| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with recurrent and/or metastatic platinum refractory Squamous Cell Carcinoma of the Head and Neck (SCCHN), with poor prognosis and no effective chemotherapy options. |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To estimate the incidence of high-grade (i.e. Grade 3-5 of CTCAE v4.0) adverse events of interest (AEI) in patients with recurrent and/or metastatic platinum refractory SCCHN treated with nivolumab in monotherapy. AEI are defined as adverse reactions known to be related to nivolumab (i.e. skin, endocrinopathy, astrointestinal, hepatic, renal, pulmonary, and hypersensitivity adverse events) and other adverse events not related to carcinoma progression or to intercurrent disease clearly identified. |
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| E.2.2 | Secondary objectives of the trial |
- To characterize the type and outcome of high-grade AEI in patients receiving nivolumab monotherapy (time of onset, time to resolution, need for immune modulating concomitant medication or hormone replacement, need for therapy stop temporary or definitively).
- To estimate the rate of low-grade (i.e. 1-2) AEI
- To estimate the efficacy of nivolumab in terms of Overall Survival (OS) and Progression Free Survival (PFS) in all treated patients and pre-defined sub-groups
- To estimate investigator-assessed Objective Response Rate (ORR) during nivolumab treatment in all treated patients and pre-defined sub-groups, using RECIST 1.1 and iRECIST
- To assess the proportion of pseudo-progression for the entire trial population and by pre-defined sub-groups
- To study biological and radiological biomarkers of response or progression
* See the sub-groups definition in STATISTICAL ANALYSIS (p. 9) |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Adult men and women ≥ 18 years.
2. Histologically confirmed recurrent and/or metastatic SCCHN (oral cavity, pharynx, larynx), stage III/IV and not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy).
3. Patients with Eastern Cooperative Oncology Group (ECOG) performance status ≤2.
4. Documentation of p16-positive or p16-negative disease to determine human papillomavirus (HPV) status of tumor for SCC of the oropharynx
5. Tumor progression or recurrence after a platinum therapy in the adjuvant (ie with radiation after surgery), primary (ie, with radiation), recurrent, or metastatic setting. In the adjuvant or primary setting, the recurrence must have occurred within 6 months after the last dose of platinum therapy. Clinical progression after platinum therapy is an allowable event for entry and is defined as progression of a lesion at least 10 mm in size that is amenable to caliper measurement (eg superficial skin lesion as per RECIST 1.1) or a lesion that has been visualized and photographically recorded with measurements and shown to have progressed.
6. Measurable disease by CT or MRI per RECIST 1.1 criteria
7. Prior curative radiation therapy must have been completed at least 4 weeks prior to study drug administration. Prior focal palliative radiotherapy must have been completed at least 2 weeks before study drug administration.
8. Immunosuppressive doses of systemic medication, such as steroids or absorbed topical steroids (doses > 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks before study drug administration
9. Patients with brain metastases will be eligible if they are: asymptomatic, without edema, not on corticosteroids, have been treated and there is no magnetic resonance imaging (except where contraindicated in which CT scan is acceptable) evidence of progression for at least 4 weeks after treatment is complete
10. Screening laboratory values must meet the following criteria (using CTCAE v4) and should be obtained within 7 days prior to the first study drug administration :
a. WBC ≥ 2000/μL
b. Polynuclear neutrophils ≥ 1.5 x 109/L
c. Platelets≥ 75 x 109/L
d. Hemoglobin ≥ 8.0 g/mL
e. ALAT/ASAT≤ 3.0 x ULN in the absence of liver metastases or ≤ 5x ULN in the presence of liver metastases
f. Total Bilirubin ≤ 1.5 x ULN (except Gilbert Syndrome : < 3.0 mg/dL)
g. Creatinine clearance ≥ 40 mL/min (measured or calculated by Cockroft and Gault formula) or serum creatinine ≤2.0 x ULN
11. Calcium levels must be normalized and maintained within normal limits for study entry and on treatment. Medical management of calcium levels is permitted. Note: Normal calcium levels may be based on ionized calcium or adjusted for albumin.
12. Subjects with an initial magnesium < 0.5 mmol/L (1.2 mg/dL) may receive corrective magnesium supplementation but should continue to receive either prophylactic weekly infusion of magnesium and/or oral magnesium supplementation (eg, magnesium oxide) at the investigator’s discretion.
13. Potentially reproductive patients must agree to use an effective contraceptive method or practice adequate methods of birth control or practice complete abstinence, 14 days before starting drug and while on treatment, and for at least 31 weeks (≈ 7 months) for males and 23 weeks (≈ 5 months) for females after the last dose of study drug. Azoospermic males and women of childbearing potential who are continuously not heterosexually active are exempt from contraceptive requirements.
14. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25IU/L or equivalent units of HCG) done within 24 hours prior to the first dosing.
15. Women who are breastfeeding should discontinue nursing prior to the first dose of study drug and until 6 months after the last dose.
16. Provision of signed and dated, written informed consent prior to any study specific procedures, sampling and analyses.
17. Patients with social insurance coverage. |
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| E.4 | Principal exclusion criteria |
1. Histologically confirmed recurrent and/or metastatic carcinomas of the nasopharynx, squamous cell carcinoma of unknown primary, and salivary gland or non-squamous histologies (eg mucosal melanoma) are not allowed.
2. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results.
3. 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.
4. Subjects with active, known or suspected autoimmune disease. Subjects with 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 are permitted to enrol.
5. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
6. Patients having received prior therapy with 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).
7. Patients receiving anti-cancer therapies must be discontinued at least 2 weeks prior to administration of study drug. Palliative, focal radiation therapy, and immunosuppressive doses of systemic corticosteroids, except replacement organotherapy (hydrocortisone and fludrocortisone), must be discontinued at least 2 weeks before administration of study drug.
8. All toxicities attributed to prior anti-cancer therapy other than alopecia and fatigue must have resolved to grade 1 (NCI CTCAE version 4) or baseline before administration of study drug. Subjects with toxicities attributed to systemic prior anticancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enroll.
9. Patients with positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS).
10. Patients with positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection.
11. Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 4 weeks prior to study drug. The use of the inactivated seasonal influenza vaccine (Fluzone®) is allowed.
12. Known or underlying medical condition (e.g., a condition associated with diarrhea or acute diverticulitis) that, in the investigator’s opinion, would make the administration of study drug hazardous to the patient or obscure the interpretation of toxicity determination or adverse events.
13. History of uncontrolled seizures, central nervous system disorders or psychiatric disability judged by the investigator to be clinically significant, precluding informed consent, or interfering with compliance of oral drug intake (if applicable).
14. Unwillingness to give written informed consent, unwillingness to participate, or inability to comply with the protocol for the duration of the study.
15. Individuals deprived of liberty or placed under the authority of a tutor.
16. Treatment with any other investigational agent, or participation in another clinical trial within 28 days, prior to first study drug administration and during the treatment period. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint of this study is the incidence of high-grade (CTCAE v4.0 Grade 3-4 and Grade 5) adverse events of interest (AEI), that are adverse reactions known to be related to nivolumab (i.e. skin, endocrinopathy, gastrointestinal, hepatic, renal, pulmonary, and hypersensitivity adverse events) and other adverse events not related to carcinoma progression or to intercurrent disease clearly identified.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The period of observation of adverse events of interest is the period of Nivolumab treatment and 100days after the end of treatment. The grade used for analysis is the highest grade of the AE observed during this period. |
|
| E.5.2 | Secondary end point(s) |
- Time to onset of grade 3+ AEI,
- Time to resolution of grade 3-4 AEI to grade 1
- Rate of patients with at least one or more doses of nivolumab delayed (or cancelled) due to AE
- Rate of patients with nivolumab definitively withdrawn due to AE
- Rate of nivolumab-related deaths
- Rate of patients who received immune modulating concomitant medication (e.g., corticosteroids (> 10 mg prednisone or equivalent), infliximab, cyclophosphamide, IVIG, mycophenolate mofetil, etc), or hormonal replacement therapy
- Duration of all immune modulating medications given for the select event and summary of patients with resolution of AEs after initiating these therapies.
- Rate of AEI of maximum grade 1-2
- Overall survival (OS)
- Progression free survival (PFS)
- Objective response rate (ORR) (complete response and partial response according to RECIST 1.1 and to iRECIST) during nivolumab treatment
- Pseudo progression as defined to a progression according to RECIST 1.1 under treatment (≥ 20% increase in the sum of diameters of target lesions or unequivocal progression of existing non target lesions or new lesion) that is not confirmed at the next evaluation done 4 to 6 weeks later using iRECIST. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Study of biological and radiological biomarkers of response or progression |
|
| 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 | No |
| 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 | 30 |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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