Primary ObjectivePart A: To compare disease-free survival (DFS) per Blinded Independent Central Review (BICR) of nivolumab combined with ipilimumab versus placebo infusions in participants with localized RCC, with a predominantly clear cell…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary endpoint is DFS. The primary endpoint of DFS will be
programmatically determined based on the disease recurrence date provided by
the BICR. DFS is defined as the time from randomization to development of local
disease recurrence (ie, recurrence of primary tumor in situ or occurrence of a
secondary RCC primary cancer), distance metastasis, or death, whichever came
first.
Secondary outcome
- OS, defined as the time between the date of randomization and the date of
death. For participants without documentation of death, OS will be censored on
the last date the participants were known to be alive.
-Safety and tolerability endpoint: type, incidence, severity (graded by the
National Cancer Institute [NCI] Common Terminology Criteria for Adverse
Events [CTCAE, Version 4.0], timing, seriousness, and relatedness, and
laboratory abnormalities in all treated participants
-DFS and OS in contemporaneously randomized combination and monotherapy
participants.
Background summary
This study is a multi-centre phase 3 study involving investigational drugs
Nivolumab and Ipilimumab in patients 18 years or older who have had a partial
or complete nephrectomy (removal of some or all of the kidney) but are at high
risk of the tumor coming back. Approximately 2000 patients will be enrolled and
1600 treated across with world with approximately 39 in the Netherlands.
Renal cell cancer is the eighth most common cancer in the world with the
incidence increasing. Despite the early detection and surgical removal of small
kidney tumors, death rate is increasing suggesting the need to optimise early
management. The purpose of this study is to find out if treatment with a
combination of Nivolumab plus Ipilimumab and Nivolumab monotherapy given as
adjuvant therapy will improve the outcomes of patients who have had a partial
or full nephrectomy. To understand if the drugs improve the outcome 50% of the
patients in Part A and 25% of the patients in Part B and will receive a dummy
drug (placebo). The study treatment is blinded so neither you nor your doctor
will know which treatment you will receive.
Cancer immunotherapy is based on the knowledge that tumors can be tumors can be
recognized as foreign rather than as self and can be effectively attacked by an
activated immune system. Nivolumab ad Ipilimumab are types of immunotherapy
drugs called monoclonal antibodies that work by blocking inhibitory signalling
pathways in the immune response. This results in stimulation of the body*s own
immune system to help attack the cancer cells.
Nivolumab has demonstrated clinical activity and been approved for the
treatment of serval tumor types, including melanoma, NSCLC and renal cell
cancer. Ipilimumab is approved for the treatment of melanoma (alone or in
combination with Nivolumab). The safety profile of Nivolumab plus ipilimumab is
characterized by immune-related toxicities such as diarrhoea, rash, liver
toxicity. Most adverse events are low level with relatively few higher-grade
events.
Study objective
Primary Objective
Part A: To compare disease-free survival (DFS) per Blinded Independent Central
Review (BICR) of nivolumab combined with ipilimumab versus placebo infusions in
participants with localized RCC, with a predominantly clear cell histology who
have undergone a nephrectomy.
Part B: To compare disease-free survival (DFS) per Blinded Independent Central
Review (BICR) of nivolumab versus placebo infusions in participants with
localized renal cell carcinoma, with a predominantly clear cell histology, who
have undergone a nephrectomy.
Secondary Objectives
Part A: To compare OS, including the 5- year OS rates, of nivolumab combined
with ipilimumab versus placebo infusions in participants with localized RCC
with a predominantly clear cell histology who have undergone a nephrectomy.
Part B: To compare overall survival (OS), including the 5-year OS rates, of
nivolumab combined with ipilimumab vs versus placebo infusions in
participants with localized renal cell carcinoma with a predominantly clear
cell histology who have undergone a nephrectomy.
Part B: To evaluate differences in disease-free survival (DFS) per Blinded
Independent Central Review (BICR) and overall survival (OS) of
contemporaneously randomized nivolumab combined with ipilimumab participants
versus nivolumab participants with localized renal cell carcinoma, with a
predominantly clear cell histology, who have undergone a nephrectomy.
To describe the safety and tolerability of nivolumab combined with ipilimumab
and nivolumab monotherapy.
Study design
This is a double blind, randomized trial of Nivolumab monotherapy or Nivolumab
combined with Ipilimumab versus placebo infusions in patients with localized
renal cell carcinoma with predominantly clear cell histology who underwent
radical or partial nephrectomy. Approximately 2,000 patients will be screened,
and approximately 1600 patients will be randomized globally.
Patients will be randomized between 2 parts of the study (part A or B) to
receive one of the below treatments.
Part A Treatments (Number of subjects ~ 800) in 1:1 ratio
A1.Nivolumab/Ipilimumab combination therapy (nivolumab 240 mg every 2 weeks and
ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is
delayed)
A2.Placebo (Placebo infusions at the same frequency of nivolumab and ipilimumab
infusions)
Part B Treatments (Number of subjects ~ 800) in 2:1:1
B1.Nivolumab/Ipilimumab combination therapy (Nivolumab 240 mg every 2 weeks and
ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is
delayed)
B2.Placebo (Placebo infusions at the same frequency of nivolumab and ipilimumab
infusions)
B3.Nivolumab monotherapy Nivolumab 240 mg every 2 weeks and ipilimumab Placebo
every 6 weeks (or every third nivolumab dose if dosing is delayed)
Randomisation will be done by an automated system and patients will be assigned
treatment based on their tumor pathology and by type of nephrectomy procedure
(partial versus radical).
The nephrectomy must be done no less than 4 weeks and no more than (or equal
to) 12 weeks prior to randomization.
Tumor tissue obtained within 3 months prior to enrolment, preferably at the
time of the nephrectomy, must be provided for biomarker analyses.
Screening/baseline imaging should be performed at least 4 weeks post
nephrectomy and submitted to the radiology vendor for BICR (blinded independent
central review committee) confirmation of disease-free status. Pre-nephrectomy
images are also requested, if available. Patient eligibility must be confirmed
by BICR prior to randomization. As a result, pre-nephrectomy scans, if
available, and baseline scans are encouraged to be submitted to BICR within 8
weeks of the nephrectomy to allow for timely return of the decision from the
BICR.
Treatment must be completed within 36 weeks after the first dose; any cycles
not received within 36 weeks after the first dose will be omitted, and the
patient will enter the Follow-up Phase.
Tumor assessments will occur in accordance with the Schedule of Activities or
until recurrence has been identified by the investigator and is confirmed by
BICR. PK and immunogenicity samples, biomarker assessments, and Quality of life
questionnaires will be collected according to the Schedule of Activities.
Adverse event assessments will be documented at each clinic visit.
The Follow-up Phase begins at the completion of 12 cycles, when the decision to
discontinue a patient from study therapy is made (no further treatment with
study therapy), or at Week 36, whichever comes first. Patients will have 2
follow-up visits (FU1 and FU2) for safety within approximately 30 and 100 days,
respectively, from the last dose of study therapy. Any ongoing treatment
related AEs will be followed until the toxicities resolve, return to baseline,
or are deemed irreversibly. After the Follow-up 2 Visit, all patients will be
followed for overall survival status every 12 weeks (±1 week) until death,
withdrawal of consent, lost to follow-up, or end of study.
Intervention
Part A Treatments
A1.Nivolumab/Ipilimumab combination therapy (nivolumab 240 mg every 2 weeks and
ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is
delayed)
A2.Placebo (Placebo infusions at the same frequency of nivolumab and ipilimumab
infusions)
Part B Treatments
B1.Nivolumab/Ipilimumab combination therapy (Nivolumab 240 mg every 2 weeks and
ipilimumab 1 mg/kg every 6 weeks (or every third nivolumab dose if dosing is
delayed)
B2.Placebo (Placebo infusions at the same frequency of nivolumab and ipilimumab
infusions)
B3.Nivolumab monotherapy Nivolumab 240 mg every 2 weeks and ipilimumab Placebo
every 6 weeks (or every third nivolumab dose if dosing is delayed)
Each cycle will be 2 weeks (14 days). Patients will receive study drug until
the end of 12 cycles (12 nivolumab doses and 4 ipilimumab doses), recurrence
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. Blood will also be
collected at certain visits for research purposes (PK, immunogenicity and
biomarker studies).
If there is no archival tissue available, or the sample was taken too long ago
(more than 3 months), patients will be required to have a biopsy in order to
participate. A biopsy of tumor tissue at progression is optional.
In addition, patients will undergo radiographic assessment (by CT or MRI) 23,
36 and 52 weeks after their first dose. These will then continue every 6 months
until year 6 and then after every year until year 10.
The frequency of visits and number of procedures carried out in the 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
threating. An Independent Data Monitoring Committee (DMC) will be utilised in
this trial to ensure that the safety data is reviewed during the trial. New
immune system targeted therapy such as Nivolumab and ipilimumab could
potentially provide clinical benefit and improvement in the outcomes for
patients with this disease. However, with all experiential drugs and clinical
trials, there are unknown risks. Study medication ad 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.
ARC Uxbridge - Sanderson Road - New Denham - Buckinghamshire ARC Uxbridge - Sanderson Road - New Denham - Buckinghamshire
Uxbridge UB8 1DH
GB
ARC Uxbridge - Sanderson Road - New Denham - Buckinghamshire ARC Uxbridge - Sanderson Road - New Denham - Buckinghamshire
Uxbridge UB8 1DH
GB
Listed location countries
Age
Inclusion criteria
a) Kidney tumor has been completely resected with negative surgical margins
obtained. The
randomization must occur greater than 4 weeks and less than (or equal to) 12
weeks from
the date of nephrectomy. Partial nephrectomy is allowed provided all inclusion
criteria are
met.
b) Post-nephrectomy tumor shows RCC with a predominately clear cell histology,
including participants with sarcomatoid features.
c) Pathological TNM staging per AJCC staging version 2010:
i) pT2a, G3 or G4, N0M0
ii) pT2b, G any, N0M0
iii) pT3, G any, N0M0
iv) pT4, G any, N0M0
v) pT any, G any, N1M0
d) Participants must have no clinical or radiological evidence of macroscopic
residual disease or distant metastases (M0) after nephrectomy
i) Baseline tumor assessment, performed 4 to approximately 12 weeks after
nephrectomy, shows no metastasis or residual tumor lesions per local review and
as confirmed by Blinded Independent Central Review (BICR). Results of BICR of
the baseline tumor assessment confirming absence of metastasis or residual
tumor lesions must be received before randomization.
Note: participants with one or more regional lymph nodes identified with short
axis 15 mm on the baseline (Post-Operative) tumor assessments are considered to
have gross residual disease and are therefore ineligible.
e) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0-1
(Appendix 5).
f) Either a formalin-fixed, paraffin-embedded (FFPE) tissue block or unstained
tumor tissue sections, obtained within 3 months prior to enrollment, preferably
from nephrectomy, with an associated pathology report, must be submitted to the
central laboratory prior to randomization. FFPE block or 20 unstained slides is
ideal, but a minimum of 10 unstained slides will be acceptable if tumor tissue
is limited. Biopsy should be excisional, incisional, or core needle. Fine
needle aspiration is unacceptable for submission.
g) Males and Females, ages *18 years or age of majority.
h) 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
72 hours prior to the start of study treatment.
i) Women must not be breastfeeding.
j) Women of childbearing potential (WOCBP) must agree to follow instructions
for method(s) of contraception
k) Males who are sexually active with WOCBP must agree to follow instructions
for method(s) of contraception
Exclusion criteria
a) Any severe or serious, acute or chronic medical or psychiatric condition or
laboratory abnormality that may increase the risk associated with study
participation or study drug administration including ongoing or active
infection requiring parental antibiotics
b) Participants with a condition requiring systemic treatment with either
corticosteroids (> 10 mg daily prednisone equivalent) or other
immunosuppressive medications within 14 days prior to the first dose of study
drug. Topical, ocular, intra-articular, intranasal, inhaled steroids, and
adrenal replacement steroid doses > 10 mg daily prednisone or the equivalent
are permitted in the absence of active immune disease.
c) Uncontrolled adrenal insufficiency
d) Participants with an 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 enrol.
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 | EUCTR2016-004502-34-NL |
| CCMO | NL61087.056.17 |