The purpose of this study is to find out if treatment with Nivolumab monotherapy will improve recurrence-free survival (RFS) when compared to Ipilimumab monotherapy in subjects with high risk for recurrence, completely resected Stage III and Stage…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary:
•To compare the efficacy, as measured by recurrence free survival (RFS),
provided by nivolumab versus ipilimumab in subjects with completely resected
Stage IIIb/c or Stage IV NED melanoma who are at high-risk for recurrence.
The Primary purpose of Revised Protocol 06 is to extend the collection of
Overall Survival (OS) data for approximatively 5 additional years. In
addition, data associated with the primary, secondary, and exploratory efficacy
outcomes (eg. melanoma recurrence data, data on development of new primary
melanomas and non-melanoma cancers, subsequent anti-cancer therapies) will
continue to be collected on Case Report Forms. Study-drug-related serious
adverse events (SAEs) will continue to be collected, whereas follow-up
surveillance imaging assessments, plasma biomarker samples, and the EQ-5D
questionnaire will no longer be required during extended follow-up.
Secondary outcome
Secondary:
•To compare the overall survival of nivolumab vs ipilimumab in subjects with
completely resected Stage IIIb/c or Stage IV NED melanoma who are at high risk
for recurrence;
•To assess the overall safety and tolerability of nivolumab and ipilimumab in
subjects with completely resected Stage IIIb/c or Stage IV NED melanoma who are
at high risk for recurrence;
•To evaluate whether PD-L1 expression is a predictive biomarker for RFS;
•To evaluate the Health Related Quality of Life (HRQoL) as assessed by European
Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30.
Background summary
CA209238 (CheckMate 238: CHECKpoint pathway and nivoluMAb clinical Trial
Evaluation
238) is a Phase 3 randomized, double-blind study of nivolumab versus ipilimumab
in subjects with high risk for recurrence, completely resected Stage IIIb/c or
Stage IV no evidence of disease (NED) melanoma.
Currently, there is no standard of care or no available treatment for this
patient population following complete resection of their lesion(s) and who are
at the highest risk of recurrence.
Furthermore, available clinical trials for various anti-cancer agents for later
stage melanoma usually require measurable disease as an eligibility criteria.
Thus, there is a remaining need to improve the outcome for fully resected Stage
IV patients, and a willingness to improve on the benefit/risk ratio for Stage
IIIb/c melanoma patients.
Interferon, pegylated interferon therapy or observation alone are the typical
options for the Stage III patients who achieve a complete resection. Both
interferon and peg-interferon are Food and Drug Administration (FDA) approved.
Interferon is indicated for patients with malignant melanoma who are free of
disease but at high risk for systemic recurrence, within 56 days of surgery.
Peg-interferon is indicated for the adjuvant treatment of melanoma with
microscopic or gross nodal involvement within 84 days of definitive surgical
resection including complete lymphadenectomy. In a meta-analysis of interferon
trials, it was shown that interferon has an extremely modest survival benefit
with a toxicity profile that is significant.Given the unexceptional benefit and
high toxicity profile in a patient population that is free of disease, it is
controversial whether interferon can be considered standard of care for Stage
III melanoma.
Ipilimumab 10 mg/kg has shown a recurrence-free survival (RFS) benefit in the
adjuvant melanoma setting, and has proven a survival benefit in two Phase 3
randomized clinical trials in the advanced melanoma setting.
Nivolumab has shown a survival benefit in treatment naive patients with BRAF
Wild Type
(WT), metastatic melanoma in a Phase 3, randomized clinical trial.
This study will allow for direct comparison of the clinical benefit, as
measured by recurrence-free survival and overall survival, provided by
ipilimumab and nivolumab.
Study objective
The purpose of this study is to find out if treatment with Nivolumab
monotherapy will improve recurrence-free survival (RFS) when compared to
Ipilimumab monotherapy in subjects with high risk for recurrence, completely
resected Stage III and Stage IV NED melanoma. Ipilimumab is a drug which is
approved for use in Europe for people with advanced Melanoma.
Study design
This is a Phase 3, randomized, double-blinded study of nivolumab versus
ipilimumab in subjects (* 15 years) with complete resection Stage IIIb/c or
Stage IV NED melanoma at high risk for recurrence.
Approximately 800 subjects will be randomized 1:1 and stratified by PD-L1
status (positive vs negative/indeterminate) and American Joint Committee on
Cancer (AJCC) stage.
Dose reductions will not be allowed.
Subjects will be treated with one of the following:
Arm A: ipilimumab: 10 mg/kg IV q3 weeks for 4 doses, then q12 weeks starting at
Week 24 with nivolumab placebo IV q2 weeks
Arm B: nivolumab 3mg/kg IV q2 weeks with ipilimumab placebo IV q3weeks for 4
doses, then q12 weeks starting at Week 24
All subjects will be treated until recurrence of disease, unacceptable
toxicity, or subject withdrawal of consent with a maximum of 1 year of
treatment.
Intervention
The medical interventions for this trial include both Nivolumab and Ipilimumab.
All compounds will be supplied by the Sponsor Company with exception of the
placebo. (Should be sourced by investigative sites if available and permitted
by local regulations)
Solutions used as diluent or placebo (ie, 0.9% Sodium Chloride Injection or 5%
Dextrose Injection)
Subjects will be treated with one of the following:
- Arm A: Ipilimumab 10 mg/kg IV every 3 weeks for 4 doses and then every 12
weeks starting at week 24+ Nivolumab placebo IV every 2 weeks
- Arm B: Nivolumab 3 mg/kg IV every 2 weeks + Ipilimumab placebo IV every 3
weeks for 4 doses then every 12 weeks starting at week 24
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
including oxygen saturation levels, blood tests for safety assessment,pregnancy
testing (for females of child bearing potential) and monitoring for adverse
events. Subjects will be evaluated for presence or continued lack of tumor
until distant recurrence beginning 12 weeks relative to the first dose of study
treatment, and will continue to have surveillance assessment every 12 weeks for
the first 12 months. From > 12 months to 24 months after randomization,
efficacy assessments should be every 12 weeks. From > 24 months until year 5
after randomization, efficacy assessments should be performed every 6 months.
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 utilised in this trial to ensure that the
safety data is reviewed during the study.
New Immune system targeted therapy (immunotherapies) such as Nivolumab and
Ipilimumab could potentially provide clinical benefit and improvement in the
outcome for patients with this disease (disease improvement and improvement in
survival).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.
Uxbridge Business Park Sanderson Road
Uxbridge UB8 1DH Uxbridge
GB
Uxbridge Business Park Sanderson Road
Uxbridge UB8 1DH Uxbridge
GB
Listed location countries
Age
Inclusion criteria
Key Inclusion Criteria:
• At least 15 years of age
Except: where local regulations and/or institutional policies do not allow for
subjects < 18 years of age (pediatric population) to participate. For those
sites, the eligible subject population is >= 18 years of age.
• All subjects must be either Stage IIIb/c or Stage IV American Joint
Committee on Cancer (AJCC) Melanoma Staging (7th edition) and have
histologically confirmed melanoma that is completely surgically resected in
order to be eligible. Subjects must have been surgically rendered free of
disease with negative margins on resected specimens. Please refer to Appendix 1
for description of AJCC 7th editions of TNM and staging.
If Stage III melanoma (whether Stage IIIb or IIIc) the subjects usually have
clinically detectable lymph nodes that are confirmed as malignant on the
pathology report and/or ulcerated primary lesions.
Subjects who are *N2c* classification with 2-3 metastatic nodes and in transit
metastases/satellites without metastatic nodes, or, *N3*classification with any
*T* and 4+ metastatic nodes, or matted nodes, or in transit
metastases/satellites with metastatic nodes are eligible. The pathology report
for both Stage IIIb and IIIc must be reviewed, signed and dated by the
investigator; this process will be confirmed during the IVRS randomization
call. Clinically detectable lymph nodes are defined as:
(1) a palpable node (confirmed as malignant by pathology)
(2) a non-palpable but enlarged lymph node by CT scan (at least 15 mm in short
axis) and confirmed as malignant by pathology., (3) a PET scan positive lymph
node of any size confirmed by pathology
(4) evidence of pathologically macrometastatic disease in one or more lymph
nodes defined by one or more foci of melanoma at least 1cm in diameter, If
Stage IV melanoma, the pathology report confirming negative margins must be
reviewed, dated, and signed by the investigator prior to randomization.
• Complete resection of Stage III disease that is documented on the surgical
and pathology reports or complete resection of Stage IV disease with margins
negative for disease that is documented on the pathology report.
• Complete resection must be performed within 12 weeks prior to randomization
• 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 a CT scan
of the neck, chest, abdomen, pelvis and all known sites of resected disease in
the setting of Stage IIIb/c or Stage IV disease and brain magnetic resonance
(MRI) or CT (brain CT allowable if MRI is contraindicated or if there is no
known history of resected brain lesions).
• 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 (positive, negative/or indeterminate) as determined by a central
lab.
Exclusion criteria
Key Exclusion Criteria:
• History of ocular/uveal melanoma
• Subjects with active, known, or suspected autoimmune disease. Subjects with
type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis
only requiring hormone replacement, skin disorders (such as vitiligo,
psoriasis, or alopecia) not requiring systemic treatment are permitted to
enroll.
• Subjects with previous non-melanoma malignancies are excluded unless a
complete remission was achieved at least 3 years prior to study entry and no
additional therapy is required or anticipated to be required during the study
period (exceptions include but are not limited to, non-melanoma skin cancers;
in situ bladder cancer, in situ gastric cancer, in situ colon cancers; in situ
cervical cancers/dysplasia; or breast carcinoma in situ)
• Subjects with a condition requiring systemic treatment with either
corticosteroids (>= 10 mg daily prednisone or equivalent) or other
immunosuppressive medications within 14 days of randomizationstudy drug
administration. Inhaled or topical steroids are permitted in the absence of
active autoimmune disease.
• Prior therapy for melanoma except surgery for the melanoma lesion(s) and/or
except for adjuvant radiation therapy (RT) after neurosurgical resection for
central nervous system (CNS) lesions. and except for prior adjuvant interferon
(see qualifier below). Specifically subjects who received prior therapy with
interferon, anti- PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4
antibody (including ipilimumab or any other antibody or drug specifically
targeting T cell co-stimulation or checkpoint pathways) are not eligible.
i) Prior treatment with adjuvant interferon is allowed if completed >= 6 months
prior to randomization.
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 |
|---|---|
| EudraCT | EUCTR2014-002351-26-NL |
| CCMO | NL51400.042.15 |