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

NCT03700905 | Unknown Phase 3 DMC

• 1 other identifier: CA209-934
• Study Type: interventional
• Target: 276
• Locations: 1 country
• Sites: 7

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

Conditions

Head and Neck Cancer

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• 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

Study Arms (2)

Neoadjuvant/adjuvant Nivolumab and Ipilimumab

EXPERIMENTAL

* 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; Radiation: Adjuvant radio(-chemo)therapy; Drug: Neoadjuvant Nivolumab; Drug: Adjuvant Nivolumab; Drug: Adjuvant Nivolumab and Ipilimumab

Surgical resection + adjuvant radio(-chemo)therapy

ACTIVE COMPARATOR

* 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; Radiation: Adjuvant radio(-chemo)therapy

Interventions

Surgical resection of primary tumor PROCEDURE

Surgical resection of primary tumor including neck dissection according to standard of care

Neoadjuvant/adjuvant Nivolumab and Ipilimumab; Surgical resection + adjuvant radio(-chemo)therapy

Adjuvant radio(-chemo)therapy RADIATION

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)

Neoadjuvant/adjuvant Nivolumab and Ipilimumab; Surgical resection + adjuvant radio(-chemo)therapy

Neoadjuvant Nivolumab DRUG

Neoadjuvant dose with Nivolumab 3mg/kg after randomization within 2 weeks before surgery

Neoadjuvant/adjuvant Nivolumab and Ipilimumab

Adjuvant Nivolumab DRUG

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

Neoadjuvant/adjuvant Nivolumab and Ipilimumab

Adjuvant Nivolumab and Ipilimumab DRUG

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

Neoadjuvant/adjuvant Nivolumab and Ipilimumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Universitätsklinikum Hamburg-Eppendorf: lead
• University Hospital, Essen: collaborator
• Westpfalz-Clinical Center GmbH: collaborator
• Charite University, Berlin, Germany: collaborator

Study Sites (7)

Universitätsklinikum Ulm

Ulm, Baden-Wurttemberg, 89075, Germany

Location

Technische Universität München, Klinikum rechts der Isar

München, Bavaria, 81675, Germany

Location

Universitätsklinikum Gießen

Giessen, Hesse, 35392, Germany

Location

Klinikum Bielefeld

Bielefeld, North Rhine-Westphalia, 330604, Germany

Location

HELIOS Klinikum Erfurt GmbH

Erfurt, Thuringia, 99089, Germany

Location

Universitätsklinikum Hamburg Eppendorf

Hamburg, 20246, Germany

Location

Katholisches Marienkrankenhaus Hamburg

Hamburg, 22087, Germany

Location

Related Publications (9)

• Gold KA, Lee HY, Kim ES. Targeted therapies in squamous cell carcinoma of the head and neck. Cancer. 2009 Mar 1;115(5):922-35. doi: 10.1002/cncr.24123.

  PMID: 19156911 RESULT

• Cho YA, Yoon HJ, Lee JI, Hong SP, Hong SD. Relationship between the expressions of PD-L1 and tumor-infiltrating lymphocytes in oral squamous cell carcinoma. Oral Oncol. 2011 Dec;47(12):1148-53. doi: 10.1016/j.oraloncology.2011.08.007. Epub 2011 Sep 10.

  PMID: 21911310 RESULT

• Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.

  PMID: 26028407 RESULT

• Robert C, Long GV, Brady B, Dutriaux C, Maio M, Mortier L, Hassel JC, Rutkowski P, McNeil C, Kalinka-Warzocha E, Savage KJ, Hernberg MM, Lebbe C, Charles J, Mihalcioiu C, Chiarion-Sileni V, Mauch C, Cognetti F, Arance A, Schmidt H, Schadendorf D, Gogas H, Lundgren-Eriksson L, Horak C, Sharkey B, Waxman IM, Atkinson V, Ascierto PA. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30. doi: 10.1056/NEJMoa1412082. Epub 2014 Nov 16.

  PMID: 25399552 RESULT

• Robert C, Schachter J, Long GV, Arance A, Grob JJ, Mortier L, Daud A, Carlino MS, McNeil C, Lotem M, Larkin J, Lorigan P, Neyns B, Blank CU, Hamid O, Mateus C, Shapira-Frommer R, Kosh M, Zhou H, Ibrahim N, Ebbinghaus S, Ribas A; KEYNOTE-006 investigators. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. 2015 Jun 25;372(26):2521-32. doi: 10.1056/NEJMoa1503093. Epub 2015 Apr 19.

  PMID: 25891173 RESULT

• Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, Heath K, McClanahan T, Lunceford J, Gause C, Cheng JD, Chow LQ. Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial. Lancet Oncol. 2016 Jul;17(7):956-965. doi: 10.1016/S1470-2045(16)30066-3. Epub 2016 May 27.

  PMID: 27247226 RESULT

• Ferris RL, Blumenschein G Jr, Fayette J, Guigay J, Colevas AD, Licitra L, Harrington K, Kasper S, Vokes EE, Even C, Worden F, Saba NF, Iglesias Docampo LC, Haddad R, Rordorf T, Kiyota N, Tahara M, Monga M, Lynch M, Geese WJ, Kopit J, Shaw JW, Gillison ML. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med. 2016 Nov 10;375(19):1856-1867. doi: 10.1056/NEJMoa1602252. Epub 2016 Oct 8.

  PMID: 27718784 RESULT

• Hanna GJ, Adkins DR, Zolkind P, Uppaluri R. Rationale for neoadjuvant immunotherapy in head and neck squamous cell carcinoma. Oral Oncol. 2017 Oct;73:65-69. doi: 10.1016/j.oraloncology.2017.08.008. Epub 2017 Aug 17.

  PMID: 28939078 RESULT

• Zech HB, Moeckelmann N, Boettcher A, Muenscher A, Binder M, Vettorazzi E, Bokemeyer C, Schafhausen P, Betz CS, Busch CJ. Phase III study of nivolumab alone or combined with ipilimumab as immunotherapy versus standard of care in resectable head and neck squamous cell carcinoma. Future Oncol. 2020 Dec;16(36):3035-3043. doi: 10.2217/fon-2020-0595. Epub 2020 Sep 9.

  PMID: 32902312 DERIVED

MeSH Terms

Conditions

Head and Neck Neoplasms

Interventions

Ipilimumab

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• PD Dr. med. Chia-Jung Busch

  Universitätsklinikum Hamburg-Eppendorf

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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

Study Record Dates

• First Submitted: August 3, 2018
• First Posted: October 9, 2018
• Study Start: August 21, 2018
• Primary Completion: May 1, 2024
• Study Completion: May 1, 2024
• Last Updated: May 23, 2023

Record last verified: 2023-05

Data Sharing

• IPD Sharing: Will not share

Locations

DE (7)