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Radiotherapy With Pembrolizumab in Metastatic HNSCC

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ClinicalTrials.gov Identifier: NCT03386357
Recruitment Status : Recruiting
First Posted : December 29, 2017
Last Update Posted : August 2, 2018
Sponsor:
Information provided by (Responsible Party):
University of Erlangen-Nürnberg Medical School

Brief Summary:
Randomized phase II study of immune stimulation with Pembrolizumab and radiotherapy in second line therapy of metastatic head and neck squamous cell carcinoma.

Condition or disease Intervention/treatment Phase
Head and Neck Squamous Cell Carcinoma Combination Product: A (pembrolizumab+RT) Drug: B (pembrolizumab) Phase 2

Detailed Description:

This is an open-label, randomized, prospective, multicenter phase II clinical trial of pembrolizumab with or without local radiotherapy in patients with recurrent and/or metastatic HNSCC after progression to platinum-based therapy.

All patients will receive pembrolizumab 200mg absolute dose administered every third week. Patients in treatment arm A will receive radiotherapy of one, two or three metastases with a total tumor volume of at least 10cm³ intended to induce tumor cell death acting as an in situ vaccination. Radiotherapy will be performed conventionally fractioned with single doses of 3Gy to a total dose of 36Gy. There will be a strict time schedule. Radiotherapy will always start on Wednesday. After application of the third radiation dose (Friday) the patients will receive pembrolizumab. After an interruption of radiotherapy for two days (Saturday, Sunday), radiotherapy will be continued. Pembrolizumab will be continued on an every three week schedule until confirmed disease progression according to iRECIST criteria, unacceptable toxicity, patient's wish to stop therapy or a maximal treatment time of 12 months.

Tumor assessment will be performed every 9 weeks and will be evaluated according to iRECIST and RECIST. For each patient the same assessment method will be used throughout the study. Toxicity will be assessed according to CTCAE 4.0.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Open-label, Controlled, randomized trial
Masking: None (Open Label)
Masking Description: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Study of Immune Stimulation With Pembrolizumab and Radiotherapy in Second Line Therapy of Metastatic Head and Neck Squamous Cell Carcinoma (IMPORTANCE, Keynote-717, EudraCT NUMBER: 2017-002122-20 )
Actual Study Start Date : July 20, 2018
Estimated Primary Completion Date : December 31, 2021
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: A (pembrolizumab+RT)
Pembrolizumab (200mg absolute, q3w) combined with radiotherapy (12x3Gy) of one, two or three metastases.
Combination Product: A (pembrolizumab+RT)
Pembrolizumab (200mg absolute, q3w) combined with radiotherapy (12x3Gy) of one, two or three metastases. Only metastases that perspectively require radiotherapy will be treated. The irradiated tumor volume must be at least 10cm³. Radiotherapy of brain metastases is not allowed.
Other Name: Keytruda + RT

Active Comparator: B (pembrolizumab)
Pembrolizumab (200mg absolute, q3w) without radiotherapy
Drug: B (pembrolizumab)
Pembrolizumab (200mg absolute, q3w)
Other Name: Keytruda




Primary Outcome Measures :
  1. Best response according to iRECIST criteria [ Time Frame: Endpoint is the best response during pembrolizumab treatment (restaging every 9 weeks up to 12 months) ]
    Local radiotherapy will significantly improve the overall response rate according to iRECIST


Secondary Outcome Measures :
  1. Response rate according to RECIST [ Time Frame: restaging every 9 weeks up to 12 months ]
    RECIST 1.1 criteria

  2. Assessment of target lesion [ Time Frame: restaging every 9 weeks up to 12 months ]
    changes of the size of a (not irradiated) target lesion will be measured (%)

  3. Assessment of the duration of response [ Time Frame: restaging every 9 weeks up to 12 months ]
    The duration of the response will be evaluated in responding patients.

  4. Assessment of the progression free survival [ Time Frame: restaging every 9 weeks up to 12 months ]
    progression free survival (in months)

  5. Assessment of the overall survival [ Time Frame: restaging every 9 weeks up to 12 months ]
    Overall survival (in months)

  6. Assessment of toxicity of the combination of pembrolizumab and radiotherapy [ Time Frame: at every pembrolizumab administration (q3w) (up tp 12 months) ]
    Toxicity will be evaluated according to CTCAE 4.0


Other Outcome Measures:
  1. Assessment of changes of the immunophenotype in peripheral blood after pembrolizumab without and with radiotherapy (longitudinal analysis) [ Time Frame: week 1, at pembrolizumab administration 2, 4, 8, 12 and through study completion an average of 1 year ]
    Assessment of predictive value of PD-L1 in combination with tumor-infiltrating lymphocytes



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 100 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

In order to be eligible for participation in this trial, the subject must:

  1. Be willing and able to provide written informed consent/assent for the trial.
  2. Be >18 years of age on day of signing informed consent.
  3. Metastatic HNSCC (at least two distinct lesions: Lesion planned for radiotherapy with ≥10 ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥10 ml tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume ≥10ml) OR Locally recurrent HNSCC not suitable for curative local treatment within or outside the previously irradiated tissue (at least two distinct lesions: Lesion planned for radiotherapy with ≥10 ml tumor volume, or ≥3 lesions: 1 lesion planned for radiotherapy with ≥10 ml tumor volume or 2 lesions planned for radiotherapy with a cumulative tumor volume ≥10ml).
  4. Progression to first line platinum-based or any second/third line chemotherapy OR Progression within 6 months after platinum-based radiochemotherapy of locally advanced disease
  5. Histological confirmation of HNSCC
  6. Have at least one measurable lesion according to iRECIST that receives less than 10% of the prescribed dose of the irradiated lesion(s) (not considering doses from previous radiotherapy)
  7. Have a performance status of 0-1 on the ECOG Performance Scale.
  8. Demonstrate adequate organ function
  9. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  10. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication.

    Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

  11. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

Exclusion Criteria:

The subject must be excluded from participating in the trial if the subject:

  1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
  2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
  3. Has a known history of active TB (Bacillus Tuberculosis)
  4. Hypersensitivity to pembrolizumab or any of its excipients.
  5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier.
  6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse events due to a previously administered agent.

    • Note: Subjects with ≤ grade 2 neuropathy are an exception to this criterion and may qualify for the study.
    • Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
  7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  8. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  10. History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis
  11. Has an active infection requiring systemic therapy.
  12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  13. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  14. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
  15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
  16. Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  17. Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).
  18. Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.
  19. Have a performance status of ≥2 on the ECOG Performance Scale.

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): NCT03386357


Contacts
Contact: Dorota Lubgan, Ph.D. ++49(0)9131-85-33968 Dorota.Lubgan@uk-erlangen.de
Contact: Markus Hecht, M.D. ++49(0)9131-85-33968 markus.hecht@uk-erlangen.de

Locations
Germany
Bochum, St. Josef-Hospital, Abteilung für Hämatologie und Onkologie Not yet recruiting
Bochum, Germany, 44791
Contact: Anke Reinacher-Schick, Prof.    +49234-509-3591    anke.reinacher@rub.de   
Chemnitz, Klinikum gGmbH Not yet recruiting
Chemnitz, Germany, 09116
Contact: Gunther Klautke, M.D.    +4937133342538    g.klautke@skc.de   
Dresden, Onkologische Gemeinschaftspraxis Not yet recruiting
Dresden, Germany, 01307
Contact: Thomas Illmer, M.D.    +49351/4472340    illmer@onkologie-dresden.net   
Düsseldorf, Universitätsklinikum, Klinik für Strahlentherrapie und Radiologische Onkologie Not yet recruiting
Düsseldorf, Germany, 40225
Contact: Bálint Tamaskovics, M.D.    +49221/81 16894    balint.tamaskovics@med.uni-duesseldorf.de   
Erlangen, Universitätsklinikum Strahlenklinik Recruiting
Erlangen, Germany, 91054
Contact: Rainer Fietkau, Prof.    +499131-85-33405    rainer.fietkau@uk-erlangen.de   
Frankfurt, Universitätsklinikum, Klinik für Strahlentherapie und Onkologie Not yet recruiting
Frankfurt, Germany, 60590
Contact: Panagiotis Balermpas, M.D.    +4969/6301-5130    panagiotis.balermpas@kgu.de   
Homburg, Universitätsklinikum, Klinik für Strahlentherapie und Radioonkologie Not yet recruiting
Homburg, Germany, 66421
Contact: Patrick Melchior, M.D.    +496841/162-4820    patrick.melchior@uks.eu   
Magdeburg, Universitätsklinikum Not yet recruiting
Magdeburg, Germany, 392120
Contact: Thomas Brunner, Prof.    +493916715791    thomas.brunner@med.ovgu.de   
Paderborn, Brüderkrankenhaus, Klinik für Hämatologie und Onkologie Not yet recruiting
Paderborn, Germany, 33098
Contact: Harald Müller-Huesmann    +495251-702 3570    h.mueller-huesmann@bk-paderborn.de   
Regensburg, Universitätsklinikum, Klinik für Strahlentherapie Not yet recruiting
Regensburg, Germany, 93042
Contact: Matthias Hautmann, M.D.    +49941/9447610    matthias.hautmann@ukr.de   
Sponsors and Collaborators
University of Erlangen-Nürnberg Medical School
Investigators
Principal Investigator: Rainer Fietkau, Prof. Universitätsklinikum Erlangen, Strahlenklinik
Study Chair: Wilfried Budach, Prof. Universitätsklinikum Düsseldorf
Study Chair: Markus Hecht, M.D. Universitätsklinikum Erlangen
Study Chair: Hausmann Jan, M.D. Universitätsklinikum Düsseldorf
Study Chair: Udo Gaipl, Prof. Universitätsklinikum Erlangen

Responsible Party: University of Erlangen-Nürnberg Medical School
ClinicalTrials.gov Identifier: NCT03386357     History of Changes
Other Study ID Numbers: IMPORTANCE, Keynote-717
First Posted: December 29, 2017    Key Record Dates
Last Update Posted: August 2, 2018
Last Verified: August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Carcinoma, Squamous Cell
Head and Neck Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Neoplasms by Site
Pembrolizumab
Antineoplastic Agents