Importance

Randomized phase II study of immune stimulation with Pembrolizumab and radiotherapy in second line therapy of metastatic head and neck squamous cell carcinoma (IMPORTANCE)

Study design: open-label, randomized, prospective, multicenter phase II clinical trial of pembrolizumab with or without local radiotherapy

Patientpopulation: recurrent and/ or metastatic HNSCC after progression to platinum-based therapy or as first line treatment if CPS≥1.

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 tumor lesions with a total tumor volume of at least 5ml 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. After application of the third radiation dose the patients will receive pembrolizumab. After an interruption of radiotherapy for two days, 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 revised NCI Common Terminology Criteria for Adverse Events Version 4.0.

Primary Objective & Hypothesis
Assessment of the effect of local radiotherapy on systemic response to pembrolizumab
Hypothesis: Local radiotherapy will significantly improve the overall response rate according to iRECIST

Secondary Objectives & Hypotheses 
(1) Objective: Assessment of the effect of local radiotherapy on different response criteria to pembrolizumab
Hypothesis: Local radiotherapy will tend to improve: 
- Response rate according to RECIST 
- changes of (not irradiated) target lesion -
- duration of response
- progression free survival
- overall survival

(2) Objective: Assessment of safety and tolerability of the combination of pembrolizumab and radiotherapy
Hypothesis: Local radiotherapy will not increase toxicity grade 3 or higher according to CTCAE 4.0

Exploratory Objective
(1) Objective: Assessment of changes of the immunophenotype in peripheral blood after pembrolizumab without and with radiotherapy (longitudinal analysis)
(2) Objective: Assessment of predictive value of PD-L1 in combination with tumor-infiltrating lymphocytes

Inclusion criteria:

  •  Be willing and able to provide written informed consent/ assent for the trial.
  •  Be ≥ 18 years of age on day of signing informed consent.
  •  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) AND/ 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). At least in one of these lesions must be a need for radiotherapy in near future (as defined in inclusion criterion 4).
  •  Need for radiotherapy in near future as defined in the following. At least one metastasis has to fulfil one of the following criteria:
    - Primary tumor causing mild pain or swallowing problems
    - Lymph node or soft tissue metastasis with distance less than 1 cm to the skin (radiotherapy to prevent weeping tumor infiltration of the skin or fistula)
    - Bone metastases causing mild pain (without risk of fracture)
    - Lung metastases, liver metastases or adrenal gland metastases with a diameter above 2 cm in an oligometastatic situation (defined as a maximum of 5 tumor lesions)
  •  Progression after first line platinum-based or any second/ third line chemotherapy OR Progression within 6 months after platinum-based radiochemotherapy of locally advanced disease  
  •  Histological confirmation of HNSCC  
  •  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)
  • Have a performance status of 0-1 on the ECOG Performance Scale.  
  • Demonstrate adequate organ function as defined in protokol, all screening labs should be performed within 10 days of treatment initiation.
  • 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. A highly sensitive pregnancy test must be used. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Female subjects of childbearing potential must be willing to use a highly effective contraceptive measure as defined in the Clinical Trial Facilitation Group (CTFG) guideline (“Recommendations related to contraception and pregnancy testing in clinical trials.”)
  • Male subjects of childbearing potential must agree to use a highly effective method of contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Exclusion criteria:

  • 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.
  • Has need for palliative radiotherapy for symptomatic metastases. This includes the following situations: 
    - New or progressive central nervous system metastases 
    - Metastases causing significant pain 
    - Instable bone metastases 
    - Lung metastases or mediastinal lymph node metastases with active bleeding
  • Other metastases that require prompt radiotherapy in the opinion of the investigatorHas only a tumor lesion perspectively requiring re-irradiation after prior radiotherapy less than three months ago.
  • 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.
  • Has a known history of active TB (Bacillus Tuberculosis).
  • Hypersensitivity to pembrolizumab or any of its excipients.
  • 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 AEs due to agents administered more than 4 weeks earlier.
  • 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 AEs due to a previously administered agent. 
  • Has known history or concurrent other malignancy. Exceptions include patients, who have been disease free for at least five years. Further exceptions are completely resected basal cell carcinoma or squamous cell carcinoma of the skin or successfully treated in situ carcinoma.
  • 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.
  • 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 (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • History of (non-infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non-infectious pneumonitis.
  • Has an active infection requiring systemic therapy.
  • 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.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • 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.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent (One single administration of an anti-PD1, anti-PD-L1 or anti-PD-L2 agent as induction treatment in locally advanced disease is no exclusion criteria).
  • Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies).
  • Has known active hepatitis B (e.g., HBsAg reactive) or hepatitis C (e.g., HCV RNA [qualitative] is detected).
  • Has received a live vaccine within 30 days of planned start of study therapy.
  • Have a performance status of