Study Comparing Pembrolizumab With Methotrexate in Elderly, Frail or Cisplatin-ineligible Patients With Head and Neck Cancers

Study Overview
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Brief Summary
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The study is designed as an open-label, randomized, prospective, multicenter, phase II study comparing pembrolizumab with methotrexate in elderly, frail or cisplatin-ineligible patients with squamous carcinoma of the head and neck (HNSCC)

Official Title
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A Randomized Phase II Study Comparing Pembrolizumab With Methotrexate in Elderly, Frail or Cisplatin-ineligible Patients With Head and Neck Cancers

Conditions
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Cancer of Head and Neck

Intervention / Treatment
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* Drug: Pembrolizumab Injection
* Drug: Methotrexate Injectable Solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cooperation and willingness to complete all aspects of the study Signed written informed consent must be given prior to study inclusion Histological or cytological confirmed recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC) not amenable to local therapies Progressive disease at study entry At least 1 measurable lesion according to RECIST 1.1 No previous systemic treatment for metastatic disease Not eligible for cisplatin-based chemotherapy, defined as: ECOG 2 [Eastern Cooperative Oncology Group] and/or Calculated CrCl [Creatinine Clearance] <60 mL/min (measured by MDRD) Age ≥ 18 years ECOG performance status 0 - 2 Brain metastases require completion of local therapy with discontinuation of steroids prior to start of treatment If of childbearing potential, willingness to use highly effective contraceptive method for the duration of the study and 120 days after last dose, such as combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally. Adequate bone marrow function, liver and renal function: Absolute neutrophil count ≥ 1.5 x 109/L Thrombocytes ≥ 100 x 109/L Hemoglobin ≥ 9 g/dL INR [international normalized ratio] ≤ 1.5 and PPT [partial prothrombin time] ≤ 1.5 x lower limit during the last 7 days before therapy Bilirubin < 1.5 x lower limit and AST (GOT) [aspartate aminotransferase] and ALT (GPT) [alanine transaminase] < 3 x lower limit (5 x lower limit in case of liver metastases) Tumor block or 20 slides must be available at study inclusion for central pathology testing Exclusion Criteria: Live expectancy less than 3 months Nasopharynx carcinoma Anticancer treatment during the last 30 days prior to start of treatment, including systemic therapy, radiotherapy or major surgery Participation in a clinical trial within the last 30 days prior to study treatment History of allogeneic tissue/solid organ transplant History of pneumonitis that has required oral or i.v. steroids Evidence of interstitial lung disease Minor surgery ≤ 24 hours prior first dose of study treatment Symptomatic acute cardiovascular or cerebrovascular disease Known active HBV [hepatitis B virus], HCV [hepatitis C virus] or HIV infection Has any other active infection requiring systemic therapy. Patients with active tuberculosis Prior therapy with an anti-Programmed cell death protein 1 (anti-PD-1), anti-PD-L1, anti-Programmed cell death-ligand 2 (anti-PD-L2), anti-CD137 (4-1BB ligand, a member of the Tumor Necrosis Factor Receptor (TNFR) family), or anti-Cytotoxic T-lymphocyte-associated antigen-4 (anti-CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways) A diagnosis of immunodeficiency or patient is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Patient has had a prior monoclonal antibody, which does significantly interfere with the immune system or which does have a systemic therapeutic effect on the tumor within 4 weeks prior to randomization. Patient has not recovered (i.e., ≤ Grade 1 or at baseline) from any toxicity due to agents administered more than 4 weeks earlier. [Subjects with ≤ Grade 2 neuropathy or alopecia are an exception to this criterion and may qualify for the study.] Has an active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. Subjects with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Subjects that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Subjects with hypothyroidism stable on hormone replacement or Sjorgen's syndrome will not be excluded from the study. Has received a live vaccine within 30 days prior to the first dose of trial treatment. Has known hypersensitivity to methotrexate or pembrolizumab or any constituent of the products.. Other active malignancy requiring treatment Lactating or pregnant women, women of child-bearing potential who do not agree to the usage of highly effective contraception methods (allowed methods of contraception, meaning methods with a rate of failure of less than 1% per year are combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation, progestogen-only hormonal contraception associated with inhibition of ovulation, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), vasectomized partner, bilateral tubal occlusion, sexual abstinence. If an oral contraception is used, a barrier method of contraception (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge) has to be applied additionally). Women of childbearing potential must have a negative pregnancy test (serum β-hCG) at Screening. Any psychiatric illness that would affect the patient's ability to understand the demands of the clinical trial Patient has already been recruited in this trial (does not include screening failures) Patient who has been incarcerated or involuntarily institutionalized by court order or by the authorities § 40 Abs. 1 S. 3 Nr. 4 AMG. Patients who are unable to consent because they do not understand the nature, significance and implications of the clinical trial and therefore cannot form a rational intention in the light of the facts [§ 40 Abs. 1 S. 3 Nr. 3a AMG].

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Patients recieve pembrolizumab or methotrexate
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A<br>Pembrolizumab 200 mg q3w i.v. until disease progression or non-tolerable toxicity (maximum 2 years) | Drug: Pembrolizumab Injection<br>* Pembrolizumab 200 mg q3w i.v. until disease progression or non-tolerable toxicity (maximum 2 years)<br>|
| Active Comparator: Arm B<br>Arm B: Methotrexate (MTX) 40 mg/m2 weekly i.v. until disease progression or non-tolerable toxicity (maximum 2 years) | Drug: Methotrexate Injectable Solution<br>* Methotrexate 40 mg/m2 weekly i.v. until disease progression or non-tolerable toxicity (maximum 2 years)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumor activity of pembrolizumab in SCCHN | Overall survival (OS) rate | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Quality of life QLQC30 [EORTC QLQ-C30] | QLQC30 | through study completion, an average of 6 years | 
| Quality of life HN35 [EORTCQLQ-H&N35] | HN35 | through study completion, an average of 6 years | 
| Predictive biomarkers | molecular-genetic pro-inflammatory markers | through study completion, an average of 6 years | 
| Predictive biomarkers | PD-L1 expression | through study completion, an average of 6 years | 
| Time to failure of strategy (TTFS) | defined as death, progressive disease (PD), treatment discontinuation ( or deterioration of Instrumental Activities of Daily Living (IADL score) by 2 points. | 1 year | 
| Efficacy of pembrolizumab in SCCHN | Objective response rate (ORR) according to RECIST 1.1 | through study completion, an average of 6 years | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | Adverse event rates due to treatment with MTX and pembrolizumab in SCCHN measured according to CTCAE 4.03 | through study completion, an average of 6 years |