This study has been transitioned to CTIS with ID 2023-509360-24-00 check the CTIS register for the current data. Primary objectives: This study has co-primary objectives:• To compare OS of nivolumab versus placebo in subjects with resected EC or GEJ…
ID
Source
Brief title
Condition
- Malignant and unspecified neoplasms gastrointestinal NEC
- Gastrointestinal neoplasms malignant and unspecified
- Gastrointestinal therapeutic procedures
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall survival and DFS are co-primary endpoints.
Overall Survival is time between the date of randomization and the date of
death. For subjects without documentation of death, OS will be censored on the
last date the subject was known to be alive.
Disease-Free Survival is time between randomization date and first date of
recurrence or death, whichever occurs first. Recurrence is defined as the
appearance of one or more new lesions, which can be local, regional, or distant
in location from the primary resected site (by imaging or pathology whichever
comes first). All deaths without prior recurrence will be included as DFS event
- regardless of cause or of how long it has been since the last known disease
evaluation. For subjects who remain alive and without recurrence, DFS will be
censored on the date of last evaluable disease assessment.
Secondary outcome
Overall survival rate at 1, 2, and 3 years is defined as the probability that a
subject is alive at 1, 2, and 3 years, respectively, following randomization.
Background summary
This is a phase III study of Nivolumab versus Placebo in patients with resected
oesophageal or gastroesophageal junction cancer.
The purpose of the study is to compare overall survival and disease-free
survival of patients who have stage II or III oesophageal or gastroesophageal
junction cancer, have undergone chemotherapy plus radiation therapy, followed
by surgery to remove their whole tumour. At present, there is no standard of
care (SOC) for such patients beyond being followed-up after their surgery for
disease return. The study will evaluate the probability of disease return in
patients who receive nivolumab versus patients receiving placebo after surgical
resection and will compare the survival of the two patient groups.
Globally, approximately 760 patients will be randomised to receive either
nivolumab or placebo, with approximately 15 of them in the Netherlands. The
study is sponsored by Bristol-Myers Squibb.
Following a screening period, two thirds of the eligible patients will receive
nivolumab (the drug under investigation) and one third will receive placebo
(dummy drug - no active substance). All patients will receive nivolumab or
placebo for up to 12 months or until disease recurrence, whichever comes
first. The first 8 infusions will be done every 2 weeks, followed by infusions
every 4 weeks. After the treatment phase, patients will be followed for
survival for up to 5 years, over the phone or through hospital visits.
Patients will undergo CT scan, physical exams, vital signs such as blood
pressure, height, weight, body temperature, blood samples for routine safety
testing and study specific testing. Patients will also be required to complete
questionnaires regularly throughout the study. Additional biopsies may be
performed or previous biopsies obtained if available and if patients consent.
Study objective
This study has been transitioned to CTIS with ID 2023-509360-24-00 check the CTIS register for the current data.
Primary objectives:
This study has co-primary objectives:
• To compare OS of nivolumab versus placebo in subjects with resected EC or GEJ
cancer.
• To compare DFS of nivolumab versus placebo in subjects with resected EC or
GEJ cancer.
Secondary objectives:
• To evaluate 1, 2, and 3 year survival rates of nivolumab versus placebo in
subjects with resected EC or GEJ cancer.
Exploratory objectives:
• To assess the overall safety and tolerability of nivolumab versus placebo in
subjects with resected EC or GEJ cancer.
• To evaluate the distant metastasis free survival (DMFS) in subject with
resected EC or GEJ cancer.
• To evaluate whether PD-L1 status is a predictive biomarker for DFS and OS in
subjects with resected EC or GEJ cancer.
• To evaluate PD-L1 status prior to CRT and at the time of surgery in subjects
with resected EC or GEJ cancer
• To explore potential biomarkers associated with clinical efficacy (DFS, and
OS) and/or incidence of adverse events of nivolumab by analyzing biomarker
measures within the tumor microenvironment and periphery (eg, blood, serum,
plasma and PBMCs) in comparison to clinical outcomes.
• To assess the effect of natural genetic variation (single nucleotide
polymorphisms (SNPs)) in select genes including, but not limited to, PD-1,
PD-L1, PD-L2 and CTLA4 on clinical endpoints and/or the incidence of adverse
events
• To characterize the pharmacokinetics and explore exposure-response
relationships with respect to safety and efficacy
• To characterize the immunogenicity of nivolumab.
• To assess the subject*s overall health status using the 3-level version of
the EQ-5D (EQ-5D-3L) index and visual analog scale
• To assess the subject*s cancer-related quality of life using the Functional
Assessment of Cancer Therapy-Esophageal (FACT-E) questionnaire and selected
components, including the Esophageal Cancer Subscale (ECS) and 7-item version
of the FACT-General (FACT-G7)
Study design
This is a phase 3, randomized, double-blind, placebo controlled study of
adjuvant nivolumab in subjects with resected esophageal cancer (EC), or
gastroesophageal junction (GEJ) cancer who have received chemoradiotherapy
(CRT) followed by surgery.
After CRT followed by surgery, subjects will sign the informed consent form.
Subjects whose tumors do not achieve pathological complete response (non-pCR)
will be randomized in a blinded fashion 2:1 ratio to two arms between nivolumab
(BMS-936558) or placebo monotherapy administered IV over 30 minutes at 240 mg
every 2 weeks for 16 weeks (8 doses) followed by nivolumab 480 mg as a 30
minute infusion every 4 weeks beginning at Week 17 (2weeks after the 8th dose).
The treatment will be given until disease recurrence, unacceptable toxicity, or
subject withdrawal of consent with a maximum of 1-year total duration of study
medication.
Stratification factors:
1) PD-L1 status
2) Pathologic lymph node status (positive **ypN1 vs. negative ypN0)
3) Histology (squamous vs. adenocarcinoma)
Intervention
Approximately 760 subjects will be randomized in a 2:1 ratio to the nivolumab
and placebo arms.
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 assessments, pregnancy testing (for females of child
bearing potential) and monitoring for adverse events. Subjects will be
evaluated for presence or continued lack of tumour.
Blood will also be collected at certain visits for research purposes (PK,
immunogenicity and biomarker studies), The frequency of visits and number of
procedures carried out during this trial would typically be 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. An Independent Data Monitoring Committee (DMC) will
be utilized in this trial to ensure that the safety data is reviewed during the
study.
New Immune system targeted therapy (immunotherapies) such as Nivolumab could
potentially provide clinical benefit and Improvement in the outcome for
patients with this disease (disease improvement and Improvement in survival).
However, as 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
Utrecht 3528 BD
NL
Orteliuslaan 1000
Utrecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
• All subjects must have Stage II or Stage III (per AJCC 7th edition) carcinoma of the esophagus or gastroesophageal junction and have histologically confirmed predominant adenocarcinoma or squamous cell carcinoma esophageal or gastroesophageal junction cancer at the time of initial diagnosis.
• Subjects must complete pre-operative chemoradiotherapy followed by surgery prior to randomization. Platinum based chemotherapy should be used. Chemotherapy and radiation regimens can be followed as local standards of care per NCCN or ESMO guidelines.
• Subject must have complete resection (R0), have been surgically rendered free of disease with negative margins on resected specimens. Subject must have residual pathologic disease, i.e. non-pathologic complete response (non-pCR) of their EC or GEJ, with at least ypN1 or ypT1 listed in the pathology report of resected specimens. The pathology reports of detectable lesion(s) confirming malignancy must be reviewed, dated, and signed by the investigator prior to randomization.
• Complete resection must be performed in a window of 4-16 weeks prior to randomization.
• ECOG performance status score of 0 or 1.
• All subjects must have disease-free status documented by a complete physical examination and imaging studies within 4 weeks prior to randomization. Imaging studies must include CT scan of chest, and abdomen.
• Tumor tissue from the resected site of disease must be provided for biomarker analyses. In order to be randomized, a subject must have a PD-L1 expression classification (>1%, < 1% or indeterminate or non-evaluable) as determined by the central lab. If insufficient tumor tissue content is provided for analysis, acquisition of additional archived tumor tissue (block and /or slides) for the biomarker analysis is required.
Exclusion criteria
• Subjects with cervical esophageal carcinoma. Location of tumor as it relates to eligibility can be discussed with BMS medical monitor.
• Subjects who do not receive concurrent CRT prior to surgery. Subjects who only receive chemotherapy or only radiation prior to surgery are not eligible.
• Subjects with Stage IV resectable disease.
• Subjects with an active, known or suspected autoimmune disease. Subjects with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
• Subjects 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 > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease.
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 | CTIS2023-509360-24-00 |
| EudraCT | EUCTR2015-005556-10-NL |
| ClinicalTrials.gov | NCT02743494 |
| CCMO | NL56855.031.16 |