Open-label, Multicenter Study of Intramuscular PRL-02 Depot in Patients With Advanced Prostate Cancer

Sponsor

Propella Therapeutics (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04729114

Collaborator

(none)

100

Enrollment

Locations

Arms

46.5

Anticipated Duration (Months)

12.5

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

A Phase 1/2a, open-label, multicenter study of intramuscular (i.m.) PRL-02 depot in participants with advanced prostate cancer.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer mCRPC mCSPC	Drug: PRL-02 Drug: Prednisone Drug: dexamethasone	Phase 1/Phase 2

Detailed Description

This is a Phase 1/2a, open-label, multicenter study of intramuscular (i.m.) PRL-02 depot in participants with advanced prostate cancer. In Phase 1 (Dose Escalation), participants will receive i.m. PRL-02 depot in 84-day treatment cycles combined with daily oral steroid, except for one Group, which will evaluate PRL-02 monotherapy (without an oral steroid). In Phase 2a (Dose Expansion), participants with advanced prostate cancer (mCSPC and mCRPC) will be treated with i.m. PRL-02 depot at one or more RP2Ds selected from Phase 1 in 84-day treatment cycles in combination with dexamethasone. In both phases, participants will undergo scheduled periodic assessments of serum testosterone levels.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

100 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

This is a 3+3 dose escalation study design with a dose expansion phase once a Phase 2 dose is identified.This is a 3+3 dose escalation study design with a dose expansion phase once a Phase 2 dose is identified.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

Phase 1/2a, Open-Label, Multicenter Study of Intramuscular PRL-02 Depot in Patients With Advanced Prostate Cancer

Actual Study Start Date :

Jun 14, 2021

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Apr 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 180 mg PRL-02 + dexamthasone or prednisone	Drug: PRL-02 abiraterone decanoate for intramuscular injection Drug: Prednisone 5 mg once daily or twice daily Drug: dexamethasone 0.5 mg administered once daily
Experimental: Cohort 2 360 mg PRL-02 + dexamthasone or prednisone	Drug: PRL-02 abiraterone decanoate for intramuscular injection Drug: Prednisone 5 mg once daily or twice daily Drug: dexamethasone 0.5 mg administered once daily
Experimental: Cohort 3 720 mg PRL-02 + dexamthasone or prednisone	Drug: PRL-02 abiraterone decanoate for intramuscular injection Drug: Prednisone 5 mg once daily or twice daily Drug: dexamethasone 0.5 mg administered once daily
Experimental: Cohort 4 1260 mg PRL-02 + dexamthasone or prednisone	Drug: PRL-02 abiraterone decanoate for intramuscular injection Drug: Prednisone 5 mg once daily or twice daily Drug: dexamethasone 0.5 mg administered once daily
Experimental: Cohort 5 1800 mg PRL-02 + dexamthasone or prednisone	Drug: PRL-02 abiraterone decanoate for intramuscular injection Drug: Prednisone 5 mg once daily or twice daily Drug: dexamethasone 0.5 mg administered once daily

Outcome Measures

Primary Outcome Measures

Safety (adverse events) [Treatment]
Determine the incidence rates for adverse events using NCI CTCAE v5.0 grading through study completion, an average of 1 year
Determination of recommended Phase 2 dose (RP2D) [Treatment]
Select RP2D of PRL-02 depot by evaluation of safety parameters up to 84 days
Testosterone suppression [Treatment]
Number of subjects with testosterone suppression to </= 1 ng/dL or >/90% reduction up to 84 days

Secondary Outcome Measures

Evaluate pharmacokinetics (PK) profile of PRL-02 [Treatment]
Determination of PK profiles of PRL-02 up to 84 days

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

Male

Accepts Healthy Volunteers:

Inclusion Criteria:

Written informed consent obtained prior to any study-related procedure being performed.
Male patients at least 18 years of age or older at time of consent.
Histological evidence of adenocarcinoma of the prostate.
Patients must have one of the following documented conditions:

Metastatic castration sensitive prostate cancer (mCSPC);
Castration sensitive prostate cancer (CSPC) with biochemical relapse (using the Prostate Cancer Working Group 3 [PCWG3] definition of PSA progression) of prostate cancer;
Castration sensitive prostate cancer (CSPC) with oligometastatic prostate cancer (e.g., Positron Emission Tomography (PET) positive);
Metastatic castration resistant prostate cancer (mCRPC);

Patients screened under protocol amendment 4 - Patients with one or more of the following:

CTC count of ≥5 cells/7.5 mL blood at screening confirmed by the central laboratory
Measurable disease according to RECIST v1.1 and a target lesion ≥1 cm in size at screening
PSA value ≥2 µg/L (2 ng/mL) at screening
Expansion Groups D and E: mCRPC and prior exposure to either abiraterone or enzalutamide

Undergone orchiectomy or ongoing GnRH agonist or antagonist therapy for at least 1 month prior to the Screening Visit.
A serum testosterone level <50 ng/dL but greater than or equal to 2 ng/dL at screening.
Adequate muscle mass for an intramuscular injection
An Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.
Adequate bone marrow reserve defined as:

Absolute neutrophil count (ANC) greater than or equal to 1500/µL
Platelet greater than or equal to 100,000/µL
Hemoglobin greater than or equal to 9gm/dL

Adequate renal function defined as a serum creatinine less than or equal to 1.5 x upper limit of normal (ULN) for the reference laboratory or a calculated creatinine clearance great than or equal to 50mL/min as determined by a validated algorithm for calculating creatinine clearance.
Adequate hepatic function defined as ALT and AST less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5 x 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 greater than or equal to 3gm/dL and serum potassium greater than or equal to 3.5 mEq/L.
Patients 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 study drug.
Phase 1 Expansion Groups D and E: Patients must have received prior abiraterone or enzalutamide respectively with documented evidence of progression with one or more of the following:

• PSA progression defined per PCWG3 criteria (Scher 2016) as ≥2 occurrences of rising PSA with a minimum of 1 week and a PSA concentration of ≥1 ng/mL if confirmed PSA rise is the only measure of progression OR worsening measurable disease on computed tomography (CT)/magnetic resonance imaging (MRI) per RECIST v1.1 criteria or at least one new documented lesion on a bone scan.

Patients Screened Under Protocol Amendment 4: Evidence of radiographic progression of metastatic disease at study entry, as assessed by the investigator, defined as measurable disease on CT/MRI per RECIST v1.1 or at least one documented bone lesion on a bone scan. Patients whose disease is limited to regional pelvic lymph nodes or local recurrence (e.g bladder, rectum) are not eligible.

Exclusion Criteria:

Patients with metastatic castration resistant prostate cancer (mCRPC) more than minimally symptomatic or with a reported pain score on an 11-point (0 - 10) numeric rating scale of >3 over the previous 7 days.
Known active central nervous system (CNS) metastases. Patients 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 patient is currently in remission and has been in remission for ≥2 years
Any other cancer from which the patient has been disease-free for ≥5 years The Medical Monitor should be contacted for any questions regarding this exclusion criterion.

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

Clinically significant cardiac arrhythmias including bradyarrhythmia and/or subjects who require anti-arrhythmic therapy (excluding beta blockers or digoxin). Subjects with controlled atrial fibrillation are not excluded.
Congenital long QT syndrome
QT interval corrected by Fredericia's formula (QTcF) ≥450 msec at screening (based on average of triplicate electrocardiograms [ECGs] at baseline). If the QT interval corrected for heart rate intervals (QTc) is prolonged in a patient with a pacemaker or bundle branch block, the patient may be enrolled in the study if confirmed by the Medical Monitor.
History of clinically significant cardiac disease or congestive heart failure

New York Heart Association Class II or left ventricular ejection fraction measurement of <50% at baseline. Patients 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 >160 mmHg or diastolic blood pressure >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).

Participated in an investigational drug study within 5 half-lives of the investigational drug or within 4 weeks of the Screening Visit, whichever is shorter
Any unresolved National Cancer Institute (NCI) CTCAE criteria v5.0 Grade >2 toxicity from previous anticancer therapy at the Screening Visit. Patients receiving ongoing replacement hormone 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 Screening Visit
History of impaired pituitary or adrenal gland function (e.g., Addison's disease, Cushing's syndrome)
Prior treatment with abiraterone, orteronel, or current treatment with systemic ketoconazole or any other CYP17 inhibitor. Exception: patients in Phase 1 Expansion Group D will have received prior abiraterone.
Current treatment with enzalutamide, flutamide, nilutamide, bicalutamide, or any other androgen receptor (AR) blocking agents. Patients who have received anti-androgens or AR blocking agents must have discontinued bicalutamide ≥6 weeks and other antiandrogens ≥4 weeks prior to the Screening Visit.
Prior treatment with estrogens within the previous 3 months
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 30 days of the Screening Visit. Patient 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 2021]. Note: Patients who switch from a high dose to a dose of 30 µg/day or less are eligible for study entry.
Required concomitant use of strong inducers of CYP3A4.
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), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid).
Hemoglobin A1c (HbA1c) >10% in patients previously diagnosed with diabetes mellitus. HbA1c >8% in patients whose diabetes mellitus is previously undiagnosed. (Excluded patients may be rescreened after referral and evidence of improved control of their condition).
Uncontrolled infection with human immunodeficiency virus (HIV+). Exception: patients with well-controlled HIV (e.g., CD4 >350/mm3 and undetectable viral load) are eligible.
Body mass index >40 kg/m2.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	First Urology	Jeffersonville	Indiana	United States	47130
2	Chesapeake Urology	Towson	Maryland	United States	21204
3	GU Research	Omaha	Nebraska	United States	68130
4	Xcancer/NM Oncology	Albuquerque	New Mexico	United States	87109
5	Centers for Advanced Urology, LLP, d/b/a: MidLantic Urology	Bala-Cynwyd	Pennsylvania	United States	19004
6	Carolina Urologic Research Center	Myrtle Beach	South Carolina	United States	29572
7	Urology Associates PC	Nashville	Tennessee	United States	37209
8	Urology San Antonio	San Antonio	Texas	United States	78229