| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| BCG-Unresponsive, High-Risk, Non-Muscle Invasive Bladder Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10005005 |
| E.1.2 | Term | Bladder cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-) To estimate complete response (CR) rate, per pathology review committee (PRC), and its duration in carcinoma in situ (CIS) participants.
-) To determine Event Free Survival (EFS), per PRC, for all non-CIS participants (high-grade papillary Ta or any T1). |
|
| E.2.2 | Secondary objectives of the trial |
-) To evaluate progression free survival (PFS), per PRC, for all participants (high grade papillary Ta, any T1, and/or CIS).
-) To describe the safety and tolerability of nivolumab and nivolumab + BMS-986205, alone or in combination with intravesical BCG. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Signed Written Informed Consent
2) Type of Participant and Target Disease Characteristics
a) Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1
b) Life expectancy ≥ 6 months
3) Pathologically demonstrated BCG-unresponsive, high-risk NMIBC defined as carcinoma in situ (CIS) with or without papillary component, any T1, or Ta high-grade lesions; diagnosis required within 8 weeks (56 days) prior to starting treatment and must be confirmed by the Pathology Review Committee (PRC).
a) Predominant histologic component (> 50%) must be urothelial (transitional cell) carcinoma
b) Must have undergone each of the following procedures within 8 weeks (56 days) of randomization. If these procedures are performed as part of the participant’s routine care, they do not need to be repeated provided that they were performed within the required time period:
i) Complete excision of all papillary disease (T1/TaHG). For participants with T1 lesions, a re-staging TURBT must be performed within 4 weeks after the initial TURBT to ensure that the pathology specimen contains muscularis propria that is free of invasive tumor per PRC.
ii) Resection or fulguration of all detectable CIS, if feasible. Fluorescence-guided cystoscopy is encouraged but not mandated. It is understood that due to the nature of this disease, complete resection of CIS cannot be assured.
iii) Random sampling of bladder mucosa for detection of occult CIS. The bladder must be mapped by visual inspection and random biopsies taken from the trigone, right and left lateral walls, posterior wall, dome and prostatic urethra (in male participants).
iv) Urine cytology must be obtained by bladder wash. Recognizing the possibility of occult CIS, cytology at screening does not need to be negative for study participation.
v) Computed tomography (CT) scan of the chest and CT or magnetic resonance imaging (MRI) of the abdomen, pelvis, and all other areas of suspected disease to exclude locally advanced or metastatic bladder cancer or synchronous UC in the upper urinary tracts within 90 days prior to randomization.
vi) Participants should either be deemed medically unfit for radical cystectomy, or should have refused radical cystectomy after consultation with their urologist or oncologist.
c) Pelvic examination, preferably under anesthesia, should be performed to exclude locally advanced disease
d) Availability of a suitable formulation and mode of administration of BMS-986205 for the participant’s needs, as detailed in the IB and pharmacy manual at the time of enrollment.
4) Age and Reproductive Status
a) Males and Females, 18 years of age, or age of majority, and older
b) Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment.
c) Women must not be breastfeeding
d) Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception (see Appendix 4) for the duration of treatment with study treatment plus 5 months after the last dose of study treatment (ie, 30 days [duration of ovulatory cycle] plus the time required for nivolumab to undergo approximately 5 halflives).
e) Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (see Appendix 4) for the duration of treatment with study treatment plus 7 months after the last dose of the study treatment (ie, 90 days [duration of sperm turnover] plus the time required for nivolumab to undergo approximately 5 halflives).
In addition, male participants must be willing to refrain from sperm donation during this time.
f) Males who are sexually active with WOCBP must agree to use a condom during penile vaginal intercourse for the duration of treatment with study treatment plus 7 months after the last dose of the study treatment (ie, 90 days [duration of sperm turnover] plus the time required for nivolumab to undergo approximately 5 half-lives). This
criterion applies to azoospermic males as well.
g) WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements, and still must undergo pregnancy testing as described in this section. |
|
| E.4 | Principal exclusion criteria |
1) Women who are pregnant or breastfeeding
2) Participants with a personal or family (ie, in a first-degree relative) history of cytochrome b5 reductase deficiency (previously called methemoglobin reductase deficiency) or other diseases that put them at risk of methemoglobinemia. All participants will be screened for methemoglobin levels prior to randomization.
3) Participants with a history of glucose-6-phosphate dehydrogenase (G6PD) deficiency or other congenital or autoimmune hemolytic disorders. All participants will be screened for G6PD deficiency prior to randomization.
4) Evidence of locally advanced or metastatic bladder cancer as seen in cross-sectional imaging of the chest, abdomen, and pelvis
5) UC in the upper genitourinary tract (kidneys, renal collecting systems, ureters) within 24 months of enrollment
6) UC and/or CIS in the prostatic urethra within 12 months of enrollment
7) Locally advanced disease demonstrated by pelvic examination preferably performed under anesthesia
8) Previous or concurrent muscle invasive or disseminated/metastatic bladder cancer
9) Prior treatment with an anti-PD-1, anti-programmed death ligand 1 (PD-L1), anti-PD-L2, or anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
10) Prior treatment with BMS-986205 or any other IDO1 inhibitors
11) Prior systemic chemotherapy or immunotherapy. Intravesical chemotherapy and/or interferon administered prior to the date of tumor sample submission is permitted.
12) Prior radiation therapy for bladder cancer
13) Prior surgery for bladder cancer other than TURBT and/or bladder biopsies |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-) Proportion of carcinoma in situ participants with Complete response, per PRC.
-) Duration of Complete response (duration of complete response), per PRC, in carcinoma in situ participants with Complete response.
-) event-free survival, per PRC, for all non-carcinoma in situ participants. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The complete response (CR) rate will be estimated at 6 and 12 months.
The overall CR rate will also be estimated as above.
Event free survival rate will be reported at 3, 6, 9, 12, 18 and 24 months. |
|
| E.5.2 | Secondary end point(s) |
-) progression-free survival, per PRC, for all participants
-) Overall safety and tolerability will be measured by the incidence of AEs, SAEs, AEs leading to discontinuation, immunemediated AEs, deaths, and laboratory abnormalities and changes from baseline. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Progression-free survival rate at 3, 6, 9, 12, 18 and 24 months will be provided.
There are no specified time points for safety. Plan is to file with CR at 12 months and then with EFS at 18 months. Safety will be reported as well.
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Chile |
| China |
| France |
| Italy |
| Mexico |
| Netherlands |
| Russian Federation |
| Spain |
| Turkey |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 28 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
