Efficacy, Safety, and Pharmacokinetics of FP-014, 22.5 mg in Patients With Advanced Prostate Cancer

This is a study in male patients with advanced prostate cancer who are eligible for androgen ablation therapy. The study duration will be up to 48 weeks.

Eligibility will be assessed during a screening period of up to 28 days. Up to 2 doses of a long-acting FP-014, 22.5 mg formulation will be given to the patients by separate SC injections 24 weeks apart in an unblinded manner. The first dose of FP-014, 22.5 mg will be administered on Day 0 (Visit 2/Week 1). When patients have tolerated the first dose of FP-014, 22.5 mg and have achieved castrate levels of serum testosterone, a second dose will be administered on Day 168 (Visit 14/Week 24) to achieve castrate levels of serum testosterone concentrations (\< 50 ng/dL). Patients will be followed for efficacy, safety, tolerability, and ancillary clinical and laboratory markers for an additional 24-week observation period (Day 336/Week 48/ Visit 24) Blood samples will be collected at Baseline (Day 0/Week 1) at least 30 minutes before the first FP-014, 22.5 mg administration, immediately thereafter and at specified time points through Day 336 (Week 48) to determine PK (triptorelin) and pharmacodynamics (PD) (testosterone, PSA, and LH) profiles.

This is a study in male patients with advanced prostate cancer who are eligible for androgen ablation therapy. The study duration will be up to 48 weeks.

Eligibility will be assessed during a screening period of up to 28 days. Up to 2 doses of a long-acting FP-014, 22.5 mg formulation will be given to the patients by separate SC injections 24 weeks apart in an unblinded manner. The first dose of FP-014, 22.5 mg will be administered on Day 0 (Visit 2/Week 1). When patients have tolerated the first dose of FP-014, 22.5 mg and have achieved castrate levels of serum testosterone, a second dose will be administered on Day 168 (Visit 14/Week 24) to achieve castrate levels of serum testosterone concentrations (\< 50 ng/dL). Patients will be followed for efficacy, safety, tolerability, and ancillary clinical and laboratory markers for an additional 24-week observation period (Day 336/Week 48/ Visit 24) Blood samples will be collected at Baseline (Day 0/Week 1) at least 30 minutes before the first FP-014, 22.5 mg administration, immediately thereafter and at specified time points through Day 336 (Week 48) to determine PK (triptorelin) and pharmacodynamics (PD) (testosterone, PSA, and LH) profiles.

To evaluate the sustained castration testosterone level after two administrations of FP-014, 22.5 mg, the first 30 enrolled patients will be considered as a subset for PK assessments. For these 30 subjects, additional PK/PD analyses will be performed on dosing days to obtain an extended PK/PD profile of serum triptorelin and testosterone levels.

The efficacy assessments will be performed in both intent-to-treat (ITT) and per-protocol (PP) populations. Efficacy assessment will include the percentage of patients who reached the castrate levels (\< 50 ng/dL) of serum testosterone on Day 28 (± 2 days; Week 4) post the first dosing of FP-014, 22.5 mg. Furthermore, the effect of FP-014, 22.5 mg on serum levels of PSA, and LH will be assessed post the first and the second dosing of FP-014, 22.5 mg, respectively. Urinary tract signs and symptoms will be evaluated for efficacy using the International Prostate Symptom Score \[I-PSS\] and recorded in the electronic case report forms (eCRFs). The acute-on-chronic (surge) effect of serum testosterone and LH levels will also be monitored in all patients. In addition, the impact of FP-014, 22.5 mg, on the percentage (rate) of patients with PSA relapse, on the percentage of patients that achieves normal serum PSA level, and on the percentage of patients with an enhanced serum testosterone concentration suppression (\< 20 ng/dL) will be determined at the end of study.

All treatment emergent adverse events (TEAEs), including adverse events of interest (AEoI), that occur during the study period and serious adverse events (SAEs) that occur during the study period will be recorded in the eCRFs and followed until they are resolved or considered stable. In addition, all SAEs will be recorded and reported as required by local and international regulatory requirements.

Other safety assessments and their results including safety clinical laboratory parameters, vital signs, physical examination, resting 12-lead electrocardiogram (ECG), injection site reactions and bone pain (assessed using visual analog scale \[VAS\]) will also be recorded in the eCRF.

Patients who discontinue early should be encouraged to remain in the study for safety evaluations.

A Data Safety Monitoring Board (DSMB) composed of independent experts will review available safety results every 3 months, and on an ad hoc basis if deemed necessary, from the moment onwards when one month data is available from approximately 5% of enrolled patients until the last patient completes the study. The composition and responsibilities of the DSMB will be defined in a separate DSMB charter.

Eligibility Criteria:
Inclusion Criteria:

1. Males aged ≥ 18 years old at Screening.
2. Histologically confirmed carcinoma of the prostate at the time of Screening.
3. Metastatic or biochemically recurrent prostate cancer disease at Screening.
4. Patient agrees to use male contraceptive methods during the study.
5. In the Investigator's opinion, the patient understands the nature of the study and any hazards of participation, communicates satisfactorily with the Investigator, and is able to participate in and comply with the requirements of the entire protocol.
6. Patients judged by the attending physician and/or Principal Investigator to be a candidate for androgen ablation therapy.
7. Patients who are able to tolerate ablation therapy but are considered unable to tolerate androgen receptor pathway inhibitors.
8. ECOG Performance Status score ≤ 2 and life expectancy of at least 18 months at Screening.
9. Baseline morning serum testosterone level \> 150 ng/dL at Screening.
10. Laboratory values at Screening:

    * Absolute neutrophil count ≥ 1,500 cells/μL;
    * Platelets ≥ 100,000 cells/μL;
    * Hemoglobin ≥ 10 gm/dL;
    * Total bilirubin ≤ 1.5 × upper limit of normal (ULN);
    * AST ≤ 2.5 × ULN;
    * ALT ≤ 2.5 × ULN;
    * Creatinine Clearance ≥ 30 mL/min or estimated Glomerular Filtration Rate (eGFR) \> 30 mL/min/1.73°m2 or evidence of acute kidney injury;
    * Lipid profile within the acceptable range according to the Investigator's opinion;
    * Serum glucose within the acceptable range according to the Investigator's opinion;
    * HbA1c within the acceptable range according to the Investigator's opinion;
    * Clinical chemistries (K, Na, Mg, Ca, and P) within the acceptable range according to the Investigator's opinion;
    * Normal urinalysis results:

      * red blood cells (RBCs) ≤ 3 RBCs/hpf;
      * white blood cells (WBCs) ≤ 5 WBCs/hpf;
      * nitrate: negative;
      * glucose: \<0.1 g/dL in patients without diabetes mellitus Type II and \< 1.0 g/dL in patients with diabetes mellitus Type II.

Exclusion Criteria:

1. Receipt of chemotherapy, immunotherapy, cryotherapy, radiotherapy, or anti- androgen therapy within 8 weeks prior to Screening, for treatment of carcinoma of the prostate.
2. Receipt of any luteinizing hormone-releasing hormone (LH-RH) suppressive therapy within 6 months of the Screening Visit.
3. Receipt of any vaccination (including influenza) within 2 weeks of the Screening Visit.
4. History of blood donation within 2 months of the Screening Visit.
5. History of anaphylaxis to any LH-RH analogues.
6. Contraindication to triptorelin or an LH-RH agonist as indicated on the package labeling.
7. Previous exposure to triptorelin mesylate.
8. Major surgery, including any prostatic surgery (excluding prostatic biopsy), within 4 weeks of the Screening Visit.
9. History of bilateral orchiectomy, adrenalectomy, or hypophysectomy.
10. History of clinical and radiographic evidence of central nervous system dysfunction.
11. Spinal cord metastases and patients at risk for spinal cord compression.
12. Clinical evidence of uncontrolled active urinary tract obstruction and patients at risk for urinary obstruction.
13. Clinically significant abnormal ECG at Screening and/or history of clinically significant ECG.
14. Cardiovascular disease that is clinically significant as judged by the Investigator.
15. History of Uncontrolled diabetes, HbA1C \>9.5%, urine glycosuria \>1.0 g/dl, or presence of diabetic ketoacidosis.
16. History of liver dysfunction, including patients with moderate (Child-Pugh B) or severe (Child-Pugh C) impairment or disordered coagulation.
17. End-stage renal diseases on peritoneal dialysis or hemodialysis.
18. History or presence of hypogonadism; or receipt of exogenous testosterone supplementation within 6 months of Screening Visit.
19. Use of systemic corticosteroids at a dose \> 10 mg/day at Screening.
20. Use of 5-alpha reductase inhibitor within the last 6 months of Screening Visit.
21. Use of any over-the-counter (OTC) medication within 4 weeks of the Screening Visit, except for those listed as permitted concomitant treatment.
22. History of drug and/or alcohol abuse within 6 months of Screening Visit.
23. Use of any investigational agent within 4 weeks of the Screening Visit.
24. Use of any therapeutics with strong inhibitors and strong inducers of CYP3A4 or CYP2C8 \[e.g., rifampicin, ketoconazole, phenytoin, ritonavir, macrolide antibiotics (e.g. telithromycin)\] at the time of Screening.