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Tolerance and Efficacy of Pembrolizumab or Cetuximab Combined With RT in Patients With Locally Advanced HNSCC (PembroRad)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02707588
Recruitment Status : Active, not recruiting
First Posted : March 14, 2016
Last Update Posted : April 9, 2021
Sponsor:
Information provided by (Responsible Party):
Groupe Oncologie Radiotherapie Tete et Cou

Tracking Information
First Submitted Date  ICMJE February 29, 2016
First Posted Date  ICMJE March 14, 2016
Last Update Posted Date April 9, 2021
Actual Study Start Date  ICMJE May 18, 2016
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
Locoregional Control [ Time Frame: 15 months from the end of radiation therapy ]
To compare between the 2 arms the rate of patients achieving Locoregional Control (LRC) at 15 months from the end of radiation therapy
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 26, 2017)
  • Progression free survival [ Time Frame: At 24 months after treatment initiation ]
    Minimum time from randomization to progression/relapse at any site (local, regional or distant) as defined by RECIST 1.1 criteria or to death from any cause. Patients who don't have any of these events are censored at the date of last follow-up.
  • Locoregional progression and distant metastasis [ Time Frame: At 24 months after treatment initiation ]
    To estimate the respective contribution of locoregional progression, distant progression and death as first event in the progression-free survival, the cumulative incidences of these three types of events were calculated within a competing risk framework.
  • Overall survival [ Time Frame: At 24 months after treatment initiation ]
    Time to death from any cause measured from randomization.
  • Acute adverse events [ Time Frame: At 24 months after treatment initiation ]
    According to NCI-CTCAE version 4, the maximal grade of each toxicity observed during immune-radiotherapy will be used. All grades of toxicity will be tabulated by type of toxicity and by treatment arm.
  • Delayed toxicity According to RTOG late toxicity scale [ Time Frame: At 24 months after treatment initiation ]
    According to RTOG late toxicity scale
  • Duration of the feeding tube dependence [ Time Frame: At 24 months after treatment initiation ]
    It will be presented by treatment arm and analysed by Student t-test.
  • Compliance to Pembrolizumab and Cetuximab [ Time Frame: At 24 months after treatment initiation ]
    Insufficient compliance to cetuximab or Pembrolizumab is defined as a patient receiving less than 75% of the planned dose, even if the dose reduction is due to toxicity
  • Health related quality of life (QL) [ Time Frame: At 24 months after treatment initiation ]
    Assessment by EORTC QLQ-C30 and H&N35 questionnaires
  • Impact of p16 / HPV tumor status on the efficacy of the 2 regimens in patients with oropharyngeal initial tumor [ Time Frame: At 24 months after treatment initiation ]
    Assessment by CISH DNA method
Original Secondary Outcome Measures  ICMJE
 (submitted: March 8, 2016)
  • Progression free survival [ Time Frame: At 24 months after treatment initiation ]
    Minimum time from randomization to progression/relapse at any site (local, regional or distant) as defined by RECIST 1.1 criteria or to death from any cause. Patients who don't have any of these events are censored at the date of last follow-up.
  • Locoregional progression and distant metastasis [ Time Frame: At 24 months after treatment initiation ]
    To estimate the respective contribution of locoregional progression, distant progression and death as first event in the progression-free survival, the cumulative incidences of these three types of events were calculated within a competing risk framework.
  • Overall survival [ Time Frame: At 24 months after treatment initiation ]
    Time to death from any cause measured from randomization.
  • Acute adverse events [ Time Frame: At 24 months after treatment initiation ]
    According to NCI-CTCAE version 4, the maximal grade of each toxicity observed during immune-radiotherapy will be used. All grades of toxicity will be tabulated by type of toxicity and by treatment arm.
  • Delayed toxicity According to RTOG late toxicity scale [ Time Frame: At 24 months after treatment initiation ]
    According to RTOG late toxicity scale
  • Duration of the feeding tube dependence [ Time Frame: At 24 months after treatment initiation ]
    It will be presented by treatment arm and analysed by Student t-test.
  • Compliance to Pembrolizumab and Cetuximab [ Time Frame: At 24 months after treatment initiation ]
    Insufficient compliance to cetuximab or Pembrolizumab is defined as a patient receiving less than 75% of the planned dose, even if the dose reduction is due to toxicity
  • Health related quality of life (QL) [ Time Frame: At 24 months after treatment initiation ]
  • Exploratory analyses: [ Time Frame: At 24 months after treatment initiation ]
    To explore potential correlations between treatment outcome and the immune landscape
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Tolerance and Efficacy of Pembrolizumab or Cetuximab Combined With RT in Patients With Locally Advanced HNSCC
Official Title  ICMJE A Phase II Randomized Study to Determine the Tolerance and Efficacy of Pembrolizumab or Cetuximab Combined With Radiation Therapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck
Brief Summary The general aim of the study is to evaluate the anti-tumour activity and the tolerance profile of Pembrolizumab + RT in comparison to cetuximab + RT in patients with locally advanced HNSCC and to explore potential correlations between treatment outcome and the immune landscape.
Detailed Description

A majority of HNSCC are locally advanced and commonly treated with concomitant chemo-radiotherapy (CT-RT). However, a large proportion of patients with locally advanced stage are not suitable for receiving cisplatinum-based chemotherapy (CT) concomitant with radiotherapy (RT) either due to age, general and/or medical condition(s).

An alternative standard treatment has been established, combining RT and cetuximab.

However, both CT-RT and cetuximab-RT which are considered as standard approaches in locally advanced non operated HNSCC are associated with poor outcome in patients with the most advanced T stage (T4) and/or N stage (>=N2) and/or HPV negative tumours. A new and promising approach could target immune response.

Pembrolizumab is a high-affinity monoclonal anti-PD1 antibody which showed antitumor activity in melanoma and NSCLC. In the KEYNOTE-012 (multi-center, nonrandomized Phase Ib HNSCC), Pembrolizumab was well tolerated and safe with no serious drug related AEs reported. About 51% (26/51) of patients had decreased tumor burden which was seen both in HPV (-) and HPV(+) HNSCC.

This observation led to the hypothesis generated in the current study that Pembrolizumab is potentially a very active drug in HNSCC and that the combination of Pembrolizumab with radiotherapy will be well tolerated, given the very good toxicity profile of the drug and will improve the outcome of patients with locally advanced HNSCC non suitable for CT-RT, as compared to the treatment of reference combining cetuximab and RT.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Squamous Cell Carcinoma of the Head and Neck
Intervention  ICMJE
  • Drug: Pembrolizumab

    200mg IV infusion every 3 weeks, i.e. on day 1, 22, 43 during the course of radiotherapy.

    Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).

    Other Name: antibody
  • Drug: Cetuximab

    Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of radiotherapy.

    Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).

    Other Name: antibody
  • Radiation: Radiotherapy
    Radiotherapy will be delivered daily for 5 days per week to a total dose of 69.96 Gy in 2.12 Gy daily fractions over 6.5 weeks (33 fractions).
    Other Name: Conventional Radiotherapy
Study Arms  ICMJE
  • Experimental: Pembrolizumab and radiotherapy
    200 mg IV infusion every 3 weeks, i.e. on day 1, 22, 43 during the course of radiotherapy
    Interventions:
    • Drug: Pembrolizumab
    • Radiation: Radiotherapy
  • Active Comparator: Cetuximab and radiotherapy
    Loading dose of 400 mg/m² IV on Day-8, followed by weekly dose of 250 mg/m² IV during the whole course of radiotherapy.
    Interventions:
    • Drug: Cetuximab
    • Radiation: Radiotherapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: October 26, 2017)
133
Original Estimated Enrollment  ICMJE
 (submitted: March 8, 2016)
114
Estimated Study Completion Date  ICMJE December 2021
Estimated Primary Completion Date August 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Written informed consent
  2. Age ≥18 ≤ 80 years.
  3. Performance Status ECOG 0-1
  4. Histologically confirmed diagnosis of previously untreated locally advanced HNSCC (Stage III, IVa and IVb according to the American Joint Committee on Cancer Staging System) of one or more of the following sites: oral cavity, oropharynx, hypopharynx and larynx
  5. Availability of pre-treatment tumour tissue (for biomarker analysis, PD -L1, TILs and immune-monitoring)
  6. p16 expression from tumor sample (immunohistochemistry)
  7. Recording of the smoking history
  8. No viral infection (HIV, Hepatitis B/C)
  9. No autoimmune disease
  10. No immunodeficiency or immunosuppressive therapy
  11. No active CNS disease
  12. No interstitial lung disease
  13. No active infection
  14. Women of child-bearing potential: negative serum pregnancy test at screening and use of appropriate contraception methods from study entry
  15. Patients not proposed cisplatin-based chemotherapy because of age, general condition, if medically unfit or patient refusal.
  16. Adequate organ laboratory values
  17. Health insurance coverage

Exclusion Criteria:

  1. Nasopharyngeal, paranasal sinuses, nasal cavity tumours or thyroid cancers;
  2. Squamous cell cancer involving cervical neck nodes with unknown primary site;
  3. Metastatic disease;
  4. Any prior or current treatment for invasive head and neck cancer. This will include but is not limited to: prior tyrosine kinase inhibitors, any monoclonal antibody, prior neoadjuvant therapy, prior surgical resection, or use of any investigational agent;
  5. Weight loss of >10% during the last 3 weeks prior the screening visit;
  6. Concurrent treatment with any other systemic anti-cancer therapy that is not specified in the protocol;
  7. Concomitant treatment with any drug on the prohibited medication list such as live vaccines (for details, see the protocol);
  8. History of another malignancy within the last 3 years (exception of in situ carcinoma and skin carcinomas);
  9. If female, pregnant or lactating;
  10. Significant disease which, in the judgment of the investigator, as a result of the medical interview, physical examinations, or screening investigations would make the patient inappropriate for entry into the trial.
  11. Known hypersensitivity reaction to study medication;
  12. Any social, personal, medical and/or psychologic factor(s) that could interfere with the observance of the patient to the protocol and/or the follow-up and/or the signature of the informed consent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02707588
Other Study ID Numbers  ICMJE GORTEC 2015-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Responsible Party Groupe Oncologie Radiotherapie Tete et Cou
Study Sponsor  ICMJE Groupe Oncologie Radiotherapie Tete et Cou
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jean Pr BOURHIS, MD CHU Vaudois, Rue du Bugnon 46, CH-1011 Lausanne, Suisse
PRS Account Groupe Oncologie Radiotherapie Tete et Cou
Verification Date April 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP