| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| renal cell cancer of non-clear cell subtypes |
|
| 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 | 21.1 |
| 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 |
|
| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
To compare the OS rate at 6 and 18 months of Nivolumab combined
with Ipilimumab to Standard of Care 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 median OS 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:
1. KPS equal to 70%
2. Less than 1 year from diagnosis to randomization
3. Hemoglobin less than the lower limit of normal (LLN)
4. Corrected calcium concentration greater than the upper limit
of normal (ULN)
5. Absolute neutrophil count greater than the ULN
6. 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.
3. Age and Reproductive Status
a) Males and Females, 18 years of age
b) WOCBP must have a negative serum or urine pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) within
24 hours prior to the start of study drug.
c) Women must not be breastfeeding
d) WOCBP must agree to follow instructions for method(s) of
contraception for a period of 30 days (duration of ovulatory cycle)
plus the time required for the investigational drug to undergo five
half-lives. The terminal half-lives of Nivolumab and Ipilimumab
are up to 25 days and 18 days, respectively. The terminal half-life
of the active metabolite of Sunitinib is up to 110 hours. The
terminal half-life of other Standard of Care agents has to be
derived from the product information.
i. WOCBP randomized to receive Nivolumab + Ipilimumab
should use an adequate method to avoid pregnancy for 23
weeks (30 days plus the time required for Nivolumab to
undergo five half-lives) after the last dose of
investigational drug.
ii. WOCBP randomized to receive a Standard of Care agent
should use an adequate method to avoid pregnancy for at
least 8 weeks (30 days plus the time required for the active
metabolite of the Standard of Care agent to undergo five
half-lives)
e) Males who are sexually active with WOCBP must agree to follow
instructions for method(s) of contraception for a period of 90 days
(duration of sperm turnover) plus the time required for the
investigational drug to undergo five half-lives. The terminal
half-lives of Nivolumab and Ipilimumab are up to 25 days and 18
days, respectively. The terminal half-life of the active metabolite
of Sunitinib is up to 110 hours.
i. Males randomized to receive Nivolumab combined with
Ipilimumab who are sexually active with WOCBP must
continue contraception for 31 weeks (90 days plus the time
required for Nivolumab to undergo five half-lives) after the
last dose of investigational drug.
ii. Males randomized to receive Standard of Care who are
sexually active with WOCBP must continue contraception
for at least16 weeks (90 days plus the time required for the
active metabolite of the Standard of Care agent to undergo
five half-lives) after the last dose of investigational drug.
f) Azoospermic males and WOCBP who are continuously not
heterosexually active are exempt from contraceptive requirements.
However they must still undergo pregnancy testing as described in
this section.
Investigators shall counsel WOCBP and male subjects who are sexually
active with WOCBP on the importance of pregnancy prevention and the
implications of an unexpected pregnancy Investigators shall advise
WOCBP and male subjects who are sexually active with WOCBP on the
use of highly effective methods of contraception. Highly effective
methods of contraception have a failure rate of < 1% when used
consistently and correctly |
|
| 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) 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.
f) 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.
g) Uncontrolled adrenal insufficiency.
h) 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
i) Poorly controlled hypertension (defined as systolic blood
pressure (SBP) of 150 mmHg or diastolic blood pressure
(DBP) of 90 mmHg), despite antihypertensive therapy.
j) 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.
k) History of cerebrovascular accident including transient
ischemic attack within the past 12 months.
l) History of deep vein thrombosis (DVT) unless adequately
treated with low molecular weight heparin
m) History of pulmonary embolism within the past 6 months
unless stable, asymptomatic, and treated with low molecular
weight heparin for at least 6 weeks.
n) History of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within the past 6 months.
o) Serious, non-healing wound or ulcer.
p) Evidence of active bleeding or bleeding susceptibility; or
medically significant hemorrhage within prior 30 days.
q) Any requirement for anti-coagulation, except for low
molecular weight heparin.
r) 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.
s) Known history of testing positive for human
immunodeficiency virus (HIV) or known acquired
immunodeficiency syndrome (AIDS).
t) Any positive test for hepatitis B or hepatitis C virus indicating
acute or chronic infection.
u) 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.
v) Major surgery (eg, nephrectomy) less than 28 days prior to the
first dose of study drug.
w) 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.
x) Receiving concomitant CYP3A4 inducers or strong CYP3A4
inhibitors
y) 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).
z) Hypersensitivity to Standard of Care agent or any of the
excipients
aa) Patients who were vaccinated with a live vaccine 2 weeks prior
to the start of the CT
for further exclusion criteria please see Protocol 4.1 , Page 18-19
|
|
| 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 |
• OS rate at 6 and 18 months
|
|
| 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 | 40 |
| 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
|
| End of trial is latest 30 months after last patient in |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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