Clinical trial NCT03850795: HC-1119 Versus Enzalutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Official title: PROCADE: A Multinational Phase 3, Randomized, Double-Blind, Non-inferiority, Efficacy and Safety Study of Oral HC-1119 Versus Enzalutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Prostate Cancer Metastatic
Castration-resistant Prostate Cancer
Keywords: HC-1119
enzalutamide
Lead sponsor: Hinova Pharmaceuticals USA, Inc.
Sponsor class: INDUSTRY
First posted: 2019-02-22
Enrollment: 104
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is a multinational Phase 3, randomized, double-blind, non-inferiority, efficacy and safety study of oral HC-1119 (80 mg/day) versus enzalutamide (160 mg/day) in asymptomatic or mildly symptomatic patients with progressive metastatic castration-resistant prostate cancer (mCRPC).

The following assessment of prostate cancer status will be collected during the course of the trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance imaging (MRI), bone disease on radionuclide bone scans, FACT-P and EQ-5D, Brief Fatigue Inventory, and PSA.

Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms (ECGs). Blood samples for population pharmacokinetics for HC-1119 and enzalutamide and related metabolites will be collected.

Detailed description: This study is a multinational Phase 3, randomized, double-blind, non-inferiority, efficacy and safety study of oral HC-1119 (80 mg/day) versus enzalutamide (160 mg/day) in asymptomatic or mildly symptomatic patients with progressive metastatic castration-resistant prostate cancer (mCRPC). Patients must not have been previously treated with next generation AR-Inhibitors or Androgen-biosynthesis Inhibitors, or prior progression on ketoconazole.

The following assessments of prostate cancer status will be collected during the course of the trial: soft tissue disease on computed tomography (CT) scan or on magnetic resonance imaging (MRI), bone disease on radionuclide bone scans, FACT-P and EQ-5D, Brief Fatigue Inventory, and PSA. Radiographic disease progression is defined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1) for soft tissue disease, or the appearance of two or more new bone lesions on bone scan.

Throughout the study, safety and tolerability will be assessed by the recording of adverse events, monitoring of vital signs and physical examinations, safety laboratory evaluations, and 12-lead electrocardiograms (ECGs). Blood samples for population pharmacokinetics for HC-1119 and enzalutamide and related metabolites will be collected pre-dose on Day 1 and prior to dosing on Days 8 (Week 2), 15 (Week 3) and 22 (Week 4), 29 (Week 5), 57 (Week 9), 85 (Week 13) and Day 169 (Week 25). Blood samples for calculating a 24 hour pharmacokinetic profile of HC-1119 and enzalutamide and related metabolites will be collected in a subset of 24 Caucasian (non-Chinese) patients on Day 1 and at steady state in week 9.

Patients will have a safety follow-up visit 30 days after their last dose of study drug or prior to initiation of any new therapy, or an investigational agent, whichever occurs first.

Eligibility criteria: Inclusion Criteria:

Subjects must meet the following inclusion criteria:

1. Age 18 or older and willing and able to give informed consent.
2. Histologically or cytologically confirmed adenocarcinoma of the prostate without significant and relevant neuroendocrine differentiation or small cell features, per investigator's judgment.
3. Ongoing ADT with a GnRH analogue, antagonist or bilateral orchiectomy (i.e., surgical or medical castration).
4. For patients who have not had a bilateral orchiectomy, there must be a plan to maintain effective GnRH analogue or antagonist therapy for the duration of the trial.
5. Serum testosterone level \< 1.7 nmol/L (50 ng/dL) at the Screening visit.
6. Patients receiving bisphosphonate or denosumab therapy must have been on stable doses for at least four weeks (from Day 1 visit).
7. Progressive disease at study entry defined as one or more of the following three criteria that occurred while the patient was on ADT as defined in eligibility criterion #3:

   1. PSA progression defined by a minimum of two rising PSA levels with an interval of ≥ 1 week between each determination. Patients who received an anti-androgen agent must have progression after withdrawal (≥ 4 weeks since last flutamide or ≥ 6 weeks since last bicalutamide or nilutamide). The PSA value at the Screening visit should be ≥ 2 µg/L (2 ng/mL)
   2. Soft tissue disease progression defined by RECIST 1.1
   3. Bone disease progression defined by PCWG3 with two or more new lesions on bone scan
8. Metastatic disease documented by measurable soft tissue disease by CT/MRI per RECIST 1.1 criteria. Patients are allowed to have any metastatic disease (i.e. bone metastasis) as long as they also have measurable soft tissue lesions per RECIST 1.1..
9. No prior cytotoxic chemotherapy for prostate cancer.
10. Asymptomatic or mildly symptomatic from prostate cancer.
11. ECOG performance status of 0-1 per the Investigators' clinical assessment
12. Estimated life expectancy of ≥ 6 months
13. Able to swallow the study drug and comply with study requirements
14. All sexually active patients are required to use a condom as well as meet 1 of the following:

    1. Patient is non-fertile (orchiectomy) or has a female partner of non-childbearing potential (i.e., post-menopausal, surgically sterilized, hysterectomy)
    2. Patient and his female partner must agree to use an adequate contraceptive method from the first day of dosing until 3 months after the last dose to prevent pregnancies. Adequate contraceptive method is defined as:

    i. Established use of oral, injected, or implanted hormonal methods of contraception.

    ii. Placement of an intra-uterine device or intra-uterine system. iii. Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.

    iv. Tubal ligation for at least 6 months prior to screening.
15. Male patient engaged in sexual activity with a pregnant female is required to use a condom from the first day of dosing until 3 months after the last dose of treatment with study drugs.

Exclusion Criteria:

Subjects must NOT meet any of the following exclusion criteria:

1. Severe concurrent disease, infection, or co-morbidity that, in the judgment of the investigator, would make the patient inappropriate for enrollment.
2. Known or suspected brain metastasis or active leptomeningeal disease.
3. Regular daily use of opiate analgesics for pain from prostate cancer within four weeks of enrollment (Day 1 visit).
4. WBC count \< 3,000/µL, or absolute neutrophil count \< 1,500/µL, or platelet count \< 100,000/µL, or hemoglobin \< 5.6 mmol/L (9 g/dL) at the Screening visit (NOTE: patients may not have received any growth factors or blood transfusions or any therapeutic invention within 14 days of the hematologic laboratory values obtained at the Screening visit).
5. Total bilirubin, alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \> 2.5 times the upper limit of normal at the Screening visit; no therapeutic invention within 14 days before screening.
6. Creatinine clearance \< 30 mL/min as calculated using the Cockcroft-Gault equation at the Screening visit. Creatinine Clearance (mL/min) = \[\[140-Age (years)\] \* Weight (kg)\] / \[72 \* Serum Creatinine (mg/dL)\]
7. Albumin \< 30 g/L (3.0 g/dL) at the Screening visit, no therapeutic invention within 14 days before screening.
8. History of another malignancy within the previous two years other than curatively treated non-melanomatous skin cancer.
9. Treatment with flutamide within four weeks of enrollment (Day 1 visit).
10. Treatment with bicalutamide or nilutamide within six weeks of enrollment (Day 1 visit).
11. Treatment with 5-α reductase inhibitors (finasteride, dutasteride), estrogens within four weeks of enrollment (Day 1 visit).
12. Treatment with systemic biologic therapy for prostate cancer (other than approved bone targeted agents) within four weeks of enrollment (Day 1 visit).
13. Use of herbal products that may have hormonal anti-prostate cancer activity and/or are known to decrease PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone/prednisolone per day within four weeks of enrollment (Day 1 visit).
14. Prior use, or participation in a clinical trial, of an agent that blocks androgen synthesis (e.g., abiraterone) or blocks the AR (e.g., apalutamide, darolutamide, enzalutamide, proxalutamide).
15. Participation in a previous clinical trial of HC-1119.
16. Use of an investigational agent within four weeks of enrollment (Day 1 visit).
17. Radiation therapy for treatment of the primary tumor within three weeks of enrollment (Day 1 visit).
18. Radionuclide therapy (Radium 223) for treatment of metastasis within four weeks of enrollment (Day 1 visit).
19. Clinically significant cardiovascular disease or condition
20. Treatment with strong CYP2C8 inhibitors and inducers, CYP3A4 inducers, medications which are known to prolong the QT interval (see Appendix C).
21. History of seizure or any condition that may predispose to seizure.
22. Conditions that predispose subjects to increased risk for falls or fractures according to the discretion of the Investigator.
23. Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last three months).
24. Major surgery within four weeks prior to enrollment (Day 1 visit).
25. Have active infection with HBV measured by hepatitis B surface antigen (HBsAg) test, HCV measured by RNA test and HIV measured by antibody test.
26. Have known active tuberculosis.
27. Known hypersensitivity to HC-1119, enzalutamide, or any of the excipients.
28. Rare hereditary problems of fructose intolerance due to sorbitol

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: Week 24
Secondary outcomes:
measure: PSA decline of ≥50% from baseline
timeFrame: Week 24
measure: Radiographic Progression-free Survival (rPFS)
timeFrame: Week 24
measure: Overall Survival (OS)
timeFrame: Week 24
measure: Safety and Tolerability (based on Common Terminology Criteria for Adverse Events (CTCAE), version 5.0)
timeFrame: Week 24
Other outcomes:
Locations:
city: Denver
country: United States
facility: Urology Center of Colorado, 2777 Mile High Stadium Circle
state: Colorado
city: Washington
country: United States
facility: Urologic Surgeons of Washington
state: District of Columbia
city: Jeffersonville
country: United States
facility: First Urology PSC, 101 Hospital Boulevard
state: Indiana
city: Middleburg Heights
country: United States
facility: Clinical Research Solutions PC
state: Ohio
city: Bala-Cynwyd
country: United States
facility: MidLantic Urology
state: Pennsylvania
city: Lancaster
country: United States
facility: Keystone Urology Specialists
state: Pennsylvania
city: San Antonio
country: United States
facility: Urology San Antonio Stone Oak, 18915 Meisner Drive
state: Texas
city: Lacey
country: United States
facility: Providence Regional Cancer System
state: Washington
city: Southport
country: Australia
facility: Icon Cancer Care Gold Coast
state: Queensland
city: Kurralta Park
country: Australia
facility: Ashford Cancer Centre Research
state: South Australia
city: Nedlands
country: Australia
facility: Affinity Clinical Research
city: Linz
country: Austria
facility: Kepler Universitätsklinikum Linz
city: Oakville
country: Canada
facility: Fe/Male Health Centre
state: Ontario
city: Sherbrooke
country: Canada
facility: CIUSSS de l'Estrie-CHUS
state: Quebec
city: Aalborg
country: Denmark
facility: Aalborg Universitetshospital
city: Odense C
country: Denmark
facility: Odense Universitetshospital
city: Helsinki
country: Finland
facility: Helsinki University Hospital Comprehensive Cancer Center - PPDS
city: Oulu
country: Finland
facility: Oulun Yliopistollinen Sairaala
city: Seinäjoki
country: Finland
facility: Seinäjoen Keskussairaala
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: Suresnes
country: France
facility: Hopital Foch
state: Hauts-de-Seine
city: Le Mans
country: France
facility: Centre Jean Bernard Clinique Victor Hugo
city: Lille Cedex
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: Centre Léon Berard
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Saint-Mandé
country: France
facility: Hopital d'Instruction des Armées de Begin
city: Nürtingen
country: Germany
facility: Urologische Studienpraxis
state: Baden-Württemberg
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Tübingen
country: Germany
facility: Universitätsklinikum Tübingen
city: Wuppertal
country: Germany
facility: UroGynZentrum Wall
city: Terni
country: Italy
facility: Azienda Ospedaliera S Maria Di Terni
state: Umbria
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata Di Verona
city: Sneek
country: Netherlands
facility: Antonius Ziekenhuis
state: Friesland
city: Nijmegen
country: Netherlands
facility: Canisius Wilhelmina Ziekenhuis
state: Gelderland
city: Eindhoven
country: Netherlands
facility: Catharina Hospital
state: Noord-Brabant
city: Den Haag
country: Netherlands
facility: Hagaziekenhuis
state: Zuid-Holland
city: Mysłowice
country: Poland
facility: NZOZ Centrum Urologiczne Sp zoo
state: Slaskie
city: Poznań
country: Poland
facility: Clinical Research Center Spolka z Ograniczona
state: Wielkopolskie
city: Lublin
country: Poland
facility: Onko-Centrum Sp. z o.o.
city: Siedlce
country: Poland
facility: Urologica Praktyka Lekarska Adam Marcheluk
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy
city: Barnaul
country: Russian Federation
facility: Altay Regional Oncology Center
city: Ivanovo
country: Russian Federation
facility: Ivanovo Regional Oncology Dispensary
city: Obninsk
country: Russian Federation
facility: Federal State Institution Medical Radiology Research Center
city: Omsk
country: Russian Federation
facility: Clinical Oncology Dispensary
city: Saint Petersburg
country: Russian Federation
facility: First St. Petersburg State Medical University n.a. I.P Pavlov
city: Saint Petersburg
country: Russian Federation
facility: GBUZ Saint Petersburg Clinical Research Center of Specialized Types of Care (Oncology)
city: Saint Petersburg
country: Russian Federation
facility: Hospital Orkli LLC
city: Córdoba
country: Spain
facility: C.H. Regional Reina Sofia - PPDS
city: Lugo
country: Spain
facility: Hospital Lucus Augusti
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Málaga
country: Spain
facility: Hospital Regional Universitario de Malaga - Hospital Civil
city: Sevilla
country: Spain
facility: Hospital Universitario Virgen del Rocio - PPDS
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
city: Grimsby
country: United Kingdom
facility: Diana Princess of Wales Hospital
state: South Humberside
city: Belfast
country: United Kingdom
facility: Belfast City Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital - London
city: Northwood
country: United Kingdom
facility: Mount Vernon Hospital
Study officials:
References: