Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy

Study Overview
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Brief Summary
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Multicenter randomized controlled phase III study of nivolumab alone or in combination with ipilimumab as immunotherapy vs standard follow-up in surgical resectable HNSCC after adjuvant therapy

Detailed Description
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Surgically treated locally advanced head and neck squamous cell carcinoma often requires postoperative chemoradiation with high risk of acute and late toxicity. DFS after 2 years is approximately 70%. Combining anti-PD-1 and anti-CTLA4 as a maintenance therapy may improve DFS due to anti-tumor effects of immunotherapy by enhancing cross-presentation of tumor antigens.

Official Title
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Multicenter Randomized Controlled Phase III Study of Nivolumab Alone or in Combination With Ipilimumab as Immunotherapy vs Standard Follow-up in Surgical Resectable HNSCC After Adjuvant Therapy

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Procedure: Surgical resection of primary tumor
* Radiation: Adjuvant radio(-chemo)therapy
* Drug: Neoadjuvant Nivolumab
* Drug: Adjuvant Nivolumab
* Drug: Adjuvant Nivolumab and Ipilimumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven SCC of the oropharynx, oral cavity, hypopharynx, and larynx (not older than 3 months before randomization) clinical stage III-IVB (T1, N2-3; T2, N2-3; T3, N0-3; T4a, N0-3) Oropharyngeal cancer HPV-negative (p16 immunohistochemistry negative) Primary tumor and neck metastasis must be resectable Written and signed informed consent Performance Status of 0 or 1 using ECOG Male and female with age ≥ 18 Curative treatment intent (cM0) Screening laboratory values must meet the following criteria and should be obtained within 4 weeks prior to randomization 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) Women of childbearing potential (WOCBP)1 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 investigational drug 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 nivolumab. Women must not be breastfeeding 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. Exclusion Criteria: Patients should be excluded if they have an active, known or suspected autoimmune disease. 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 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. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease. As there is potential for hepatic toxicity with nivolumab or nivolumab/ipilimumab combinations, drugs with a predisposition to hepatoxicity should be used with caution in patients treated with nivolumab-containing regimen. Patients should be excluded if they have had prior 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 costimulation or immune checkpoint pathways Prior invasive malignancy except controlled skin cancer or carcinoma in situ of cervix Unknown primary (CUP), nasopharyngeal or salivary gland cancer Distant metastatic disease or adenopathy below the clavicles Serious co-morbidity, e.g. high-grade carotid artery stenosis, congestive heart failure NYHA grade 3 and 4, liver cirrhosis CHILD C. If clinically suspected, further diagnostic is indicated according to the judgement of the investigator. Pregnancy or lactation Women of child-bearing potential with unclear contraception Previous treatment for the study cancer with chemotherapy, radiotherapy, EGFR-targeting agents or surgery exceeding biopsy in head and neck Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study screening Patients should be excluded if they are positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or chronic infection Patients should be excluded if they have known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) Allergies and Adverse Drug Reaction: History of severe hypersensitivity reaction to any monoclonal antibody History of allergy to study drug components Social situations that limit compliance with study requirements or patients with an unstable condition (e.g., psychiatric disorder, a recent history of drug or alcohol abuse, interfering with study compliance, within 6 months prior to screening) or otherwise thought to be unreliable or incapable of complying with the requirements of the protocol Patients institutionalized by official means or court order Deficient dental preservation status or not accomplished wound healing

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Arm Ia and Arm Ib are summarized in one Arm, due to central ethics committee, as they both include neoadjuvant and adjuvant treatment compared to Arm II
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neoadjuvant/adjuvant Nivolumab and Ipilimumab<br>Neoadjuvant dose with Nivolumab 3mg/kg after randomization within 2 weeks before surgery Surgical resection of primary tumor including neck dissection according to standard of care 6-7 weeks risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43, or Cisplatin once weekly (40mg/m2) for high risk patients only), start within 6 weeks post-surgery Arm Ia: • Adjuvant administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months Arm Ib: • Adjuvant administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks and Ipilimumab 1mg/kg i.v. d1 every 6 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months | Procedure: Surgical resection of primary tumor<br>* Surgical resection of primary tumor including neck dissection according to standard of care<br>Radiation: Adjuvant radio(-chemo)therapy<br>* Risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43, or Cisplatin once weekly (40mg/m2) for high risk patients only)<br>Drug: Neoadjuvant Nivolumab<br>* Neoadjuvant dose with Nivolumab 3mg/kg after randomization within 2 weeks before surgery<br>Drug: Adjuvant Nivolumab<br>* Administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months<br>Drug: Adjuvant Nivolumab and Ipilimumab<br>* Administration of Nivolumab 3mg/kg i.v. d1 every 2 weeks and Ipilimumab 1mg/kg i.v. d1 every 6 weeks within 6 weeks after end of radiotherapy until progression or up to 6 months<br>|
| Active Comparator: Surgical resection + adjuvant radio(-chemo)therapy<br>Surgical resection of primary tumor including neck dissection according to standard of care 6-7 weeks risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43 or Cisplatin once weekly (40mg/m2) in high risk patients), start within 6 weeks post-surgery Standard follow-up | Procedure: Surgical resection of primary tumor<br>* Surgical resection of primary tumor including neck dissection according to standard of care<br>Radiation: Adjuvant radio(-chemo)therapy<br>* Risk-adapted adjuvant radio(-chemo)therapy 56-66 Gy (chemotherapy Cisplatin 100 mg/m2 on days 1, 22, 43, or Cisplatin once weekly (40mg/m2) for high risk patients only)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | disease free survival (DFS) at 3 years of nivolumab alone or in combination with ipilimumab as adjuvant immunotherapy after adjuvant radio(chemo)therapy in locally advanced resected HNSCC | approximately 71 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Local regional control (LRC) | Disease assessment (CT/ MRI) and Panendoscopy and FFPE in case of suspicion or recurrence | Time from randomization to date of first observed histologically proven or death, up to 36 month | 
| Distant metastasis free survival (DMFS) | Disease assessment (CT/ MRI) | Time from randomization to date of first observed histologically proven or death, up to 36 month | 
| Overall survival (OS) | Follow Up- Visits after end of treatment every 3 months until month 36 after randomization, afterwards every 6 months | until end of study (36 months after end of therapy of the last patient), approximately 71 months | 
| Acute toxicity and late morbidity | Adverse Events Assessment | AEs/SAEs should be collected continuously until 12 months after randomization | 
| Quality of life (QoL): QLQ-C30 | Questionaire EORTC QLQ-C30 | through study completion, an average of 3 years | 
| Quality of life (QoL): Questionnaire H&N43 | Questionnaire H&N43 | through study completion, an average of 3 years | 
| Comparison of nivolumab alone group vs control and nivolumab & ipilimumab group vs control in terms of DFS | We compare disease free survival, defined as time from randomization to date of first observed either histologically proven recurrence (local, locoregional or distant), or death from any cause whatever occurs first, of arm Ia to arm II and of arm Ib to arm II | assessed up to 36 month | 
| Survival depending on PD-L1 Status | Assessment of PD-L1 Status | after surgery, up to 4 weeks after surgery |