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

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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

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.

Condition or disease Intervention/treatment Phase
Squamous Cell Carcinoma of the Head and Neck Drug: Pembrolizumab Drug: Cetuximab Radiation: Radiotherapy Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 133 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : May 18, 2016
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : December 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Pembrolizumab and radiotherapy
200 mg IV infusion every 3 weeks, i.e. on day 1, 22, 43 during the course of radiotherapy
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

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

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.
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




Primary Outcome Measures :
  1. 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


Secondary Outcome Measures :
  1. 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.

  2. 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.

  3. Overall survival [ Time Frame: At 24 months after treatment initiation ]
    Time to death from any cause measured from randomization.

  4. 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.

  5. Delayed toxicity According to RTOG late toxicity scale [ Time Frame: At 24 months after treatment initiation ]
    According to RTOG late toxicity scale

  6. 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.

  7. 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

  8. Health related quality of life (QL) [ Time Frame: At 24 months after treatment initiation ]
    Assessment by EORTC QLQ-C30 and H&N35 questionnaires

  9. 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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02707588


Locations
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France
Centre Guillaume le conquérant
Le Havre, France, 76000
Sponsors and Collaborators
Groupe Oncologie Radiotherapie Tete et Cou
Investigators
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Principal Investigator: Jean Pr BOURHIS, MD CHU Vaudois, Rue du Bugnon 46, CH-1011 Lausanne, Suisse
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Responsible Party: Groupe Oncologie Radiotherapie Tete et Cou
ClinicalTrials.gov Identifier: NCT02707588    
Other Study ID Numbers: GORTEC 2015-01
First Posted: March 14, 2016    Key Record Dates
Last Update Posted: April 9, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Keywords provided by Groupe Oncologie Radiotherapie Tete et Cou:
Determine the tolerance and efficacy of Pembrolizumab
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Pembrolizumab
Cetuximab
Antibodies
Immunoglobulins
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents