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

May 21, 2023 updated by: Universitätsklinikum Hamburg-Eppendorf

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

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

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Anticipated)

276

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Germany
      • Hamburg, Germany, 20246
        • Universitätsklinikum Hamburg Eppendorf
      • Hamburg, Germany, 22087
        • Katholisches Marienkrankenhaus Hamburg
    • Baden-Württemberg
      • Ulm, Baden-Württemberg, Germany, 89075
        • Universitatsklinikum Ulm
    • Bayern
      • München, Bayern, Germany, 81675
        • Technische Universität München, Klinikum rechts der Isar
    • Hessen
      • Gießen, Hessen, Germany, 35392
        • Universitätsklinikum Gießen
    • Nordrhein-Westfalen
      • Bielefeld, Nordrhein-Westfalen, Germany, 330604
        • Klinikum Bielefeld
    • Thüringen
      • Erfurt, Thüringen, Germany, 99089
        • HELIOS Klinikum Erfurt GmbH

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: 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
Procedure: Surgical resection of primary tumor
Surgical resection of primary tumor including neck dissection according to standard of care
Radiation: Adjuvant radio(-chemo)therapy
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)
Drug: Neoadjuvant Nivolumab
Neoadjuvant dose with Nivolumab 3mg/kg after randomization within 2 weeks before surgery
Drug: Adjuvant Nivolumab
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
Drug: Adjuvant Nivolumab and Ipilimumab
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
Active Comparator: 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
Procedure: Surgical resection of primary tumor
Surgical resection of primary tumor including neck dissection according to standard of care
Radiation: Adjuvant radio(-chemo)therapy
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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
approximately 71 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Local regional control (LRC)
Time Frame: Time from randomization to date of first observed histologically proven or death, up to 36 month
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)
Time Frame: Time from randomization to date of first observed histologically proven or death, up to 36 month
Disease assessment (CT/ MRI)
Time from randomization to date of first observed histologically proven or death, up to 36 month
Overall survival (OS)
Time Frame: until end of study (36 months after end of therapy of the last patient), approximately 71 months
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
Time Frame: AEs/SAEs should be collected continuously until 12 months after randomization
Adverse Events Assessment
AEs/SAEs should be collected continuously until 12 months after randomization
Quality of life (QoL): QLQ-C30
Time Frame: through study completion, an average of 3 years
Questionaire EORTC QLQ-C30
through study completion, an average of 3 years
Quality of life (QoL): Questionnaire H&N43
Time Frame: through study completion, an average of 3 years
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
Time Frame: assessed up to 36 month
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
Time Frame: after surgery, up to 4 weeks after surgery
Assessment of PD-L1 Status
after surgery, up to 4 weeks after surgery

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Universitätsklinikum Hamburg-Eppendorf

Collaborators

Charite University, Berlin, Germany
University Hospital, Essen
Westpfalz-Clinical Center GmbH

Investigators

  • Principal Investigator: PD Dr. med. Chia-Jung Busch, Universitatsklinikum Hamburg-Eppendorf

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

August 21, 2018

Primary Completion (Anticipated)

May 1, 2024

Study Completion (Anticipated)

May 1, 2024

Study Registration Dates

First Submitted

August 3, 2018

First Submitted That Met QC Criteria

October 8, 2018

First Posted (Actual)

October 9, 2018

Study Record Updates

Last Update Posted (Actual)

May 23, 2023

Last Update Submitted That Met QC Criteria

May 21, 2023

Last Verified

May 1, 2023

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CA209-934

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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