A Phase 3 Study Evaluating the Efficacy and Safety of NDV-01 in Participants With Non-muscle Invasive Bladder Cancer (RESCUE)
试验速览
- 阶段
- 3 期
- 状态
- 尚未招募
- 入组人数
- 393
- 主要终点
- Disease Free Survival in participants with Intermediate Risk NMIBC
研究概览
简要总结
Study REL-NDV01-303 is a Phase 3, open-label, multi-center study to determine the safety and efficacy of NDV-01 in adult participants with NMIBC. The study will include two cohorts:
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Cohort 1: a randomized, open-label, parallel group, multi-center, Phase 3 study evaluating the efficacy and safety of the NDV-01 versus observation in participants with histologically confirmed IR-NMIBC.
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Cohort 2: an open-label, multi-center, single-arm Phase 3 study evaluating the efficacy and safety of the NDV-01 in two populations of high-risk NMIBC:
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Cohort 2a: will include participants with HR-NMIBC who have a biopsy-proven recurrence with CIS ± papillary disease after receiving one or 2 lines of therapy for BCG-unresponsive NMIBC (approved or in development).
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Cohort 2b: will include participants with high-risk papillary-only disease (without CIS) NMIBC who have a biopsy-proven recurrence with HG papillary disease after receiving one or 2 lines of therapy for BCG-unresponsive NMIBC (approved or in development).
This study will evaluate the safety and efficacy of intravesical administration of NDV-01, and its effect on disease recurrence and progression in patients with NMIBC who have IR disease and have recently undergone a TURBT (Cohort 1) and in patients who have HR BCG-unresponsive disease and who have recurred after first-line therapy for BCG-unresponsive patients - both approved and in development - and are unwilling or unable to undergo radical cystectomy (Cohort 2). Both GEM and DOCE have established safety and efficacy across a range of tumor types, including IR and BCG-unresponsive NMIBC. By combining both GEM and DOCE in an intravesical extended-release formulation, Relmada believes that NDV-01 has the potential to be an agent for second-line therapy in patients who have recurred after first-line therapy in BCG-unresponsive disease, thereby avoiding radical cystectomy. This study will serve as a master protocol for all cohorts included in the study.
详细描述
The study is comprised of two cohorts, described in the sections that follow.
Cohort 1 (Intermediate Risk)
Cohort 1 is a randomized, open-label, parallel group, multi-center, Phase 3 study evaluating the efficacy and safety of the NDV-01 versus observation in participants with histologically confirmed IR-NMIBC. Eligible participants must have IR-NMIBC according to the AUA/Society of Urologic Oncology (SUO) guidelines definition and at least one of the following risk factors: multiple LG tumors (Ta), solitary LG tumor >3 cm, solitary HG tumor < 3 cm, early recurrence of LG tumor (<1 year), frequent recurrence (>1 per year), or recurrence after prior intravesical chemotherapy. LGT1 tumors are the exception. The IR-NMIBC diagnosis qualifying the participant for the study must be within 90 days of randomization. All participants in Cohort 1 will have undergone TURBT with complete resection of all papillary diseases and will be confirmed to be disease-free within 90 days prior to randomization. All enrolled participants will have histologically confirmed IR-NMIBC.
A target of 276 participants will be randomized 1:1 (N=138 per arm) to treatment with either NDV-01 (Treatment Group) or observation (Control Group). Participants will be stratified based on 1) low-grade vs. high-grade disease and 2) the use of perioperative chemotherapy (Yes/No). Eligible participants should have had a TURBT or tumor excision within 90 days of randomization. The TURBT procedure may include a single dose of perioperative chemotherapy per the Investigators' decision and local standard of care.
Participants in the Treatment Group will have NDV-01 instilled into the bladder via a urethral catheter on Day 1 of the Treatment Phase (i.e., start of Week 0) and NDV-01 will be delivered biweekly for 12 weeks, followed by maintenance therapy once every month for up to 12 months after Day 1.
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
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Cohort 1 Inclusion Criteria:
- •Be ≥18 years of age (or the legal age of majority in the jurisdiction in which the study is taking place) at the time of informed consent.
- •Have a histologically confirmed diagnosis (within 90 days of randomization) of IR NMIBC based on the AUA/SUO criteria of IR NMIBC (excluding LGT1 tumors).
- •Participant must be willing to undergo all study procedures (e.g., multiple cystoscopies from Screening through the end of study and TURBT for assessment of recurrence/progression) and receive the assigned treatment, including intravesical chemotherapy if randomized into that arm.
- •Participant must have ≥ 1 IBCG risk factors: 1) multiple tumors, 2) early recurrence (within 1 year), 3) frequent recurrences (> 1 per year), 4) tumor size (> 3 cm), 5) failure of prior induction intravesical therapy.
- •Visible papillary disease must be fully resected prior to randomization, and absence of disease must be documented at Screening cystoscopy. The same method for visualizing disease at Screening cystoscopy should be used throughout for the participant (white light versus enhanced cystoscopic method [e.g., blue light cystoscopy, narrow-band imaging]).
- •All pathology specimens must be predominantly urothelial (transitional cell) and have less than 20% variant (e.g., sarcomatoid, squamous component) histology.
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or
排除标准
- •Histologically confirmed stage T1 tumors.
- •Histologically confirmed diagnosis of HR NMIBC (including CIS) or muscle-invasive bladder cancer (MIBC), locally advanced, nonresectable, or metastatic urothelial carcinoma at any time prior to enrollment.
- •Has had urothelial carcinoma outside of the urinary bladder (including prostatic urethra, ureter, or renal pelvis) or has a predominant histological variant of urothelial carcinoma (UC). Ta/any T1, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study.
- •Participant has tumor(s) involving the prostatic urethra (ductal or stromal).
- •N+ and/or M+ per computed tomography (CT)/magnetic resonance (MR) urography.
- •Received an investigational treatment for bladder cancer within 6 months prior to randomization, before the planned first dose of study treatment, or is currently enrolled in an investigational study.
- •Received adjuvant induction intravesical chemotherapy within 3 months of current diagnosis. Peri-operative instillation of a single dose of intravesical chemotherapy is allowed per institutional guidelines.
- •Received prior intravesical treatment with immunotherapy, including BCG, within 3 months prior to randomization.
- •Cohort 2 Inclusion Criteria:
- •Cohort 2a: BCG-unresponsive NMIBC with CIS of the bladder, with or without coexisting papillary Ta/T1 tumor(s) who are ineligible for or have elected not to undergo cystectomy at the time of enrollment and have received 1 or 2 lines of therapy after meeting criteria for BCG unresponsiveness and experienced biopsy confirmed CIS disease within 12 months of last treatment, where:
- •Adequate BCG regimen consists of at least 2 courses of BCG, where the first course (induction) must have included at least 5 of 6 doses and the second course may have included a re-induction (at least 2 of 6 treatments) or maintenance (at least 2 of 3 doses). Adequacy of the BCG regimen will be determined by the Investigator in conjunction with the Sponsor.
- •Treatment after BCG unresponsiveness includes either approved or in development therapy
- •Post-treatment presence of CIS must be documented or indicated by pathology at screening or within 4 months of screening (provided no therapy for CIS disease was given after the most recent biopsy).
- •For inclusion, a participant with BCG-unresponsive disease (as defined above) must have received up to two lines of therapy for BCG-unresponsive disease and who are being considered for radical cystectomy. Such therapies may include agents approved or in development (e.g., pembrolizumab, nadofaragene firodenovec, nogapendekin alfa inbakicept-pmln, cretostimogene grenadenorepvec, detalimogene voraplasmid, TARA-002, gemcitabine intravesical system (INLEXZO®), gemcitabine-docetaxel, gemcitabine, MMC, or valrubicin monotherapy. Participant will have demonstrated biopsy-proven recurrence with HG papillary disease (without CIS) after one or two first-line therapy(ies).
- •Cohort 2b: BCG-unresponsive NMIBC of the bladder, with papillary Ta/T1 tumor(s) and without co-existing CIS, who are ineligible for or have elected not to undergo cystectomy at the time of enrollment and have experienced recurrent Ta/T1 disease within 12 months of treatment with 1 or 2 lines of therapy after BCG-unresponsive status.
- •For inclusion, a participant with BCG-unresponsive disease (as defined above) must have received up to two lines of therapy for BCG-unresponsive disease and who are being considered for radical cystectomy. Such therapies may include agents approved or in development (e.g., pembrolizumab, nadofaragene firodenovec, nogapendekin alfa inbakicept-pmln, cretostimogene grenadenorepvec, detalimogene voraplasmid, TARA-002, gemcitabine intravesical system (INLEXZO®), gemcitabine-docetaxel, gemcitabine, MMC, or valrubicin monotherapy. Participant will have demonstrated biopsy-proven recurrence with HG papillary disease (without CIS) after one or two first-line therapy(ies).
- •All Cohort 2
- •A participant with HG T1 may be eligible after repeat-TURBT showing non-invasive (Ta or less) or no disease. Either original or repeat-TURBT must confirm that muscularis propria is present and uninvolved in the specimen.
- •All specimens must be predominantly urothelial (transitional cell) carcinoma with or without squamous or glandular differentiation. Pure squamous or glandular tumors will not be included. A participant with less than 10% micropapillary histology will be included. All other variant histology (e.g., plasmacytoid, small cell, nested, trophoblastic variants) will not be included.
- •Cohort 2 Exclusion Criteria:
- •Has had urothelial carcinoma outside of the urinary bladder (i.e., urethra, ureter, or renal pelvis) or has a predominant histological variant of UC. Ta/any T1, CIS of the upper urinary tract is allowable if treated with complete nephroureterectomy more than 24 months prior to initiating study and is considered to be without evidence of recurrent disease.
- •Participants have tumor(s) involving the prostatic urethra (ductal or stromal).
- •N+ and/or M+ per computerized tomography (CT)/Magnetic Resonance Imagery (MR) urography.
- •History of prior T2/T3 urothelial carcinoma of the bladder.
- •Concurrent treatment with any chemotherapeutic agent.
- •Intravesical chemotherapy within 3 months of enrollment (including INLEXZO®, gemcitabine-docetaxel)
研究组 & 干预措施
Intermediate Risk NMIBC, NDV-01 Treatment Group
NDV-01 (sustained-release gemcitabine-docetaxel)
干预措施: NDV-01 (sustained-release gemcitabine-docetaxel) (Drug)
Intermediate Risk NMIBC, Observation Group
Surveillance with Cystoscopy, Urine Cytology, and Biopsy (if indicated)
BCG-Unresponsive High-Risk NMIBC, NDV-01 Treatment Group
NDV-01 (sustained-release gemcitabine-docetaxel)
干预措施: NDV-01 (sustained-release gemcitabine-docetaxel) (Drug)
结局指标
主要结局
Disease Free Survival in participants with Intermediate Risk NMIBC
时间窗: From date of randomization to at least 2 years of follow-up assessing for DFS events.
Time from randomization to either time of the first recurrence or progression, or death due to any cause, whichever occurs first. It is hypothesized that sustained local delivery of GEM and DOCE (via NDV-01) in participants with IR-NMIBC will result in longer DFS than achieved with observation after TURBT. Under the exponential distribution assumption for DFS, this translates into testing the statistical hypothesis that the hazard ratio is significantly less than 1.0. Primary endpoint will be tested using a one-sided 2.5% level of significance.
To evaluate the efficacy of NDV-01 (determined by complete response [CR] anytime) administered by intravesical instillation in patients with BCG-unresponsive NMIBC who have recurred after first-line intravesical therapy (approved or in development).
时间窗: From date of randomization through 3 years of follow-up assessing for CR.
Percentage of participants with CR at anytime based on cystoscopy, urine cytology, and biopsies. Protocol-driven mapping biopsies (as assessed by central pathology) will be performed at 12 months
次要结局
未报告次要终点