E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable locally advanced or metastatic, non-clear cell renal cell carcinoma, rare head and neck cancer, rare skin cancer, MSI-nonCRC or penile cancer, which is resistant or refractory to standard therapy, or for which standard therapy does not exist, or is not considered appropriate, and for which no other experimental treatment options are available. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
The primary objective of the trial is to evaluate the efficacy response to nivolumab monotherapy in cohorts of patients with unresectable locally advanced or metastatic, non-clear cell RCC, rare head and neck cancer, rare skin cancer, MSI-nonCRC or penile cancer, which is resistant or refractory to standard therapy, and for which no other treatment options are available. |
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E.2.2 | Secondary objectives of the trial |
• To identify populations, for which the IP is expected to have a clinical benefit. • To assess the efficacy of nivolumab monotherapy in each cohort in terms of survival, progression occurrence and quality of response. • To assess the safety profile of nivolumab monotherapy. • To define predictive factors including biomarkers related to the response to nivolumab; in particular to explore whether the immunohistochemical expression of PD-L1 and other immune markers (CD3, CD4, FOXP3, CD8 or CD68/CD163) in the tumour samples (both in the tumour cells and the immune cells) is correlated with response to nivolumab. • To test if the mutational load measured in tumour samples from some of the studied cohorts can be correlated with response to nivolumab. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Biological Ancillary Study : The aim of the proposed ancillary studies is to address specific scientific questions related to potential predictive biomarkers of efficacy and the mechanism of action of the antitumour immune response, such as: • Which biomarkers are specifically associated with tumour response to treatment? • Which biomarkers are specifically associated with treatment-related toxicity? • What are the common immune parameters modified by the treatment in all patients? • Which tumour immune infiltration patterns are seen in responding versus non-responding patients? • Are identified biomarkers unique to a particular tumour, or universally present across all tumour types |
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E.3 | Principal inclusion criteria |
1. Patient information sheet and written informed consent (PIS/ICF) form signed. 2. Histologically confirmed diagnosis of a pathology corresponding to one of the following selected cancer types: • Non-clear cell renal-cell carcinomas: papillary renal cell carcinoma (pRCC, type I, type II and non-classified pRCC), chromophobe RCC (ChRCC), renal medullary carcinoma (RMC), collecting duct/Bellini duct carcinoma (CDC), microphthalmia-associated transcription (MiT) family translocation renal cell carcinoma (tRCC), renal cell carcinoma with a prominent sarcomatoid component (sarcRCC). • Rare head and neck cancers: principal and accessory salivary gland tumours, facial tissue tumours. • Rare skin cancers: adnexal carcinomas, basal cell carcinoma resistant to vismodegib. • Non-colorectal cancers with microsatellite instability determined locally by immunohistochemistry or polymerase chain-reaction (PCR) • Squamous cell carcinoma of penis. 3. Metastatic disease or unresectable locally advanced malignancy that is resistant or refractory to standard therapy or for which standard therapy does not exist or is not considered appropriate by the Investigator. 4. Aged ≥ 18 years old. 5. Measurable disease according to RECIST v1.1 guidelines for solid tumours (Eisenhauer, 2009; Appendix 1). 6. Able to provide a FFPE biopsy sample of a metastatic site or primitive tumour tissue. Note: Patients for whom suitable archived biopsy material is not available must be willing to undergo a biopsy of a tumour lesion prior to study entry, unless this is medically contraindicated (e.g. site inaccessible or patient safety concerns). 7. Patients must have a mandatory treatment-free interval of at least 21 days following previous systemic anti-cancer treatments. 8. Patients who have received previous systemic anticancer treatment and/or radiotherapy should have recovered from any treatment related toxicity, to a level of ≤ grade 1 (according to NCI-CTCAE criteria, v 4.0, Appendix 2) with the exception of Grade 2 alopecia. 9. Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1.0 x109/L, platelets ≥ 100 x109/L, haemoglobin (Hb) ≥ 9 g/L) measured within 14 days of treatment initiation. 10. Adequate renal function (creatinine clearance ≥ 50 mL/ using the MDRD or CKI EPI method) measured within 14 days of treatment initiation. 11. Adequate hepatic function (serum bilirubin ≤ 1.5 x the reference upper limit of normal (ULN) unless due to Gilbert’s syndrome; aspartate aminotransferase [ASAT] and alanine aminotransferase [ALAT] ≤ 2,5 xULN) measured within 14 days of treatment initiation. For patients with documented liver metastasis ASAT/ALAT ≤ 5x ULN is acceptable. 12. Strictly normal blood levels of calcium and magnesium, measured within 14 days of treatment initiation. 13. Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1 (Oken, 1982; Appendix 3). 14. Estimated life expectancy ≥ 90 days. 15. Patients who are sexually active must agree to use a medically accepted method of contraception (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner, for participating women; condoms for participating men) or practice complete abstinence, beginning 14 days before the first administration of IP, while on treatment and for at least 5 months after the last administration of IP for female patients, and 7 months after the last administration of IP for male patients. 16. Women of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to the first administration of IP. If urine test results are positive or cannot be confirmed as negative, a serum pregnancy test will be required. 17. Women who are breastfeeding should discontinue nursing prior to the first administration of IP and for at least 90 days after the last administration of IP. 18. Patients must be affiliated to a Social Security System or equivalent. |
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E.4 | Principal exclusion criteria |
1. Prior treatment with an anti-PD1 or anti-PD-L1 antibody 2. Eligible, and willing, to participate in a clinical trial of an alternative anticancer therapy targeting their disease which is open to accrual in France. 3. Concurrent steroid medication at a dose greater than prednisone 10 mg/day or equivalent (Appendix 4). 4. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 5. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis. 6. History of severe hypersensitivity reaction to any monoclonal antibody therapy 7. Radiotherapy (except for brain and extremities) within 21 days prior to the first administration of IP. 8. Treatment with other investigational drugs or participation in another clinical trial within 21 days prior to the first administration of IP or concomitantly with the trial. 9. Has known symptomatic central nervous system (CNS) metastases. Patients with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. 10. Has known carcinomatous meningitis or a history of leptomeningeal disease. 11. Serum creatinine > 1.5 xULN or glomerular filtration rate (GFR) < 50 ml/min. 12. Lymphocytes count below 1,000/mm3 and CD4+ count below 500/mm3 as assessed by routine blood phenotyping. 13. Other malignancies within the past 5 years other than basal cell skin cancer or carcinoma in situ of the cervix. 14. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy. 15. Active or chronic hepatitis B, hepatitis C and/or human immunodeficiency virus (HIV) infection (HIV 1/2 antibodies), or a known history of active Tuberculosis bacillus. 16. Has received a live vaccine within 30 days of planned start of study treatment. Note: Seasonal influenza vaccines for injection are generally inactivated vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. 17. Active alcohol or drug abuse. 18. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule. 19. Any condition which in the Investigator’s opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Objective response rate per cohort, defined as the percentage of patients in each cohort with a CR or PR measured at the first scheduled disease assessment following study treatment initiation (Day 84, ± 7 days) as assessed by an Independent Review Committee (IRC) according to the Response Evaluation Criteria in Solid Tumours version 1.1. (RECIST v1.1; Eisenhauer, 2009; Appendix 1). Patients who withdraw from the study prior to this time point and patients with non-evaluable disease will be considered as ’non-responders’ in the analysis.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
An initial analysis will be performed separately for each cohort after 10 patients have been enrolled and completed one on treatment disease assessment. For cohorts which continue to recruit patients, subsequent analysis of the primary endpoint will be performed after each 5 additional patients enrolled until recruitment is stopped or maximum sample size (25 patients) is reached. |
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E.5.2 | Secondary end point(s) |
• Progression-free survival, defined as the time from inclusion until documented disease progression (PD) according to RECIST v1.1 or death, whichever occurs first. • Overall survival, defined as the time from inclusion until death due to any cause. • Best response to treatment according to RECIST v1.1, measured at any disease assessment during the course of the study. • Response duration, defined as the time from first observation of objective response (i.e. PR or CR) according to RECIST v.1.1 until PD or death, whichever occurs first. • Time to response, defined as the time from inclusion until observation of objective response (i.e. PR or CR) according to RECIST v.1.1. • Frequency and severity of adverse events assessed according to the National Cancer Institute (NCI) Common terminology criteria for adverse events, version 4 (CTCAE v4, Appendix 2). • Progression-free survival, OS and ORR in subgroups of subjects according to expression level of PD L1 and other immune markers (high versus low expression with a cutoff value set at the median for the population measured). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary endpoints will be analysed after all enrolled patients have completed the specified follow-up period. |
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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 | Yes |
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.8.3 |
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 | 100 |
E.8.5 | The trial involves multiple Member States | No |
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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |