| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| advanced or metastatic renal cell carcinoma (RCC) |
| fortgeschrittenes oder metastasiertes Nierenzellkarzinom |
|
| E.1.1.1 | Medical condition in easily understood language |
| advanced or metastatic renal cell carcinoma (RCC) |
| fortgeschrittener oder metastasierter Nierenzell-Krebs |
|
| 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 | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10073251 |
| E.1.2 | Term | Clear cell renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10067946 |
| E.1.2 | Term | Renal cell carcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 | 10038409 |
| E.1.2 | Term | Renal cell carcinoma NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 assess the survival benefit from an early switch approach from sunitinib or pazopanib to nivolumab (anti-angiogenic to immunotherapy switch) |
|
| E.2.2 | Secondary objectives of the trial |
• to compare efficacy of early switch to nivolumab vs. continuation of either sunitinib or pazopanib
• to compare health-related quality of life (HR-QoL) during TKI and nivolumab treatment after early switch
• to assess the influence of response to previous TKI treatment on nivolumab efficacy
• to assess safety and toxicity
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent and any locally-required
authorization (EU Data Privacy Directive in the EU) obtained
from the subject prior to performing any protocol-related
procedures, including screening evaluations.
2. Subject is willing and able to comply with the protocol for the
duration of the study including undergoing treatment and
scheduled visits and examinations including follow up.
3. Age ≥ 18 years at time of study entry
4. ECOG performance status 0-2.
5. Metastatic or locally advanced RCC with clear cell
component, not amenable to surgery with curative intention.
6. First-line treatment with a TKI for 10-12 weeks (limited to
sunitinib or pazopanib).
7. Patients with measurable disease (at least one unidimensionally
measurable target lesion by CT-scan or MRI)
according to modified Response Evaluation Criteria in Solid
Tumors (RECIST 1.1). If prior palliative radiotherapy to
metastatic lesions: ≥ 1 measurable lesion that has not been
irradiated. Patients with bone lesions as the only measurable
lesion are eligible, provided that lesions consist of soft tissue,
which is assessed via CT or MRI.
8. Documented partial response or stable disease to first-line
TKI exposure at 10-12 weeks.
9. Prior therapies other than indicated in the exclusion critiria
and surgeries are allowed if completed 4 weeks (for minor surgery and palliative radiotherapy for bone pain: 2 weeks)
prior to start of treatment and patient recovered from toxic
effects.
10. Adequate blood count, liver-enzymes, and renal function
(obtained no later than 14 days prior to start of study
treatment):
WBC ≥ 2000/μL
Neutrophils ≥ 1500/μL
Platelets ≥ 100 x103/μL
Hemoglobin > 9.0 g/dL
Serum creatinine ≤ 1.5 x ULN or creatinine
clearance (CrCl) ≥ 40 mL/min (if using the
Cockcroft-Gault formula below):
Female CrCl = (140 - age in years) x weight in kg x 0.85/
72 x serum creatinine in mg/dL
Male CrCl = (140 - age in years) x weight in kg x 1.00/
72 x serum creatinine in mg/dL
AST/ALT ≤ 3 x ULN
Total Bilirubin ≤ 1.5 x ULN (except subjects
with Gilbert Syndrome, who can have total
bilirubin < 3.0 mg/dL)
11. Women of childbearing potential (WOCBP) must use
appropriate method(s) of contraception. WOCBP 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 nivolumab.
12. Women of childbearing potential 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
nivolumab
13. Men who are sexually active with WOCBP must use any
contraceptive method with a failure rate of less than 1% per
year. Men receiving nivolumab and who are sexually active
with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational
product. Women who are not of childbearing potential (ie,
who are postmenopausal or surgically sterile as well as
azoospermic) men do not require contraception. |
|
| E.4 | Principal exclusion criteria |
1. Prior systemic therapy other than 10-12 weeks SOC TKI
treatment for advanced or metastatic RCC.
2. Standard of care 1st-line TKI treatment for advanced or
metastatic RCC for longer than 12 weeks.
3. Complete remission (CR) or progression during SOC TKI 1st-
line treatment.
4. Termination of first-line treatment with TKI due to intolerance
5. Previous malignancy (other than renal cell cancer), requiring
active treatment or diagnosed in metastatic state. Basal cell
cancer of the skin, pre-invasive cancer of the cervix, T1a
prostate carcinoma or superficial bladder tumor [Ta, Tis and
T1] are exempted.
6. Brain metastases mandating active treatment. Subjects with
brain metastases are eligible if metastases have been treated
and there is no magnetic resonance imaging (MRI) evidence
of progression for 4 weeks after treatment is completed and
within 28 days prior to the first dose of nivolumab
administration. There must also be no requirement for
immunosuppressive doses of systemic corticosteroids (> 10
mg/day prednisone equivalents) for at least 2 weeks prior to
study drug administration.
7. Prior therapy with anti-tumor vaccines or other immunostimulatory
antitumor agents.
8. Administration of a live, attenuated vaccine within 4 weeks of
start of therapy
9. Any previous treatment with an anti-PD-1, anti-PD-L1, anti-
PD-L2, anti-CTLA-4 antibody, or any other antibody or drug
specifically targeting T-cell co-stimulation or immune
checkpoint pathways
10. Subjects must have recovered from the effects of major
surgery or significant traumatic injury at least 14 days before
the first dose of study treatment.
11. Patients should be excluded if they have an active, known or
suspected autoimmune disease. NOTE: Subjects are
permitted to enroll if they have vitiligo, type I diabetes
mellitus, residual hypothyroidism due to autoimmune
condition only requiring hormone replacement, psoriasis not
requiring systemic treatment, or conditions not expected to
recur in the absence of an external trigger
12. Patients should be excluded if they have a condition requiring
systemic treatment with either corticosteroids (> 10 mg daily
prednisone equivalents) or other immunosuppressive
medications within 14 days of study drug administration.
NOTE: Inhaled or topical steroids and adrenal replacement
doses > 10 mg daily prednisone equivalents are permitted in
the absence of active autoimmune disease.
13. Known chronic infection (i.e. hepatitis B or C, HIV)
14. Patients should be excluded if they have been positively
tested for hepatitis B virus surface antigen (HBV sAg) or
hepatitis C virus ribonucleic acid (HCV antibody) indicating
acute or chronic infection.
15. Patients should be excluded if they have a known history of
testing positive for human immunodeficiency virus (HIV) or a
known acquired immunodeficiency syndrome (AIDS).
16. History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the product.
17. Uncontrolled intercurrent illness including, but not limited to,
ongoing or active infection, symptomatic congestive heart
failure, uncontrolled hypertension, unstable angina pectoris,
cardiac arrhythmia, active peptic ulcer disease or gastritis,
active bleeding diatheses including any subject known to
have a psychiatric illness/social situations that would limit
compliance with study requirements or compromise the
ability of the subject to give written informed consent
18. Uncontrolled severe hypertension (failure of diastolic blood
pressure to fall below 95 mmHg under adequate medication)
19. Current cardiac events such as arrhythmias, myocardial
infarction, CHF, apoplexy, lung embolism
20. Idiopathic pulmonary fibrosis or other risk for pneumonitis
21. History of allogeneic solid organ or tussie transplant including allogeneic hematopoetic stem cell transplantation.
22. Female subjects who are pregnant, breast-feeding or male or
female patients of reproductive potential who are not
employing an effective method of birth control
23. Any other serious or uncontrolled medical disorder, active
infection, physical examfinding, laboratory finding, altered
mental status, or psychiatric condition that, in the opinion of
the investigator, would limit a subject’s ability to comply with
the study requirements, substantially increase risk to the
subject, or impact the interpretability of study results.
24. Previous enrollment or randomization in the present study.
25. Involvement in the planning and/or conduct of the study
26. Patient who might be dependent on the sponsor, site or the
investigator.
27. Patients who are unable to consent because they do not
understand the nature, significance and implications of the
clinical trial and therefore cannot form a rational intention in
the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].
28. Patient who has been incarcerated or involuntarily
institutionalized by court order or by the authorities § 40 Abs.
1 S. 3 Nr. 4 AMG. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
after death of the patient
|
|
| E.5.2 | Secondary end point(s) |
Key Secondary Endpoint:
• Best overall response (PR+CR) throughout the 1st-line treatment according to modified RECIST
Additional secondary endpoints:
• PFS and OS from time of randomization to death from any cause
• OS rates at 24
• PFS and OS from start of 1st line TKI therapy
• Duration of response
• Health related-Quality of Life (Functional Assessment of Cancer Therapy-Kidney Symptom Index FKSI 15 score and changes in the FKSI 15 score)
• proportion of subjects with increase from baseline in FKSI 15 (MID 3 points)
• time to deterioration, measured as a composite endpoint consisting of decrease of QoL (defined by the minimal clinical relevant difference) or death (TUDD)
• tumor shrinkage, i.e. relative change from baseline in sum of longest diameter
• AEs / SAEs / Treatment Emergent Adverse Events according to CTCAE 4.03
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS and OS from time of randomization to death from any cause: after death of the patient
- OS rates at 24 months: at 24 months after study entry
- AEs / SAEs / Treatment Emergent Adverse Events according to CTCAE 4.03: until up to 100 days after EOT
- others: after EOT |
|
| 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 | Yes |
| 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 | Yes |
| 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 | No |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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 | No |
| 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 study (EoS) is defined as the time point when the last patient in (LPI) has completed a 24 month treatment and follow-up observation phase period. |
|
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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