled HIV (e.g., CD4 \>350/mm3 and undetectable viral load) are eligible.
* Body mass index \>40 kg/m2

The Following Exclusion Criteria Apply to Dose Escalation Group H Only

* Clinically significant cardiac disease, defined as any of the following:

  * NYHA class III or IV congestive heart failure or a history of NYHA class III or IV congestive heart failure, unless a screening echocardiogram or multigated acquisition scan performed within 3 months before the randomization date demonstrates a left ventricular ejection fraction of ≥45%
  * History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
  * Hypotension as indicated by systolic BP \<86 mm Hg at screening
  * Bradycardia as indicated by a heart rate of ≤45 beats per minute on the screening ECG
* Participant has a history of seizure or any condition that may predispose to seizure.
* Use or required use of any prohibited medication.
* Participant has a gastrointestinal disorder affecting absorption.
* Participant has shown hypersensitivity reaction to the active pharmaceutical ingredient or any of the study capsule components, including Labrasol®, butylated hydroxyanisole, and butylated hydroxytoluene.

Primary outcomes:
measure: Incidence of Dose Limiting Toxicities (DLTs)
timeFrame: Up to 28 days
measure: Number of Participants with Adverse Events (AEs)
timeFrame: Up to 4 years
measure: Number of Participants with Serious Adverse Events (SAEs)
timeFrame: Up to 4 years
measure: Number of Participants with laboratory value abnormalities and/or AEs
timeFrame: Up to 4 years
measure: Number of Participants with electrocardiogram (ECG) abnormalities and/or AEs
timeFrame: Up to 4 years
measure: Number of Participants with vital sign abnormalities and/or AEs
timeFrame: Up to 4 years
measure: Number of Participants with physical exam abnormalities and/or AEs
timeFrame: Up to 4 years
measure: Number of Participants with Eastern Cooperative Oncology Group (ECOG) performance status score
timeFrame: Up to 4 years
measure: Testosterone Suppression of Participants as Assessed by Testosterone Levels
timeFrame: Up to 4 years
Secondary outcomes:
measure: Pharmacokinetics (PK) of Abiraterone in plasma: Maximum Concentration (Cmax)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: Cmax
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: Cmax
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: Minimum Concentration (Cmin)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: Cmin
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: Cmin
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: Time of maximum concentration (tmax)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: tmax
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: tmax
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: apparent volume of distribution (Vd/F)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: Vd/F
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: Vd/F
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: oral clearance (CL/F)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: CL/F
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: CL/F
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: area under the curve from time 0 to the time of the last measurable concentration (AUClast)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: AUClast
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: AUClast
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: Area Under the Concentration-time Curve from the Time of Dosing Extrapolated to Time Infinity (AUCinf)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: AUCinf
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: AUCinf
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: area under the plasma concentration-time curve during a dosage interval (AUCtau)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: AUCtau
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: AUCtau
timeFrame: Up to 455 days
measure: PK of Abiraterone in plasma: Terminal Elimination Half-life (t1/2)
timeFrame: Up to 455 days
measure: PK of Abiraterone Decanoate in plasma: t1/2
timeFrame: Up to 455 days
measure: PK of Abiraterone Metabolite in plasma: t1/2
timeFrame: Up to 455 days
measure: Composite Response Rate
timeFrame: Up to 4 years
measure: Best overall response (BOR) per RECIST v1.1
timeFrame: Up to 4 years
measure: PSA decline of ≥50% response from baseline (PSA50)
timeFrame: Up to 4 years
measure: PSA decline of ≥90% response from baseline (PSA90)
timeFrame: Up to 4 years
measure: Percentage of participants achieving a PSA level <0.2 ng/mL
timeFrame: Up to 4 years
measure: Duration of response (DOR)
timeFrame: Up to 4 years
measure: Radiographic progression-free survival (rPFS)
timeFrame: Up to 4 years
measure: Overall response rate (ORR) using RECIST v1.1
timeFrame: Up to 4 years
measure: Time to PSA progression
timeFrame: Up to 4 years
measure: Overall survival (OS)
timeFrame: Up to 4 years
measure: Time to first symptomatic skeletal-related event (SSRE)
timeFrame: Up to 4 years
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Arizona Urology Specialists
state: Arizona
city: Anaheim
country: United States
facility: Los Angeles Cancer Network
state: California
city: Santa Rosa
country: United States
facility: Providence Medical Group Oncology Santa Rosa
state: California
city: Tampa
country: United States
facility: Florida Urology Partners
state: Florida
city: Fort Wayne
country: United States
facility: Fort Wayne Medical Oncology and Hematology, Inc.
state: Indiana
city: Jeffersonville
country: United States
facility: First Urology
state: Indiana
city: Wichita
country: United States
facility: Wichita Urology Group
state: Kansas
city: Towson
country: United States
facility: Chesapeake Urology
state: Maryland
city: Omaha
country: United States
facility: XCancer Center Omaha/Urology Cancer Center
state: Nebraska
city: Morristown
country: United States
facility: Garden Sate Urology
state: New Jersey
city: Albuquerque
country: United States
facility: New Mexico Oncology Hematology Consultants Ltd
state: New Mexico
city: Durham
country: United States
facility: Duke Cancer Center
state: North Carolina
city: Middleburg Heights
country: United States
facility: Helios Clinical Research, LLC
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinical Cancer Center
state: Ohio
city: Bala-Cynwyd
country: United States
facility: MidLantic Urology
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Carolina Urologic Research Center
state: South Carolina
city: Nashville
country: United States
facility: Urology Associates PC
state: Tennessee
city: Dallas
country: United States
facility: Urology Clinics of North Texas
state: Texas
city: Houston
country: United States
facility: Houston Metro Urology
state: Texas
city: Houston
country: United States
facility: Oncology Consultants
state: Texas
city: San Antonio
country: United States
facility: Urology San Antonio
state: Texas
city: Charlottesville
country: United States
facility: University of Virginia Cancer Center
state: Virginia
city: Tacoma
country: United States
facility: Northwest Medical Specialties
state: Washington
city: San Juan
country: Puerto Rico
facility: Pan American Center for Oncology Trials, LLC
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Central Contact
role: STUDY_DIRECTOR
References: