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

This is an interventional treatment trial for Prostate Cancer focused on measuring 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 1/2a, Propella Read More

Inclusion Criteria:

1. Written informed consent obtained prior to any study-related procedure being performed.
2. Male patients at least 18 years of age or older at time of consent.
3. Histological evidence of adenocarcinoma of the prostate.

4. 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
5. Undergone orchiectomy or ongoing GnRH agonist or antagonist therapy for at least 1 month prior to the Screening Visit.
6. A serum testosterone level <50 ng/dL but greater than or equal to 2 ng/dL at screening.
7. Adequate muscle mass for an intramuscular injection
8. An Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

9. 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
10. 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.
11. 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.
12. Serum albumin greater than or equal to 3gm/dL and serum potassium greater than or equal to 3.5 mEq/L.
13. 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.

14. 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.

15. 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:

1. 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.
2. 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.
3. Impending bone fracture due to bone metastases

4. 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.

5. 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).
6. 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
7. 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.
8. Has not recovered from recent major surgery or trauma
9. Received a blood transfusion within 2 weeks of the Screening Visit
10. History of impaired pituitary or adrenal gland function (e.g., Addison's disease, Cushing's syndrome)
11. 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.
12. 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.
13. Prior treatment with estrogens within the previous 3 months
14. Need for systemic glucocorticoids greater than replacement doses; the use of topical, intraocular, inhalational, intranasal, or intra-articular glucocorticoids is permitted.
15. 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.
16. 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.
17. Required concomitant use of strong inducers of CYP3A4.
18. Known hypersensitivity to PRL-02, abiraterone, abiraterone decanoate, prednisone, or dexamethasone or any of their excipients or components.
19. 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).
20. 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).
21. Uncontrolled infection with human immunodeficiency virus (HIV+). Exception: patients with well-controlled HIV (e.g., CD4 >350/mm3 and undetectable viral load) are eligible.
22. Body mass index >40 kg/m2.