| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with previously untreated (1st line) or pretreated (2nd line), intermediate or high risk, advanced or metastatic renal cell carcinoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Subjects with previously untreated or pretreated, intermediate or high risk, advanced or metastatic renal cell carcinoma |
|
| 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 | 10038400 |
| E.1.2 | Term | Renal carcinoma stage IV |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10038399 |
| E.1.2 | Term | Renal carcinoma stage III |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 | 10050076 |
| E.1.2 | Term | Metastatic renal carcinoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To estimate the best ORR based on investigator assessment using RECIST 1.1 of the TITAN regimen in untreated (1st line) and pretreated (2nd line) subjects with IMDC intermediate and high risk, advanced RCC with clear cell component |
|
| E.2.2 | Secondary objectives of the trial |
- PFS (Progression free survival), DOR (Duration of response), Time to Immunotherapy Resistance (TIR) and OS (Overall survival) in untreated (1st line) and pretreated (2nd line) patients, and the overall cohort
- PFS, DOR, TIR and OS in subgroups of IMDC intermediate and high risk patients (1st line, 2nd line, and the overall cohort)
- RR (Remission rate), TTR (Time to response) and DOR after nivolumab/ipilimumab combination “boost” for initial SD (Stable disease) and PD (Progressive disease), respectively
- RR, TTR and DOR after nivolumab/ipilimumab combination “boost” for PD during nivolumab maintenance (including re-treatment)
- Treatment emergent adverse events according to NCI-CTC version 4 (to assess the overall safety and tolerability of the TITAN regimen)
-To assess disease related symptoms in each arm based on the NCCN Functional Assessment of Cancer Therapy-Kidney Symptom Index 19 (Version 2)
- immunological analysis |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed Written Informed Consent
- Subjects or legally acceptable representatives 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.
- Subjects or legally acceptable representatives must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing, and other requirements of the study.
2. Target Population
- Histological confirmation of RCC with a clear-cell component.
- Advanced (not amenable to curative surgery or radiation therapy) or metastatic (AJCC Stage IV) RCC
- One (antioangiogenic or temsirolimus) or no prior systemic therapy for RCC with the following exception:
One prior adjuvant or neoadjuvant therapy for completely resectable RCC if such therapy did not include an agent that targets VEGF or VEGF receptors as well as CTLA-4- or PD-1/PD-L1 immune checkpoint inhibitors, respectively, and if recurrence occurred at least 6 months after the last dose of adjuvant or neoadjuvant therapy.
- KPS of at least 70% (See Appendix 2)
- Measurable disease as per RECIST v1.1
- Tumor tissue (FFPE archival or recent acquisition) must be received by the central pathology (block or unstained slides). (Note: Fine Needle Aspiration [FNA] and bone metastases samples are not acceptable for submission).
- Patients with risk group intermediate or poor will be eligible for the study.
To be eligible as intermediate or poor-risk, at least one of the following prognostic factors as per the International Metastatic RCC Database Consortium (IMDC) criteria must be present:
1. KPS equal to 70%
2. Less than 1 year from initial diagnosis of RCC (eg, nephrectomy or first diagnostic biopsy) to registration (1st line) or to start of first-line targeted therapy (2nd line), respectively
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 not eligible (risk group favorable).
3. Age and Reproductive Status
- Males and Females, ≥ 18 years of age
- 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 24 hours prior to the start of study drug.
- Women must not be breastfeeding
- Women of childbearing potential (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. 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 investigational drug.
- 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. Males who 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.
Comment: Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, WOCBP must still undergo pregnancy testing as described in this section
|
|
| E.4 | Principal exclusion criteria |
1.Target Disease Exceptions
- Any history of or current CNS metastases. Baseline imaging of the brain by MRI (preferred) or CT scan is required within 28 days prior to registration.
2. Medical History and Concurrent Diseases
- Prior systemic treatment with more than one of the following drugs: mTOR, VEGF or VEGF receptor targeted therapy (including, but not limited to, temsirolimus, everolinus, sunitinib, pazopanib, axitinib, tivozanib, and bevacizumab).
- 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.
- 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.
- 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.
- 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.
- Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
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.
- Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
- 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.
- Presence of any toxicities attributed to prior anti-cancer therapy, other than alopecia, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
3. Physical and Laboratory Test Findings
- Any of the following laboratory test findings:
i) WBC < 2,000/mm3
ii) Neutrophils < 1,500/mm3
iii) Platelets < 100,000/mm3
iv) AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
v) Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
vi) Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula):
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
4. Allergies and Adverse Drug Reaction
- History of severe hypersensitivity reaction to any monoclonal antibody or any constituent of the product
5. Other Exclusion Criteria
-Subjects 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 and who don’t have a legally acceptable representative.
- Subject who has been incarcerated or involuntarily institutionalized by court order or by the authorities.
- Participation in another clinical intervention trial 30 days prior to registration
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| ORR based on investigator assessment using RECIST 1.1 of the TITAN regimen in untreated (1st line) and pretreated (2nd line) subjects with IMDC intermediate and high risk, advanced RCC with clear cell component or metastatic RCC 30 weeks after last patient first treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| 30 weeks after all subjects have been treated (30 weeks after last patient first treatment) |
|
| E.5.2 | Secondary end point(s) |
Remission Rate, Time to response, Duration of Response, Progresion free Survival, Time to Immunotherapy Resistance and Overall survival all as assessed by investigators among all treated subjects, first line subjects, and second line subjects.
Patients with IMDC intermediate and high risk will be analysed separately. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 26 |
| 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
|
|
| 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 |
Print
