| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
To compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to
standard of care in patients with previously untreated and advanced non-clear cell RCC |
|
| E.1.1.1 | Medical condition in easily understood language |
| Survival of patients with kidney cancer. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10038415 |
| E.1.2 | Term | Renal cell carcinoma stage unspecified |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To compare the of OS rate at 12 months of Nivolumab combined with Ipilimumab to
standard of care in patients with previously untreated and advanced non-clear cell RCC. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives are to examine if the following is achieved:
To compare the OS rate at 6 and 18 months of Nivolumab combined with Ipilimumab to
standard of caremonotherapy in previously untreated and advanced non-clear cell RCC
Duration of reponse (DOR) for both arms and subgroups
To compare the PFS of Nivolumab combined with Ipilimumab to standard of care with
previously untreated metastatic non-clear cell RCC
To compare the medianOS of Nivolumab combined with Ipilimumab to standard of care
in subjects with previously untreated metastatic non-clear cell RCC C (based on hazard
ratio)
To estimate the objective response rate (ORR) of Nivolumab combined with Ipilimumab to standard of care in subjects with previously untreated mRCC |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
a) Subjects must have signed and dated an IRB/IEC approved
written informed consent form in accordance with regulatory and
institutional guidelines. This must be obtained before the
performance of any protocol related procedures that are not part
of normal subject care.
b) Subjects must be willing and able to comply with scheduled
visits, treatment schedule, laboratory testing, and other
requirements of the study.
2. Target Population
a) Histological confirmation of non-clear RCC with at least 50%
non-clear cell component according to actual WHO
classification36
b) Advanced (not amenable to curative surgery or radiation therapy)
or metastatic (AJCC Stage IV) RCC
c) Karnofsky > 70%
d) Measurable disease as per RECIST v 1.1 documented by an
English radiology report
e) Tumor tissue (FFPE archival or recent acquisition) must be
available and sent to the central pathological in order to confirm
the diagnosis. (Note: Fine Needle Aspiration [FNA] and bone
metastases samples are not acceptable for submission).
f) Patients with all risk categories will be eligible for the study.
Patients will be stratified for papillary or non-papillary non-clear
cell histology and IMDC risk score Patients will be categorized
according to favorable versus intermediate versus poor risk status
at registration according to the International Metastatic RCC
Database Consortium (IMDC) criteria:
i. KPS equal to 70%
ii. Less than 1 year from diagnosis to randomization
iii. Hemoglobin less than the lower limit of normal (LLN)
iv. Corrected calcium concentration greater than the upper limit of normal (ULN)
v. Absolute neutrophil count greater than the ULN
vi. Platelet count greater than the ULN
If none of the above factors are present, subjects are only eligible for the
favorable-risk cohort, if 1-2 factors are present subjects are categorized
as intermediate risk and > 3 factors as poor risk.
|
|
| E.4 | Principal exclusion criteria |
1. Target Disease Exceptions
a) Any active brain metastases requiring systemic corticosteroids.
Baseline imaging of the brain by MRI is required in patients with
clinical signs of potential CNS involvement within 28 days prior
to randomization.
b) Tumors with a clear-cell component of > 50%
Medical History and Concurrent Diseases
c) Prior systemic treatment with VEGF or VEGF receptor targeted
therapy (including, but not limited to, Sunitinib, pazopanib,
axitinib, tivozanib, and bevacizumab) or prior treatment with an
mTOR inhibitor or cytokines.
d) Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-
CD137, or anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint
pathways.
e) Administration of an immune checkpoint inhibitor as standard of
care
f) Any active or recent history of a known or suspected
autoimmune disease or recent history of a syndrome that required
systemic corticosteroids (> 10 mg daily prednisone equivalent) or
immunosuppressive medications except for syndromes which
would not be expected to recur in the absence of an external
trigger. Subjects with vitiligo or type I diabetes mellitus or
residual hypothyroidism due to autoimmune thyroiditis only
requiring hormone replacement are permitted to enroll.
g) Any condition requiring systemic treatment with corticosteroids
(> 10 mg daily prednisone equivalents) or other
immunosuppressive medications within 14 days prior to first
dose of study drug. Inhaled steroids and adrenal replacement
steroid doses > 10 mg daily prednisone equivalents are permitted
in the absence of active autoimmune disease.
h) Uncontrolled adrenal insufficiency.
i) Ongoing symptomatic cardiac dysrhythmias, uncontrolled atrial
fibrillation, or prolongation of the Fridericia corrected QT
(QTcF) interval defined as > 450 msec for males and > 470 msec
for females, where QTcF = QT / 3√RR
j) Poorly controlled hypertension (defined as systolic blood pressure (SBP) of 150 mmHg or diastolic blood pressure
(DBP) of 90 mmHg), despite antihypertensive therapy.
k) History of any of the following cardiovascular conditions within
12 months of enrollment: cardiac angioplasty or stenting,
myocardial infarction, unstable angina, coronary artery by-pass
graft surgery, symptomatic peripheral vascular disease, class III
or IV congestive heart failure, as defined by the New York Heart
Association.
l) History of cerebrovascular accident including transient ischemic
attack within the past 12 months.
m) History of deep vein thrombosis (DVT) unless adequately treated
with low molecular weight heparin
n) History of pulmonary embolism within the past 6 months unless
stable, asymptomatic, and treated with low molecular weight
heparin for at least 6 weeks.
o) History of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within the past 6 months.
p) Serious, non-healing wound or ulcer.
q) Evidence of active bleeding or bleeding susceptibility; or
medically significant hemorrhage within prior 30 days.
r) Any requirement for anti-coagulation, except for low molecular
weight heparin.
s) 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.
t) Known history of testing positive for human immunodeficiency
virus (HIV) or known acquired immunodeficiency syndrome
(AIDS).
u) Any positive test for hepatitis B or hepatitis C virus indicating
acute or chronic infection.
v) Known medical condition (eg, a condition associated with
diarrhea or acute diverticulitis) that, in the investigator’s opinion,
would increase the risk associated with study participation or
study drug administration or interfere with the interpretation of
safety results.
w) Major surgery (eg, nephrectomy) less than 28 days prior to the
first dose of study drug.
x) Anti-cancer therapy less than 28 days prior to the first dose of
study drug or palliative, focal radiation therapy less than 14 days
prior to the first dose of study drug.
y) Receiving concomitant CYP3A4 inducers or strong CYP3A4
inhibitors
z) Impairment of gastrointestinal function or gastrointestinal disease
that may significantly alter the absorption of the standard of care
agent (eg, malabsorptive disorder, ulcerative disease,
uncontrolled nausea, vomiting, diarrhea, or small bowel
resection).
aa) Hypersensitivity to standard of care agent or any of the
excipients
bb) Patients who were vaccinated with a live vaccine 2 weeks prior
to the start of the CT
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the overall survival rate at 12 months (OS12) (landmark). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 12 months after start of treatment of patient. |
|
| E.5.2 | Secondary end point(s) |
Secondary endpoints were:
OS rate at 6 and 18 months in overall population and histological and prognostic subgroups.
Overall survival (OS)
Progression-free survival (PFS)
Objective response rate (ORR)
Safety/tolerability
Quality of Life (QoL) as assessed by FKSI-DRS questionnaire |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints were:
OS rate at 6 and 18 months in overall population and histological and prognostic subgroups.
Overall survival (OS)
Progression-free survival (PFS)
Objective response rate (ORR)
Safety/tolerability
Quality of Life (QoL) as assessed by FKSI-DRS questionnaire |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study will end 18 months after the last patient is in. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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