This study has been transitioned to CTIS with ID 2022-502354-14-00 check the CTIS register for the current data. Primary Objective:To measure the efficacy provided by nivolumab therapy on its own compared to placebo in participants who have had…
ID
Source
Brief title
Condition
- Skin neoplasms malignant and unspecified
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Recurrence-free survival provided by nivolumab monotherapy versus placebo in
participants with completely resected stage IIB/C melanoma with no evidence of
disease who are at high risk for recurrence.
Secondary outcome
Overall survival (OS) provided by nivolumab monotherapy versus placebo in
participants with completely resected stage IIB/C melanoma with no evidence of
disease, who are at high risk for recurrence.
Adverse events, clinical laboratory values, vital signs, ECGs, or other safety
biomarkers of of nivolumab monotherapy in participants with completely resected
stage IIB/C melanoma with no evidence of disease.
Distant-metastases free survival (DFMS)
* Objective response rates
* Duration of treatment on next-line therapies
* Progression-free survival through next-line therapy (PFS2) is defined as the
time from randomization to recurrence/objective disease progression after the
start of the next-line of systemic anti-cancer therapy, or to the start of a
second next-line systemic therapy, or to death from any cause, whichever occurs
first.
* End-of-next-line-treatment: To be used for situations where PFS2 cannot be
reliably determined. Event defined as end or discontinuation of next-line
treatment, second objective disease progression, or death from any cause,
whichever occurs first.
Background summary
This is a multicentre, phase 3 study to test the effectiveness (how well the
drug works), safety, and tolerability of an investigational drug called
nivolumab. The study is for patients with early stage (IIB/C) melanoma (a type
of skin cancer) who have had their tumours completely removed via surgery, but
could possibly have their cancer return in the future.
Around 1000 participants over the age of 12 will be enrolled in this study,
with approximately 30 patients participating from the Netherlands. Participants
will be randomly assigned to one of two treatment arms to receive either
nivolumab (66% chance) or placebo (33% chance). A placebo is a *dummy
treatment* that looks like the real one but contains no active study drug.
Participants will receive study treatment for a maximum of 12 months, and will
then enter an initial follow up phase of up to approximately 100 days, then an
additional follow up period of up to approximately 5 years. The treatment will
be blinded, i.e., neither the participants, nor the study doctor will know
which treatment the participant is receiving. Participants who have their
cancer return and meet certain criteria, may be able to receive nivolumab as
part of this study.
Participants will undergo the following procedures during the study: imaging
assessments (CT/MRI scans), physical examinations, provide urine blood samples
for routine safety and study-specific testing and complete questionnaires
relating to their health/quality of life. Participants will also need to have
adequate tumour sample from previous surgery or biopsy.
Nivolumab is a type of immunotherapy drug that is designed to boost the body*s
own immune system to fight cancer cells. Nivolumab is approved for the
treatment of certain types of cancer including the skin, kidney, blood, and
lung, in multiple countries including the United States, the European Union,
and Japan. Nivolumab is also approved for use in patients after complete
surgical removal of melanoma that has spread to either the local/regional lymph
nodes or other distant areas of the body. As nivolumab is not yet approved in
early stage IIB/C melanoma, positive results from this research study may help
to gain approval in the future.
This study is sponsored by Bristol-Myers Squibb.
Study objective
This study has been transitioned to CTIS with ID 2022-502354-14-00 check the CTIS register for the current data.
Primary Objective:
To measure the efficacy provided by nivolumab therapy on its own compared to
placebo in participants who have had their stage IIB/C cancer completely
removed, and have no evidence of disease, but are at high risk of recurrence.
Efficacy will be measured by recurrence-free survival (RFS). RFS is the length
of time after primary treatment for a cancer ends that the patient survives
without any signs or symptoms of that cancer. In a clinical trial, measuring
the RFS is one way to see how well a new treatment works.
Secondary and exploratory objectives:
To compare the overall survival (OS) provided by nivolumab monotherapy versus
placebo in participants with completely resected stage IIB/C melanoma with no
evidence of disease, who are at high risk for recurrence.
To assess safety and toxicity of nivolumab monotherapy in participants with
completely resected stage IIB/C melanoma with no evidence of disease.
To evaluate distant metastases-free survival (DMFS).
To evaluate investigator-assessed outcomes on next-line therapies.
To evaluate freedom from relapse (FFR) defined asthe time from randomization to
recurrence, with censoring of data for participants who had died from causes
other than melanoma or treatment-related toxic effects.
To evaluate treatment-free interval (TFI) defined as the time from last dose of
study treatment to the start of subsequent systemic therapy or the last known
date alive (for those who never received subsequent cancer therapy).
- To assess the participant*s cancer-related Quality of Life (QoL) using the
EORTC QLQ-C30.
- To characterise participant perceptions of the bothersomeness of symptomatic
AEs based on FACIT GP5 item.
- To assess the participant*s quality of life and overall health status using
the EQ-5D-5L utility index and visual analog scale, respectively.
To explore potential association of biomarkers (e.g., PD-L1 expression) with
clinical efficacy (RFS, DMFS, and OS) and/or incidence of adverse events of
nivolumab by analyzing biomarker measures within the tumor microenvironment and
periphery (eg, blood, serum, plasma, tumour tissue, and PBMCs) in comparison to
clinical outcomes.
- To assess tumor mutational burden (TMB).
- To explore the role of circulating tumour DNA (ctDNA) to understand minimal
residual disease (MRD) and disease recurrence predictability.
To characterise the pharmacokinetics (PK) and explore exposure-response
relationships with respect to safety and efficacy.
- To characterise the immunogenicity of nivolumab.
- To assess the impact of SARS-CoV-2 serologic status on subjects receiving
nivolumab and to support heath authority requests.
Study design
This is a phase 3, randomised, double-blind study of Adjuvant Immunotherapy
with Nivolumab compared to placebo after complete resection of stage IIB/C
melanoma in adults and paediatric participants over the age of 12.
Around 1000 participants over the age of 12 will be enrolled in this study.
Participants will be randomly assigned to one of two treatment arms A and B to
receive either nivolumab or placebo. A placebo is a *dummy treatment* that
looks like the real one but contains no active study drug.
Arm A:
Adult dose:
Nivolumab 480 mg flat dose over approximately 30 minutes every 4 weeks (Q4W).
Paediatric dose:
• 12-17 years of age and weighing >=40 kgs: Nivolumab 480 mg IV Q4W.
• 12-17 years of age and weighing < 40 kgs: 6 mg/kg Q4W up to a maximum of 240
mg.
• For sites that do not prefer to use flat dosing: 6 mg/kg Q4W (maximum of 240
mg for weight < 40 kgs; maximum of 480 mg for weight >=40 kgs).
• All nivolumab infusions to be administered over approximately 30 minutes.
Arm B: Adult and paediatric dose
Nivolumab matched placebo (0.9% Sodium Chloride for Injection / 5% Dextrose for
Injection) over approximately 30 minutes Q4W.
Participants have a 66% chance of being assigned to arm A to receive nivolumab,
and a 33% of being assigned to arm B to receive placebo. Nivolumab or placebo
are administered by intravenous (IV) infusion, meaning the drug is a solution
given through a vein. The infusions can take about 30 minutes.
There are three parts to this study: screening period (about 1 month), a
blinded treatment period (up to 1 year) and follow-up period (up to 5 years).
During the blinded treatment period, neither the participant nor the study
doctor will know which treatment the participant is receiving. In an emergency,
it will be possible for the study doctor to know which treatment the
participant is receiving.
In addition, participants who experience disease recurrence during study
participation, either during study treatment or during follow-up, may be
qualified to participate in an optional Open-Label (OL) treatment. *Open-label*
means that both the participant and the study doctor will know which treatment
the participant is receiving at all times.
The optional OL treatment will consist of nivolumab and will not have a placebo
arm.
Treatment will continue until recurrence, unacceptability toxicity, withdrawal
of consent, or a maximum of 12 months from the first dose of study treatment,
whichever occurs first. Participants will continue to be followed for survival
status for up to 5 years from the first dose of study treatment (either blinded
or open-label treatment).
A Data Monitoring Committee (DMC) will be established and meet regularly during
the study to ensure that subject safety is carefully monitored and to provide
oversight regarding safety and efficacy considerations.
Intervention
Participants will be randomly assigned to one of two treatment arms A and B to
receive either nivolumab or placebo. Allocation of study treatment will be via
an interactive response technology, and will be double-blinded.
Arm A:
Adult dose:
Nivolumab 480 mg flat dose over approximately 30 minutes every 4 weeks (Q4W).
Paediatric dose:
• 12-17 years of age and weighing >=40 kgs: Nivolumab 480 mg IV Q4W.
• 12-17 years of age and weighing < 40 kgs: 6 mg/kg Q4W up to a maximum of 240
mg.
• For sites that do not prefer to use flat dosing: 6 mg/kg Q4W (maximum of 240
mg for weight < 40 kgs; maximum of 480 mg for weight >=40 kgs).
• All nivolumab infusions to be administered over approximately 30 minutes.
Arm B: Adult and paediatric dose
Nivolumab matched placebo (0.9% Sodium Chloride for Injection / 5% Dextrose for
Injection) over approximately 30 minutes Q4W.
Participants have a 66% chance of being assigned to arm A to receive nivolumab,
and a 33% of being assigned to arm B to receive placebo. Nivolumab or placebo
are administered by intravenous (IV) infusion, meaning the drug is a solution
given through a vein. The infusions can take about 30 minutes.
Everyone taking part in this study will receive either the active treatment or
placebo treatment for up to 12 months (1 year). Patients will have 13 visits
during the treatment period. At each visit, patients will receive study
medication (nivolumab or placebo). The first treatment will occur on Day 1 and
subsequent visits will be every 4 weeks after that day.
At the end of the study treatment period, patients will enter the follow-up
phase, which includes includes an initial follow up period with two visits in
the first year and an additional follow up period with visits every 3 months
for up to 5 years.
Study burden and risks
As part of the trial, patients will be asked to attend the hospital for
frequent visits for the study procedures to be performed, 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. Timings of these visits will be based on the
protocol schedule but will be mutually agreed with both the hospital staff and
the patient to avoid patient and/or staff attending hospital at unsocial hours,
and to minimise any inconvenience to the patient. Patients will be reimbursed
for reasonable travel expenses incurred for attending study visits.
Patients will undergo radiographic surveillance assessments (CT and/or MRI
scans) at screening (within 28 days of randomisation). Following randomisation,
tumour assessments will be carried out every 26 weeks during the treatment
period. In the open-label part of the study, the frequency of imaging
assessments will be from every 12 weeks to every 26 weeks, depending on the
status of disease.
The frequency of CT/MRI scans might be higher than the normal standard of care.
CT scans expose patients to radiation. MRI scans are not thought to be
associated with any adverse effects on health.
Blood will also be collected at certain visits for research purposes (PK,
immunogenicity and biomarker studies) as well as optional stool samples for
microbiome analysis. The frequency of visits and number of procedures carried
out during this trial would typically be considered over and above standard of
care. These procedures are conducted by medically trained professionals and
every effort will be made to minimise any risks or discomfort to the patient.
A Data Monitoring Committee (DMC) will be established to provide oversight of
safety and efficacy considerations in Protocol CA20976K. Additionally, the DMC
will provide advice to the sponsor regarding actions the committee deems
necessary for the continuing protection of participants enrolled in the study.
The DMC will be charged with assessing such actions in light of an acceptable
benefit/risk profile for nivolumab in both blinded treatment, and in the
optional open-label nivolumab treatment after first recurrence portion of the
trial. The DMC will act in an advisory capacity to BMS and will monitor
participant safety and evaluate the available efficacy data for the study. The
oncology therapeutic area of BMS has primary responsibility for design and
conduct of the study.
Orteliuslaan 1000
Urecht 3528 BD
NL
Orteliuslaan 1000
Urecht 3528 BD
NL
Listed location countries
Age
Inclusion criteria
Participants must have been diagnosed with stage IIB/C cutaneous melanoma (AJCC
Cancer Staging, 8th edition) and have histologically confirmed melanoma that is
completely surgically resected with documented negative margins (per local
standard) for disease on resected specimens.
All melanomas, except ocular and mucosal melanoma, regardless of primary site
of disease will be allowed.
Complete resection must be performed within 12 weeks prior to randomization.
Participants must have had a negative sentinel lymph node biopsy.
Participants in whom a sentinel lymph node biopsy procedure could not be done
or a sentinel lymph node was not detected are not eligible.
Participants must have disease-free status documented by a complete physical
examination (within 14 days) and imaging studies within 4 weeks (28 days) prior
to randomization.
Imaging studies must include CT scans of the chest/abdomen/pelvis or CT scan of
the chest and MRI scans of the abdomen and pelvis, and all known sites of
resected disease (lymph nodes >= 15 mm in short axis).
Participants with signs and symptoms consistent with brain metastases should
have imaging studies done to rule out the presence of brain metastases.
Has not been previously treated for melanoma beyond complete surgical resection
of the melanoma lesion.
Has recovered adequately from toxicity and/or complications from surgery prior
to study start.
ECOG performance status of 0 or 1 at the time of enrollment.
Tumor tissue (minimum of 15 unstained slides or 1 FFPE block) from the resected
site of disease must be provided to the central lab prior to randomization.
Exclusion criteria
History of ocular and mucosal melanoma.
Participants with active, known, or suspected autoimmune disease.
Participants 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.
Prior malignancy active within the previous 3 years.
Except for locally curable cancers that have been apparently cured, such as
basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in
situ of the prostate, cervix, or breast.
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.
Women who are pregnant or breastfeeding.
Participants with serious or uncontrolled medical disorders.
Use of an investigational agent or an investigational device within 28 days
before administration of first dose of study drug
Treatment directed against the resected melanoma (e.g., chemotherapy, targeted
agents, biotherapy, or limb perfusion) that is administered after the complete
resection.
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137,
anti-CTLA-4 antibody, or agents that target IL-2 pathway any other antibody or
drug specifically targeting T-cell co-stimulation or checkpoint pathways.
Treatment with botanical preparations (eg, herbal supplements or traditional
Chinese medicines) intended for general health support or to
treat the disease under study within 2 weeks prior to randomization/treatment.
Such medications are
permitted if they are used as supportive care.
Participants who have received a live/attenuated vaccine within 30 days of
first treatment.
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 | CTIS2022-502354-14-00 |
| EudraCT | EUCTR2019-001230-34-NL |
| ClinicalTrials.gov | NCT04099251 |
| CCMO | NL71182.042.19 |