A Comparative Dose-finding Study of RS-113 in Patients With Metastatic Castration-resistant Prostate Cancer

A Phase II, Open-label, Randomized, Comparative Dose-finding Study to Evaluate Efficacy, Safety, Tolerability, and Pharmacokinetics of RS-113 in Patients With Metastatic Castration-resistant Prostate Cancer

The primary objective of the study is to determine the therapeutic dose of RS-113 in patients with metastatic castration-resistant prostate cancer based on efficacy, safety, and pharmacokinetic parameters. The secondary objectives are to assess a pilot efficacy and safety of different doses of RS-113 versus abiraterone, as well as to investigate pharmacokinetics profile and to perform a pilot evaluation of pharmacokinetics parameters of RS-113 in patients with metastatic castration-resistant prostate cancer

This is an open-label, randomized, comparative phase II clinical trial conducted in 4 treatment arms:

• Arm 1: RS-113 160 mg (2 capsules) once daily (QD)
• Arm 2: RS-113 240 mg (3 capsules) QD
• Arm 3: RS-113 320 mg (4 capsules) QD
• Arm 4: abiraterone 1000 mg (4 tablets) QD plus prednisolone 10 mg QD

All enrolled patients who have not previously undergone a surgical castration will receive androgen deprivation therapy (ADT) with luteinizing hormone-releasing hormone (LHRH) analogues throughout the study

The study will include the following periods:

1. Screening period: up to 28 days Days [-27 to -0] prior to the first dose of the study treatment

2. Core study: up to 2 years Days [1 to 728]

   Eligible patients should be randomized to one of four treatment arms (in a 1:1:1:1 ratio):

   • Arm 1: RS-113 160 mg (2 capsules) QD
   • Arm 2: RS-113 240 mg (3 capsules) QD
   • Arm 3: RS-113 320 mg (4 capsules) QD
   • Arm 4: abiraterone 1000 mg (4 tablets) QD plus prednisolone 10 mg QD

   During the core study, the treatment will continue until the earliest of the following:

   • Day 728 (+7 days)
   • Disease progression (per RECIST 1.1 and PCWG3 criteria)
   • Unacceptable toxicity
   • Patient withdrawal from the study

   During the core study tumor response assessments will be performed approximately every 8 weeks for the first 24 weeks, and every 12 weeks thereafter

3. Extension phase

   Patients who had stable disease or tumor response within 2 years of treatment may be enrolled in an extension study. During the Extension phase, patients will continue to receive the same treatment regimen as assigned in the Core study

   During the Extension phase, the treatment will be administered from Day 728 until the earliest of the following:

   • Disease progression
   • Unacceptable toxicity
   • Patient withdrawal from the study

4. Follow-up period (follow-up/FU)

   • Patients who complete the planned 2-year study treatment and are not enrolled in the Extension phase will have one in-person Follow-up (FU) visit 28±3 days after the last dose of investigational product/comparator. This will be the final study visit for these patients. Subsequent treatment will be provided through the national healthcare system (as part of routine clinical practice) if indicated.
   • Patients who discontinue treatment early due to disease progression will have one in-person FU visit 28±3 days after the last dose of investigational product/comparator (for safety data collection). Thereafter, follow-up will be conducted via telephone contacts every 12 weeks until Day 728 or death (for survival data collection).
   • Patients who discontinue treatment early for reasons other than disease progression will have one in-person FU visit 28±3 days after the last dose of investigational product/comparator (for safety data collection). Subsequently, they will undergo FU visits with tumor response assessments every 8 weeks until Day 169, and then every 12 weeks until Day 728, disease progression, or initiation of new treatment, whichever occurs first

Completing the last visit means the end of participation in the clinical trial for each particular patient

Inclusion Criteria:

1. Voluntarily signed and dated Informed Consent Form (ICF) of the patient agreed to take part in this Study

2. Histologically confirmed diagnosis of prostate adenocarcinoma showing no neuroendocrine, signet-ring cell, small cell, or ductal differentiation

3. Ongoing androgen deprivation therapy for prostate cancer aimed at testosterone suppression with a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist at a stable dose and schedule for at least 4 weeks immediately prior to Day 1, or a history of bilateral orchiectomy (i.e., medical or surgical castration). Patients who have not undergone bilateral orchiectomy must agree to continue effective continuous LHRH analogue therapy throughout the study

4. Serum testosterone level ≤ 50 ng/dL (1.73 nmol/L)

5. Prostate-specific antigen (PSA) level > 2 ng/mL

6. Evidence of progressive disease at the time of randomization, defined by one or more of the following criteria:

   • PSA progression, defined as at least two consecutive increases in PSA levels occurring ≥ 2 weeks apart, with at least one increase documented during screening; the PSA level at screening must be ≥ 2 ng/mL
   • Soft tissue disease progression based on computed tomography (CT) or magnetic resonance imaging (MRI) assessment per RECIST v1.1
   • Bone disease progression based on bone scintigraphy findings

7. Disease progression occurring during androgen deprivation therapy or during or after docetaxel chemotherapy administered as first-line treatment for metastatic hormone-sensitive prostate cancer

8. Asymptomatic or mildly symptomatic prostate cancer, defined as a score < 4 on Question 3 of the Brief Pain Inventory-Short Form (BPI-SF)

9. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

10. Life expectancy ≥ 24 weeks

11. Major organ function must meet the following criteria:

    • Absolute neutrophil count (ANC) ≥ 1,500/mm^3 (1.5 × 10^9 cells/L)
    • Platelet count ≥ 100,000/mm^3 (100 × 10^9 cells/L)
    • Hemoglobin ≥ 90 g/L
    • Total bilirubin ≤ 1.5 × ULN
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × ULN, or ≤ 3 × ULN in the presence of liver metastases
    • Serum creatinine < 1.5 × ULN or estimated glomerular filtration rate (eGFR) > 45 mL/min, calculated using CKD-EPI equations

12. Fertile male patients must agree to abstain from heterosexual intercourse or to use highly effective methods of contraception, starting from the date of signing the informed consent form, throughout the entire study treatment period, and for at least 28 days after investigational product/comparator discontinuation

Exclusion Criteria:

1. Presence of central nervous system (CNS) metastases that are progressive or associated with clinical symptoms (e.g., cerebral edema, spinal cord compression), or requiring treatment with glucocorticoids and/or anticonvulsants. Patients with brain metastases may be enrolled in case adequate treatment (surgery and/or radiotherapy) has been completed and radiographic stability has been documented for at least 4 weeks prior to the planned date of randomization. Newly diagnosed CNS metastases identified during screening that are asymptomatic and do not require treatment are not considered an exclusion criterion

2. Prior antitumor therapy:

   • Radiotherapy (except palliative irradiation of bone lesions for pain control) within 4 weeks prior to the planned date of randomization
   • Prior treatment with first-generation antiandrogens (flutamide, bicalutamide, nilutamide) within 4 weeks prior to the planned date of randomization
   • Prior treatment with second-generation antiandrogens (enzalutamide, apalutamide, darolutamide)
   • Use of bisphosphonates or denosumab is permitted only if treatment was initiated prior to the planned date of randomization

3. Clinically significant cardiovascular disease, including:

   • Myocardial infarction within 6 months prior to the planned date of randomization
   • Unstable angina within 3 months prior to the planned date of randomization
   • Chronic heart failure NYHA class III or IV
   • Clinically significant ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation)
   • QTc interval > 460 ms on ECG (calculated using Fridericia formula), or long QT syndrome identified at screening
   • Left ventricular ejection fraction ≤ 50% by echocardiography
   • Hypotension (systolic blood pressure < 80 mmHg) or bradycardia (heart rate < 50 bpm), except when drug-induced (e.g., beta-blockers), at the time of the planned randomization
   • Uncontrolled arterial hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 105 mmHg) at the time of the planned randomization

4. Clinically significant CNS disorders, including:

   • History of seizures or conditions that may predispose to seizure development
   • Presence of stroke or transient ischemic attack within 12 months prior to the planned date of randomization
   • Primary brain tumors, cerebral arteriovenous malformations, meningiomas, schwannomas, or other benign CNS disorders that may require surgical or radiation treatment (patients with such conditions may be enrolled if no surgical or radiotherapy intervention is required)
   • Traumatic brain injury or loss of consciousness within 12 months prior to the planned date of randomization

5. Presence of untreated spinal cord compression or any other severe or systemic disease increasing the risk of treatment-related complications

6. Presence of clinically significant pituitary or adrenal dysfunction that cannot be adequately controlled with stable-dose hormonal or other standard therapy for at least 28 days prior to the planned date of randomization

7. History of another malignancy that is progressive or required anticancer treatment (including hormonal therapy) within 5 years prior to the planned date of randomization, except curatively treated basal cell or squamous cell carcinoma of the skin

8. History of other significant comorbid conditions that, in the investigator's opinion, may worsen during the study, including uncontrolled diabetes mellitus

9. Prior or concomitant therapy:

   • Use of medications that may induce seizures within 4 weeks prior to the planned date of randomization
   • Use of inhibitors or inducers of CYP3A4 or CYP2D6 within 4 weeks prior to the planned date of randomization
   • Use of medications classified as QT prolongation risk class I within 4 weeks prior to the planned date of randomization; QT risk class II medications are permitted if administered at a stable dose for at least 5 half-lives prior to the planned date of randomization
   • Prior or concomitant treatment with 5-alpha reductase inhibitors or anabolic steroids within 6 months prior to the planned date of randomization
   • Prior systemic glucocorticosteroid therapy at doses equivalent to ≥ 10 mg prednisone within 3 months prior to the planned date of randomization, except corticosteroids administered following brain irradiation, if treatment has been completed prior to enrollment in the study

10. History of allergic reactions, including reactions to medicinal products or food, that are clinically significant, in the opinion of the investigator

11. Presence of conditions limiting the patient's ability to comply with protocol requirements, including dementia, neurological or psychiatric disorders, substance or alcohol abuse, or religious or personal beliefs potentially limiting standard treatment during the study. Patients receiving narcotic analgesics for pain control may be enrolled.

12. Concurrent participation in another interventional clinical trial within 30 days prior to signing the informed consent form (if at least one dose of investigational product/comparator was received), or prior participation in this study (if at least one capsule of RS-113 or one tablet of abiraterone was administered by the patient)

13. Acute infectious diseases or exacerbation of chronic infections within 14 days prior to the planned date of randomization

14. Presence of current hepatitis B or C infection, evidence of HIV infection or active syphilis

15. Use of live vaccines within 30 days prior to the planned date of randomization. For patients receiving approved SARS-CoV-2 vaccines, the instructions for use and/or local requirements must be followed. Use of the Sputnik V vaccine is permitted provided that at least 7 days have elapsed between administration of the second vaccine dose and the first dose of the investigational product

16. Inability to swallow the investigational or comparator product

17. Inability to administer intravenous contrast

18. Presence of hypersensitivity (grade ≥ 3) to any component of RS-113, abiraterone, prednisone, or LHRH agonists (goserelin, leuprorelin, triptorelin, buserelin)

19. Presence of any other significant concomitant disease or condition that, in the investigator's reasonable judgment, may adversely affect the patient's participation, safety, or interpretation of study results