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
Overview
- Phase
- Phase 3
- Intervention
- Surgical resection of primary tumor
- Conditions
- Head and Neck Cancer
- Sponsor
- Universitätsklinikum Hamburg-Eppendorf
- Enrollment
- 276
- Locations
- 7
- Primary Endpoint
- Disease Free Survival
- Status
- Active, not recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Neoadjuvant/adjuvant Nivolumab and Ipilimumab
* 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
Intervention: Surgical resection of primary tumor
Neoadjuvant/adjuvant Nivolumab and Ipilimumab
* 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
Intervention: Adjuvant radio(-chemo)therapy
Neoadjuvant/adjuvant Nivolumab and Ipilimumab
* 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
Intervention: Neoadjuvant Nivolumab
Neoadjuvant/adjuvant Nivolumab and Ipilimumab
* 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
Intervention: Adjuvant Nivolumab
Neoadjuvant/adjuvant Nivolumab and Ipilimumab
* 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
Intervention: Adjuvant Nivolumab and Ipilimumab
Surgical resection + adjuvant radio(-chemo)therapy
* 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
Intervention: Surgical resection of primary tumor
Surgical resection + adjuvant radio(-chemo)therapy
* 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
Intervention: Adjuvant radio(-chemo)therapy
Outcomes
Primary Outcomes
Disease Free Survival
Time Frame: approximately 71 months
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
Secondary Outcomes
- Quality of life (QoL): 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(assessed up to 36 month)
- Survival depending on PD-L1 Status(after surgery, up to 4 weeks after surgery)
- Local regional control (LRC)(Time from randomization to date of first observed histologically proven or death, up to 36 month)
- Distant metastasis free survival (DMFS)(Time from randomization to date of first observed histologically proven or death, up to 36 month)
- Overall survival (OS)(until end of study (36 months after end of therapy of the last patient), approximately 71 months)
- Acute toxicity and late morbidity(AEs/SAEs should be collected continuously until 12 months after randomization)
- Quality of life (QoL): QLQ-C30(through study completion, an average of 3 years)