Intensity-Modulated Radiation Therapy, Pemetrexed, and Erlotinib in Treating Patients With Recurrent or Second Primary Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Specialized radiation therapy that delivers a high dose of radiation directly to the tumor may kill more tumor cells and cause less damage to normal tissue. Drugs, such as pemetrexed and erlotinib, may make tumor cells more sensitive to radiation therapy. Erlotinib and pemetrexed may also stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving intensity-modulated radiation therapy together with pemetrexed and erlotinib may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of erlotinib when given together with intensity-modulated radiation therapy and pemetrexed and to see how well they work in treating patients with recurrent or second primary head and neck cancer.

Detailed Description
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OBJECTIVES: Primary Evaluate the acute toxicity and feasibility of intensity modulated radiotherapy (IMRT) in combination with radiosensitizing drugs pemetrexed disodium and erlotinib hydrochloride in patients with recurrent or second primary squamous cell carcinoma of the head and neck. (Phase I) Determine the maximum tolerated dose and recommended phase II dose of erlotinib hydrochloride in these patients. (Phase I) Determine progression-free survival (PFS) at 1 year in these patients. (Phase II) Secondary Determine median PFS, median overall survival (OS), and OS at 1 and 2 years in these patients. Determine objective tumor response as measured by CT scan or MRI in these patients. Evaluate the acute and chronic toxicity of IMRT in combination with radiosensitizing drugs pemetrexed disodium and erlotinib hydrochloride in these patients. Evaluate the impact of treatment on quality of life as measured by FACT-H&N, PSS-HN, MD Anderson Dysphagia Inventory (MDADI), and swallowing by direct functional measurements at different time points. Evaluate the level of phosphorylation of different tyrosine residues within the cytoplasmic domain of EGFR, bound adaptors, as well as markers of downstream pathways activation by nano LC-MS/MS in tumor tissue and correlate with levels of P-AKT and P-ERK by immunohistochemistry and with response to treatment. Measure the levels of TS and p53 and correlate with treatment response. OUTLINE: This is a phase I, dose-escalation study of erlotinib hydrochloride followed by a phase II study. Phase I: Patients undergo intensity modulated radiotherapy (IMRT) once daily, 5 days a week, for 6 weeks. Patients receive pemetrexed disodium IV over 10 minutes on day 1 of radiotherapy. Treatment with pemetrexed disodium repeats every 21 days for 2 courses in the absence of disease progression or unacceptable toxicity. Patients also receive oral erlotinib hydrochloride once daily beginning on day 1 of radiotherapy and continuing for up to 2 years in the absence of disease progression or unacceptable toxicity. Phase II: Patients undergo IMRT and receive pemetrexed sodium as in phase I. Patients also receive erlotinib hydrochloride at the maximum tolerated dose determined in phase I. Quality of life is assessed at baseline, weekly during treatment, at 1, 6, and 12 months, and then annually thereafter. After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 1 year, and then annually thereafter.

Official Title
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Phase I/II Clinical Trial of Combined Pre-Irradiation With Pemetrexed and Erlotinib Followed by Maintenance Erlotinib for Recurrent and Second Primary Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: erlotinib hydrochloride
* Drug: pemetrexed disodium
* Procedure: quality-of-life assessment
* Radiation: intensity-modulated radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion: * Histologically or cytologically confirmed diagnosis of recurrent or second primary squamous cell carcinoma (SCC) of the head and neck, including any of the following: Oral cavity Oropharynx Hypopharynx Larynx Recurrent neck metastases with unknown primary Exception from pathology confirmation of tumor recurrence is accepted for patients who originally had pathologically confirmed SCC of the Head and Neck, the new tumor is located in the head and neck area and it is clinically considered as a recurrence of the original tumor, and a tumor biopsy is technically difficult and would expose the patient to unjustified risk. The treating physicians should agree and document the clinical definition of tumor recurrence and should document the increased risk for biopsy. Measurable disease by CT scan or MRI OR evaluable disease No definitive evidence of distant metastasis Unresectable disease by a preliminary ENT evaluation OR refused surgery Patients may have received chemotherapy as a component of their primary tumor treatment but not for recurrent or metastatic disease. No prior treatment with systemic anti-EGFR inhibitors or Pemetrexed is permitted Has undergone prior head and neck radiotherapy (for SCC of the head and neck) to a dose of ≤ 72 Gy that involved most of the recurrent tumor (> 75%) OR has a second primary tumor volume in areas previously irradiated to > 45 Gy The entire tumor volume must be included in a treatment field that limits the total spinal cord dose to 54 Gy (prior plus planned dose) Must have disease recurrence or persistence for ≥ 6 months after completion of prior radiotherapy ECOG performance status 0-1 Age ≥ 18 years ANC > 1,500/µL Platelet count > 100,000/µL Total bilirubin < 1.5 times upper limit of normal (ULN) AST/ALT < 2 times ULN Creatinine < 1.5 times ULN Willing and able to take folic acid and vitamin B12 supplementation Recovered from prior surgery, chemotherapy, or radiotherapy At least 6 months since prior radiotherapy At least 5 days since prior aspirin or other non-steroidal anti-inflammatory agents (8 days for long acting agents [e.g., piroxicam]) Fertile patients must use effective contraception Exclusion: Nasopharyngeal carcinoma Concurrent uncontrolled illness, including, but not limited to, any of the following: Ongoing or active infection Psychiatric illness or social situation that would limit compliance with study requirements Significant history of uncontrolled cardiac disease (i.e., uncontrolled hypertension; unstable angina; recent myocardial infarction [within the past 3 months]; uncontrolled congestive heart failure; or cardiomyopathy with decreased ejection fraction) Active interstitial lung disease Presence of third space fluid that cannot be controlled by drainage Other concurrent investigational agents Pregnant or nursing HIV positive

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Erlotinib<br>Erlotinib | Drug: erlotinib hydrochloride<br> <br> Drug: pemetrexed disodium<br> <br> Procedure: quality-of-life assessment<br> <br> Radiation: intensity-modulated radiation therapy<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose of Erlotinib Hydrochloride (Phase I) | Dose at which 100% of participants tolerated the dose | 56 Days | 
| Progression-free Survival (PFS) at 1 Year (Phase II) | Determine Progression Free Survival at 1 year defined as the percentage of patients who are alive at 1 year after beginning of their concurrent re-irradiation and chemotherapy without loco-regional progression of their disease as measured by CT scan or MRI. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival | Median Progression Free Survival of participants reported after 2 years. | 2 years | 
| Median Overall Survival | Median Overall Survival of participants reported after 2 years. | up to 5 years | 
| Overall Survival | Overall survival of participants reported after 2 years. | 1 and 2 years | 
| Evaluation of Acute and Chronic Toxicity | Evaluate acute and chronic toxicity of the combined re-irradiation with radiosensitizing drugs: Pemetrexed and Erlotinib. Adverse events with Common Toxicity Criteria grades of 4 and 5 are reported for phase I and II. | 1 year | 
| Change in Quality of Life- FACT H&N | The Functional Assessment of Cancer Therapy-Head and Neck (FACT H&N) consists of 27 core items which assess patient function in four domains: Physical, Social/Family, Emotional, and Functional well-being, which is further supplemented by 12 site specific items to assess for head and neck related symptoms. Each item is rated on a 0 to 4 Likert type scale, and then combined to produce subscale scores for each domain. Score range is 0-156. Higher scores denotes better outcomes | baseline and 12 months | 
| Change in Quality of Life: PSS-HN | The Performance Status Scale for Head & Neck Cancer Patients (PSS-HN) is s designed to evaluate performance in areas of functioning most likely affected by head and neck cancer and its treatment, specifically Normalcy of Diet, Eating in Public, and Understandability of Speech. Each subscale is rated from 0 to 100, with higher scores indicating better performance | baseline and 6 months | 
| Change in Quality of Life: MDADI | The M.D. Anderson Dysphagia Inventory (MDADI) was used to assess effects of dysphagia on the quality of life of patients with head and neck cancer. It incorporates 3 domains (emotional, functional, and physical) as well as 1 global question. Each subscale with five possible responses scored on a scale of 1 to 5 (strongly agree, agree, no opinion, disagree and strongly disagree). Scores range from 0 (extremely low functioning) to 100 (higher functioning). Higher MDADI score represents better day-to-day functioning and better quality of life. | baseline and 12 months | 
| Evaluation of Biomarkers |  | throughout study completion, up to 2 years | 
| Objective Tumor Response | Objective Tumor Response reported on participants at 1 year (complete, partial, progression, or stable response). | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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recurrent squamous cell carcinoma of the hypopharynx, recurrent squamous cell carcinoma of the larynx, recurrent verrucous carcinoma of the larynx, recurrent squamous cell carcinoma of the lip and oral cavity, recurrent verrucous carcinoma of the oral cavity, metastatic squamous neck cancer with occult primary squamous cell carcinoma, recurrent metastatic squamous neck cancer with occult primary, recurrent squamous cell carcinoma of the oropharynx