This study has been transitioned to CTIS with ID 2024-512158-12-00 check the CTIS register for the current data. Primary Objectives: - To compare the pCR rate of neoadjuvant nivolumab/BMS-986205 + GC to neoadjuvant GC alone in all randomized…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- pCR rate, defined by the proportion of randomized participants with absence
of any cancer (T0, N0, M0) in pathology specimens after RC, based on
blinded pathology review.
- EFS, defined as the time from randomization to any of the following events:
progression of disease that precludes RC surgery, local or distant
recurrence, based on BIRC assessments, or death due to any cause.
- pCR rate, defined by the proportion of randomized participants with absence
of any cancer (T0, N0,M0) in pathology specimens after RC, based on
blinded pathology review.
- EFS, defined as the time from randomization to any of the following events:
progression of disease that precludes RC surgery, local or distant
recurrence based on BIRC assessments, or death due to any cause.
Secondary outcome
- OS, defined as the time between the date of randomization and the date of
death from any cause.
- Incidence of adverse events (AEs), serious AEs, deaths and laboratory
abnormalities in participants who received at least one dose of study
treatment.
Background summary
Urothelial cancer of the bladder is the ninth most common cancer in the world.
In 2012, approximately 430,000 new cases of bladder cancer were diagnosed
worldwide, accounting for 165,000 deaths.
Neoadjuvant chemotherapy prolongs EFS and OS in cisplatin-eligible patients and
is the current
SOC for this patient population. OS is closely associated with achieving a pCR1
after NAC, however pCR occurs in a minority of treated patients; patients who
have residual MIBC after RC have a high likelihood of relapse and death from
metastatic bladder cancer. Furthermore, there is currently no neoadjuvant SOC
for patients who are not eligible to receive cisplatin-based chemotherapy,
defining an unmet medical need. Therefore, novel therapies are needed to
increase the number of patients who qualify to receive neoadjuvant therapy and
subsequently achieve a pCR.
Individually targeting immune checkpoint receptors such as CTLA-4 and PD-1 has
been successful across multiple tumor types. It is likely, however, that
combination therapies could potentially lead to greater depth of response and
OS as has been noted with the combination of anti-PD-1 and anti-CTLA-4 in
advanced melanoma patients and in NSCLC patients.2 In addition, targeting the
immunosuppressive properties of the cancer cells and tumor-infiltrating
inflammatory cells, such as by targeting IDO1, is considered a promising
approach. IDO1 inhibitors in combination with checkpoint-targeting
immunotherapy, have the potential to achieve improved efficacy similar to
PD-1/CTLA-4 targeting combinations with potentially less toxicity.
This study aims to demonstrate that a neoadjuvant regimen consisting of
nivolumab plus BMS-986205 or nivolumab plus BMS-986205 Placebo added to SOC
chemotherapy pre-surgically, followed by continued IO therapy after RC, will
significantly increase the rate of pCR and prolong
EFS in participants with previously untreated MIBC. Additional objectives of
the study include
OS, characterization of the safety and tolerability of the treatment regimens,
and to determine if the addition of IO therapy to SOC NAC delays time to RC or
increases the toxicity associated with this operation. Pharmacokinetic
parameters, potential predictive biomarkers of efficacy and toxicity, and
changes in patient-reported outcomes for quality of life assessments will also
be characterized.
Study objective
This study has been transitioned to CTIS with ID 2024-512158-12-00 check the CTIS register for the current data.
Primary Objectives:
- To compare the pCR rate of neoadjuvant nivolumab/BMS-986205 + GC to
neoadjuvant GC alone in all randomized participants.
- To compare EFS of neoadjuvant nivolumab/BMS-986205 +GC followed by continued
nivolumab/BMS-986205 after RC versus SOC GC followed by
RC in all randomized participants.
- To compare the pCR rate of neoadjuvant nivolumab + GC to neoadjuvant GC alone
in all randomized participants.
- To compare EFS of neoadjuvant nivolumab + GC followed by continued nivolumab
after RC versus neoadjuvant SOC GC followed by RC in all
randomized participants
Secondary Objectives:
- To compare overall survival (OS) of neoadjuvant nivolumab/BMS-986205 + GC or
nivolumab + GC followed by continued IO therapy after RC versus
neoadjuvant SOC GC followed by RC in all randomized participants (Arm C vs
Arm A and Arm B vs Arm A).
- To describe the safety and tolerability of nivolumab and
nivolumab/BMS-986205 in combination with GC chemotherapy.
Study design
Phase 3, Randomized, Study of Neoadjuvant Chemotherapy alone versus Neoadjuvant
Chemotherapy plus Nivolumab or Nivolumab and BMS-986205, Followed by Continued
Post- Surgery Therapy with Nivolumab or Nivolumab and BMS-986205 in
Participants with Muscle- Invasive Bladder Cancer
Approximately 1200 patients will be enrolled for this study, of which 954 will
be treated.
Safety-Lead In
CA017078 will start with a safety lead-in for the combination of BMS-986205
with nivolumab plus Gemcitabine & Cisplatin chemotherapy at the same dosages
and frequencies as described in Arm C. After the regimen is determined safe,
the study will begin randomization.
Randomization:
Participants will be randomized in a 1:1:1 ratio to either Arm A, B, or C.
- Treatment Arm A: Gemcitabine & Cisplatin infusions every 3 weeks for 4
cycles followed by radical cystectomy within 6 weeks of completing neo-
adjuvant treatment. No further study therapy.
- Treatment Arm B: Gemcitabine & Cisplatin + Nivolumab (360mg) infusions every
3 weeks for 4 cycles + BMS-986205 Placebo (100mg) daily
followed by radical cystectomy within 6 weeks of completing neo-adjuvant
treatment. Post-surgery Nivolumab (480mg) every 4 weeks + BMS-
986205 Placebo (100mg) daily for 9 cycles.
- Treatment Arm C: Gemcitabine & Cisplatin + Nivolumab (360mg) infusions every
3 weeks for 4 cycles + BMS-986205 Blinded (100mg) daily
followed by radical cystectomy within 6 weeks of completing neo-adjuvant
treatment. Post-surgery Nivolumab (480mg) every 4 weeks + BMS-
986205 Blinded (100mg) daily for 9 cycles.
Note: Dosing for chemotherapy for all arms listed above:
• GFR >= 60 mL/min: standard GC (cisplatin 70 mg/m2 D1, gemcitabine 1000 mg/m2
D1, D8, 21D cycles
• GFR < 60 mL/min: split-dose GC (cisplatin 35 mg/m2 D1, D8, gemcitabine 1000
mg/m2 D1, D8, 21D cycles
Patients will undergo screening procedures prior to the first treatment to
assess if they are eligible to participate in the study.
Nivolumab will be given intravenously via infusion. Patients, who will receive
BMS-986205, will take a pill of BMS-986205 every day after a meal. Patients
will complete a diary to document the BMS-986205 administration. Gemcitabine &
Cisplatin will be given as per local standard.
All patients will receive treatment as per scheduled cycle until progression,
recurrence, unacceptable toxicity, withdrawal of consent by the participant,
completion of treatment, or the study ends, whichever occurs first.
Intervention
The medical interventions include treatment with Gemcitabine/Cisplatin,
Gemcitabine/Cisplatin plus Nivolumab & BMS-986205 pre-surgery and Nivolumab &
BMS-986205 post-surgery.
Patients will be randomly assigned to one of the following treatment arms:
- Treatment Arm A: Gemcitabine & Cisplatin infusions every 3 weeks for 4
cycles followed by radical cystectomy within 6 weeks of completing neo-
adjuvant treatment. No further study therapy.
- Treatment Arm B: Gemcitabine & Cisplatin + Nivolumab (360mg) infusions every
3 weeks for 4 cycles + BMS-986205 Placebo (100mg) daily
followed by radical cystectomy within 6 weeks of completing neo-adjuvant
treatment. Post-surgery Nivolumab (480mg) every 4 weeks + BMS-
986205 Placebo (100mg) daily for 9 cycles.
- Treatment Arm C: Gemcitabine & Cisplatin + Nivolumab (360mg) infusions every
3 weeks for 4 cycles + BMS-986205 Blinded (100mg) daily f
followed by radical cystectomy within 6 weeks of completing neo-adjuvant
treatment. Post-surgery Nivolumab (480mg) every 4 weeks + BMS-
986205 Blinded (100mg) daily for 9 cycles.
Note: Dosing for chemotherapy for all arms listed above:
• GFR >= 60 mL/min: standard GC (cisplatin 70 mg/m2 D1, gemcitabine 1000 mg/m2
D1, D8, 21D cycles
• GFR < 60 mL/min: split-dose GC (cisplatin 35 mg/m2 D1, D8, gemcitabine 1000
mg/m2 D1, D8, 21D cycles
Patients will receive treatment until progression, recurrence, unacceptable
toxicity, withdrawal of consent by the participant, completion of treatment, or
the study ends, whichever occurs first.
Study burden and risks
As part of the trial, patients will be expected to attend multiple clinic
visits where they will undergo physical examinations, vital sign measurements,
blood tests for safety assessment, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events & serious adverse events.
Patients will be asked to complete questionnaire*s (FACT-G, FACT-BI-Cys &
EQ-5Q-3L) about their quality of life. Blood will also be collected at certain
visits for research purposes (PK, Biomarker & Immunogenicity). If there is no
archival tumour tissue available or the sample was taken too long ago (>=4
months), patients will be required to have a biopsy in order to participate.
Radical cystectomy will be performed on patients post completion of
neo-adjuvant therapy. Patients who do not undergo radical cystectomy for
reasons other than progression, will be surveyed for disease
recurrence/progression by cystoscopy, every 3 months for the next two years,
then every 6 months for 3 additional years, then once per year for subsequent
years. For these patients, maximal TURBT of all visible tumor should be
performed on the first on-treatment cystoscopy. Patients will undergo
radiographic assessment of their tumors by CT or MRI at screening. Imaging will
continue for patients for a maximum of 5 years or until: Investigator assessed
disease progression that precludes surgery, Blinded Independent Central Review
confirms progression or recurrence, at intervals of every 12 weeks (± 1 week)
until Week 96 (from the date of first neoadjuvant dose), then every 16 weeks (±
2 weeks) from Week 96 to Week 160 and finally every 24 weeks (± 3 weeks). The
frequency of visits and number of procedures carried out during this trial
would be typically considered over and above standard of care. The procedures
are carried out by trained medical professionals and every effort will be made
to minimise any risks or discomfort to the patient. Treatment for cancer often
has side effects, including some that are life threatening. To assure an
ongoing favourable risk/benefit assessment for patients enrolled onto the
study, an Independent Data Monitoring Committee (DMC) will be established to
provide oversight of safety and efficacy considerations. Additionally, the DMC
will provide advice to the sponsor regarding actions the committee deems
necessary for the continuing protection of patients enrolled in the study.
BMS will conduct rigorous safety monitoring to ensure patients safety by
regularly & systematically reviewing safety data; the reported safety events
will be closely followed-up; sites and study investigators will receive
training on the implementation of the BMS-986205 and Nivolumab toxicity
management strategies.
New immune system targeted therapy (immunotherapies) such as Nivolumab could
potentially provide clinical benefit and improvements in the outcomes for
patients with this disease. However, with all experimental drugs and clinical
trials, there are known and unknown risks. Study medication and procedure
related risks are outlined in the patient information sheet in detail to ensure
the patients are fully informed before agreeing to take part in the study.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
- Participants with MIBC, clinical stage T2-T4a, N0 (<10 mm on CT or MRI), M0,
diagnosed at
TURBT and confirmed by radiographic imaging. Variant histology is acceptable
if there is a
predominant urothelial component
- Participant must be deemed eligible for RC by his/her urologist and/or
oncologist, and must agree
to undergo RC after completion of neo-adjuvant therapy
- Prior BCG or other intravesical treatment of non-muscle invasive bladder
cancer (NMIBC) is
permitted if completed at least 6 weeks prior to initiating study treatment
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
- Life expectancy >= 6 months
- Documentation of PD-L1 status by immunohistochemistry (IHC) performed by the
central lab
during the screening period from the TURBT or biopsy that made the diagnosis
of MIBC. No
systemic therapy (eg, adjuvant or neoadjuvant chemotherapy) should be given
after the sample
was obtained. PD-L1 results are not required prior to beginning treatment on
the safety lead-in.
Exclusion criteria
- Clinical evidence of positive LN (>= 10 mm in short axis) or metastatic
bladder cancer
- Prior systemic therapy, radiation therapy, or surgery for bladder cancer
other than TURBT or
biopsies is also not permitted
- Ineligible to receive cisplatin due to Grade 2 or higher peripheral
neuropathy or audiometric
hearing loss, or calculated (Cockcroft-Gault formula) GFR or measured
(24-hour urine) creatinine
clearance (CrCl) < 50 mL/min
- Participants with an active, known or suspected autoimmune disease.
Exceptions per protocol
- Participants with conditions known to interfere significantly with the
absorption of oral medication,
as per investigator judgement
- Participants with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily
prednisone equivalent) or other immunosuppressive medications within 14 days
of randomization.
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg
daily prednisone
equivalent, are permitted in the absence of active autoimmune disease
- Participants with uncontrolled adrenal insufficiency
- Participants with a personal or family (i.e., in a first-degree relative)
history or presence of
cytochrome b5 reductase deficiency (previously called methemoglobin
reductase deficiency) or
other diseases that puts them at risk of methemoglobinemia. All participants
will be screened for
methemoglobin levels prior to randomization.
- Participants with a history of G6PD deficiency or other congenital or
autoimmune hemolytic
disorders. All participants will be screened for G6PD deficiency prior to
randomization.
- Major surgical procedure within 14 days prior to initiating study treatment
or anticipation of the
need for a major surgical procedure (other than RC) during the course of the
study.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512158-12-00 |
| EudraCT | EUCTR2017-004692-31-NL |
| ClinicalTrials.gov | NCT03661320 |
| CCMO | NL68068.056.18 |