Metastatic Castration-resistant Prostate Cancer
Conditions
Keywords
Metastatic Castration-resistant Prostate Cancer, RS-113
Brief summary
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
Detailed description
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
Interventions
DRUGRS-113, 160 mg
Hard gelatin capsules, 80 mg
DRUGRS-113, 240 mg
Hard gelatin capsules, 80 mg
DRUGRS-113, 320 mg
Hard gelatin capsules, 80 mg
DRUGAbiraterone
Tablets, 250 mg
DRUGPrednisolone
Tablets, 5 mg
DRUGAndrogen deprivation therapy (ADT)
* Goserelin: subcutaneous implant, 3.6 mg or 10.8 mg, or * Leuprorelin: lyophilisate for solution for subcutaneous injection, 7.5 mg or 22.5 mg, or * Triptorelin: lyophilisate for solution for intramuscular injection, 3.75 mg, or * Buserelin: lyophilisate for solution for intramuscular injection, 3.75 mg
Sponsors
R-Pharm International, LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Masking description
Open label
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression-free survival (PFS) at 1 year in RS-113 treatment arms | Up to day 337 (visit 16) | Progression-free survival (PFS) expressed as the median PFS for a period of up to 1 year of treatment inclusive in RS-113 treatment arms (per RECIST 1.1 and PCWG3 criteria) PFS is defined as the time from randomization to disease progression per RECIST 1.1 (an ≥ 20% increase in the sum of diameters of target lesions taking as reference the smallest sum recorded during the study (with an absolute increase of sum at least 5 mm), or the appearance of ≥ 1 new lesions), or death due to any cause According to PCWG3, progression is defined as: * two or more new lesions detected on the first post-baseline scan with at least 2 additional lesions on a subsequent scan * two or more new lesions detected on a subsequent scan (if one or no new lesions were seen at the first post-baseline scan) and confirmed by a follow-up scan |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) rate (%) at 1 year in RS-113 treatment arms | Up to day 337 (visit 16) | Progression-free survival (PFS) expressed as the rate (%) at 1 year PFS in RS-113 treatment arms (per RECIST 1.1 and PCWG3 criteria) PFS is defined as the time from randomization to disease progression per RECIST 1.1 (an ≥ 20% increase in the sum of diameters of target lesions taking as reference the smallest sum recorded during the study (with an absolute increase of sum at least 5 mm), or the appearance of ≥ 1 new lesions), or death due to any cause According to PCWG3, progression is defined as: * two or more new lesions detected on the first post-baseline scan with at least 2 additional lesions on a subsequent scan * two or more new lesions detected on a subsequent scan (if one or no new lesions were seen at the first post-baseline scan) and confirmed by a follow-up scan |
| Prostate-specific antigen (PSA) response rate (%) in RS-113 treatment arms | at Week 9, 21, 33, 45, 57, 69, 81, 93, 101 and FU visit | Prostate-specific antigen (PSA) response rate (%) in RS-113 treatment arms |
| Number (%) of patients achieved ≥50% prostate-specific antigen (PSA) decline in RS-113 treatment arms | once at screening, on days 29 (visit 3), 57 (visit 5), 85-701 (visits 7-29) and FU visit | Number (%) of patients achieved ≥50% PSA decline at 6, 12, 18 and 24 months in RS-113 treatment arms Defined as a ≥50% reduction in PSA level from baseline at any time post-baseline. The response must be confirmed by the next PSA assessment performed at least 2 weeks later |
| Number (%) of patients achieved ≥90% prostate-specific antigen (PSA) decline in RS-113 treatment arm | once at screening, on days 29 (visit 3), 57 (visit 5), 85-701 (visits 7-29) and FU visit | Number (%) of patients achieved ≥90% PSA decline at 6, 12, 18 and 24 months in RS-113 treatment arm Defined as a ≥90% reduction in PSA level from baseline at any time post-baseline. The response must be confirmed by the next PSA assessment performed at least 2 weeks later |
| Objective response rate (ORR)(%) at 1 year in RS-113 treatment arms | once at screening, on days 57 (visit 5), 113 (visit 8), 169 (visit 10), 253 (visit 13), 337 (visit 16) and FU visit | The objective response rate (ORR)(%) is defined as the percentage of patients in RS-113 treatment arms who achieve a complete or partial response per RECIST 1.1: * Complete response (CR): disappearance of all target lesions confirmed by CT for at least 4 weeks; the short axis of any lymph node previously considered pathological (target or non-target) must be \< 10 mm * Partial response (PR): at least a 30% decrease in the sum of diameters of target lesions sustained for at least 4 weeks taking as reference the baseline sum at screening |
| Disease control rate (DCR)(%) at 1 year in RS-113 treatment arms | once at screening, on days 57 (visit 5), 113 (visit 8), 169 (visit 10), 253 (visit 13), 337 (visit 16) and FU visit | The disease control rate is defined as the percentage of patients in RS-113 treatment arms who achieve a complete response, partial response, or stable disease during treatment per RECIST 1.1: * Complete Response (CR) - disappearance of all target lesions, confirmed by CT scans for at least 4 weeks; the short axis of any lymph node previously considered pathological (target or non-target) must be \<10 mm * Partial Response (PR) - at least a 30% decrease in the sum of diameters of target lesions, maintained for at least 4 weeks taking as reference the baseline (screening) measurements * Stable Disease (SD) - neither sufficient shrinkage in the sum of diameters to qualify as partial response nor sufficient increase to qualify as progressive disease taking as reference the smallest sum recorded during the study |
| Time to Tumor Response (TTR) at 1 year in RS-113 treatment arms | once at screening, on days 57 (visit 5), 113 (visit 8), 169 (visit 10), 253 (visit 13), 337 (visit 16) and FU visit | Time to Tumor Response (TTR) at 1 year in RS-113 treatment arms |
| Duration of Response (DOR) at 1 year in RS-113 treatment arms | once at screening, on days 57 (visit 5), 113 (visit 8), 169 (visit 10), 253 (visit 13), 337 (visit 16) and FU visit | Duration of Response (DOR) at 1 year in RS-113 treatment arms |
| Time to prostate-specific antigen (PSA) progression in RS-113 treatment arms | once at screening, on days 29 (visit 3), 57 (visit 5), 85-701 (visits 7-29) and FU visit | Time to PSA progression is the time from randomization to the earliest date of confirmed PSA progression (per PCWG3 criteria). The date of PSA progression is defined as the date of a documented ≥25% increase in PSA and an absolute increase of ≥2 ng/mL above the nadir (or above baseline for patients with no PSA decline by Week 12), confirmed by two consecutive values obtained at least 3 weeks apart |
| Radiographic Progression-Free Survival (rPFS) at 1 year in RS-113 treatment arms | Up to day 337 (visit 16) | Radiographic Progression-Free Survival (rPFS) in RS-113 treatment arms, expressed as median rPFS for a period of up to 1 year of treatment inclusive (defined as the time from randomization to the first objective evidence of radiographic disease progression per RECIST 1.1 criteria or death due to any cause) |
| Overall survival (OS) rate (%) at 1 year in RS-113 treatment arms | Up to day 337 (visit 16) | Overall survival (OS) expressed as the rate (%) at 1 year OS in RS-113 treatment arms |
| Number of patients (%) with adverse drug reactions (ADRs) of any severity | Up to day 701 (visit 29) | Number of patients (%) with adverse drug reactions (ADRs) of any severity |
| Number of patients (%) with adverse events (AEs) of any severity | Up to day 701 (visit 29) | Number of patients (%) with adverse events (AEs) of any severity |
| Number of patients (%) with AEs grade ≥ 3 per CTCAE v. 5.0 | Up to day 701 (visit 29) | Number of patients (%) with AEs grade ≥ 3 per CTCAE v. 5.0 |
| Number of patients (%) with ADRs grade ≥ 3 per CTCAE v. 5.0 | Up to day 701 (visit 29) | Number of patients (%) with ADRs grade ≥ 3 per CTCAE v. 5.0 |
| Number of patients (%) with serious adverse events (SAEs) | Up to day 701 (visit 29) | Number of patients (%) with serious adverse events (SAEs) SAEs will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 |
| Number of patients (%) with serious adverse drug reactions (SADRs) | Up to day 701 (visit 29) | Number of patients (%) with serious adverse drug reactions (SADRs) SADRs will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 |
| Number of patients (%) who required discontinuation of treatment due to development of ADRs | Up to day 701 (visit 29) | Number of patients (%) who required discontinuation of treatment due to development of ADRs ADRs will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 |
| Number of patients (%) who required discontinuation of treatment due to development of SADRs | Up to day 701 (visit 29) | Number of patients (%) who required discontinuation of treatment due to development of SADRs SADRs will be graded according to the National Cancer Institute Common Terminology Criteria for adverse events (NCI-CTCAE) version 5.0 |
Countries
Russia
Contacts
STUDY_DIRECTORMikhail Samsonov
R-Pharm
Outcome results
None listed