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
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 120
- 试验地点
- 16
- 主要终点
- Median Progression-free survival (PFS) at 1 year in RS-113 treatment arms
研究概览
简要总结
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
详细描述
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:
- Screening period: up to 28 days Days [-27 to -0] prior to the first dose of the study treatment
- Core study: up to 2 years Days [1 to 728]
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
盲法说明
Open label
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Voluntarily signed and dated Informed Consent Form (ICF) of the patient agreed to take part in this Study
- •Histologically confirmed diagnosis of prostate adenocarcinoma showing no neuroendocrine, signet-ring cell, small cell, or ductal differentiation
- •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
- •Serum testosterone level ≤ 50 ng/dL (1.73 nmol/L)
- •Prostate-specific antigen (PSA) level > 2 ng/mL
- •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
- •Disease progression occurring during androgen deprivation therapy or during or after docetaxel chemotherapy administered as first-line treatment for metastatic hormone-sensitive prostate cancer
- •Asymptomatic or mildly symptomatic prostate cancer, defined as a score < 4 on Question 3 of the Brief Pain Inventory-Short Form (BPI-SF)
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- •Life expectancy ≥ 24 weeks
- •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
- •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
排除标准
- •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
- •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
- •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
- •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
- •Presence of untreated spinal cord compression or any other severe or systemic disease increasing the risk of treatment-related complications
- •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
- •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
- •History of other significant comorbid conditions that, in the investigator's opinion, may worsen during the study, including uncontrolled diabetes mellitus
- •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
- •History of allergic reactions, including reactions to medicinal products or food, that are clinically significant, in the opinion of the investigator
- •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.
- •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)
- •Acute infectious diseases or exacerbation of chronic infections within 14 days prior to the planned date of randomization
- •Presence of current hepatitis B or C infection, evidence of HIV infection or active syphilis
- •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
- •Inability to swallow the investigational or comparator product
- •Inability to administer intravenous contrast
- •Presence of hypersensitivity (grade ≥ 3) to any component of RS-113, abiraterone, prednisone, or LHRH agonists (goserelin, leuprorelin, triptorelin, buserelin)
- •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
研究组 & 干预措施
RS-113, 160 mg + androgen deprivation therapy (ADT)
RS-113 is taken once daily (QD) orally, 2 capsules at a time (160 mg), 1 hour after a meal in the morning
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: RS-113, 160 mg (Drug)
RS-113, 160 mg + androgen deprivation therapy (ADT)
RS-113 is taken once daily (QD) orally, 2 capsules at a time (160 mg), 1 hour after a meal in the morning
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: Androgen deprivation therapy (ADT) (Drug)
RS-113, 240 mg + androgen deprivation therapy (ADT)
RS-113 is taken orally QD, 3 capsules at a time (240 mg), 1 hour after a meal in the morning
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: RS-113, 240 mg (Drug)
RS-113, 240 mg + androgen deprivation therapy (ADT)
RS-113 is taken orally QD, 3 capsules at a time (240 mg), 1 hour after a meal in the morning
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: Androgen deprivation therapy (ADT) (Drug)
RS-113, 320 mg + androgen-deprivation therapy (ADT)
RS-113 is taken orally QD, 4 capsules at a time (320 mg), 1 hour after a meal in the morning
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: RS-113, 320 mg (Drug)
RS-113, 320 mg + androgen-deprivation therapy (ADT)
RS-113 is taken orally QD, 4 capsules at a time (320 mg), 1 hour after a meal in the morning
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: Androgen deprivation therapy (ADT) (Drug)
Abiraterone + prednisolone + androgen deprivation therapy (ADT)
Abiraterone is taken at a dose of 1000 mg (4 tablets of 250 mg) QD, 1 hour before a meal or 2 hours after a meal in combination with prednisolone at a dose of 10 mg (2 tablets of 5 mg) QD
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: Abiraterone (Drug)
Abiraterone + prednisolone + androgen deprivation therapy (ADT)
Abiraterone is taken at a dose of 1000 mg (4 tablets of 250 mg) QD, 1 hour before a meal or 2 hours after a meal in combination with prednisolone at a dose of 10 mg (2 tablets of 5 mg) QD
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: Prednisolone (Drug)
Abiraterone + prednisolone + androgen deprivation therapy (ADT)
Abiraterone is taken at a dose of 1000 mg (4 tablets of 250 mg) QD, 1 hour before a meal or 2 hours after a meal in combination with prednisolone at a dose of 10 mg (2 tablets of 5 mg) QD
Androgen deprivation therapy (ADT) will be administered using analogues of luteinizing hormone-releasing hormone (aLHRH):
- goserelin (at a dose of 3.6mg every 28 days or 10.8 mg every 84 days, subcutaneously, into the anterior abdominal wall), or
- leuprorelin (7.5 mg every 28 days or 22.5 mg every 3 months, subcutaneously, into the anterior abdominal wall), or
- triptorelin (3.75 mg every 28 days intramuscularly), or
- buserelin (3.75 mg every 28 days, intramuscularly)
干预措施: Androgen deprivation therapy (ADT) (Drug)
结局指标
主要结局
Median Progression-free survival (PFS) at 1 year in RS-113 treatment arms
时间窗: 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
次要结局
- Progression-free survival (PFS) rate (%) at 1 year in RS-113 treatment arms(Up to day 337 (visit 16))
- 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)
- 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 ≥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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Radiographic Progression-Free Survival (rPFS) at 1 year in RS-113 treatment arms(Up to day 337 (visit 16))
- Overall survival (OS) rate (%) at 1 year in RS-113 treatment arms(Up to day 337 (visit 16))
- Number of patients (%) with adverse drug reactions (ADRs) of any severity(Up to day 701 (visit 29))
- Number of patients (%) with adverse events (AEs) of any severity(Up to day 701 (visit 29))
- Number of patients (%) with AEs 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(Up to day 701 (visit 29))
- Number of patients (%) with serious adverse events (SAEs)(Up to day 701 (visit 29))
- Number of patients (%) with serious adverse drug reactions (SADRs)(Up to day 701 (visit 29))
- 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 SADRs(Up to day 701 (visit 29))