Palifermin in Lessening Oral Mucositis in Patients Undergoing Radiation Therapy and Chemotherapy for Locally Advanced Head and Neck Cancer

Study Overview
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Brief Summary
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RATIONALE: Growth factors, such as palifermin, may lessen the severity of mucositis, or mouth sores, in patients receiving radiation therapy and chemotherapy for head and neck cancer. It is not yet known whether palifermin is more effective than a placebo in lessening mucositis in patients receiving radiation therapy and chemotherapy for head and neck cancer. PURPOSE: This randomized phase III trial is studying palifermin to see how well it works compared to a placebo in lessening oral mucositis in patients undergoing radiation therapy and chemotherapy for locally advanced head and neck cancer.

Detailed Description
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OBJECTIVES: Primary Compare the efficacy of palifermin vs placebo, in terms of burden of acute mucositis (defined to be 105 days [15 weeks] or less from the start of treatment), in patients with squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx undergoing concurrent radiotherapy and chemotherapy. Secondary Compare incidence and time to onset of Grades 3 or 4 oral mucositis in patients treated with these regimens. Compare overall and progression-free survival and time to second primary in patients treated with these regimens. OUTLINE: This is a randomized, double-blind, placebo-controlled, multicenter study. Patients are stratified according to disease stage (III vs IVA or IVB), tumor site (oral cavity or oropharynx vs hypopharynx or larynx), and radiotherapy technique used on study (intensity-modulated radiotherapy [IMRT] vs 3-dimensional conformal radiotherapy [3D-CRT]). Patients are randomized to 1 of 2 treatment arms. Mucositis, pain, and symptom burden are assessed at baseline, during radiotherapy, and post radiotherapy. Xerostomia is assessed at baseline, during radiotherapy, and several times after completion of study therapy. After completion of study therapy, patients are followed periodically for 10 years. PROJECTED ACCRUAL: A total of 298 patients will be accrued for this study.

Official Title
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A Randomized, Phase III, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Palifermin (NSC# 740548; IND # 6370) for the Reduction of Oral Mucositis in Patients With Locally Advanced Head and Neck Cancer Receiving Radiation Therapy With Concurrent Chemotherapy (Followed by Surgery for Selected Patients)

Conditions
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Head and Neck Cancer, Mucositis, Pain, Radiation Toxicity

Intervention / Treatment
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* Biological: palifermin
* Drug: cisplatin
* Other: placebo
* Procedure: neck dissection
* Radiation: radiation therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically (histologically or cytologically) proven (from primary lesion and/or lymph nodes) diagnosis of squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx; Patients must have at least 2 mucosal sites of the oral cavity/oropharynx mucosa assessable by visual transoral inspection that will receive at least 66 Gy; -2.1 Patients with tumors of the larynx or hypolarynx are eligible only if it is anticipated that the 2 index sites in the oral cavity/oropharynx mucosa will receive at least 66 Gy; Patients must be able to be evaluated for the primary endpoint; therefore, patients must be able to eat at least soft solids and not require a feeding tube for nutrition or hydration at study entry. Selected Stage III (excluding T1N1MO) or IVA-B (AJCC, 6th edition) at study entry, including no distant metastases, based upon the following minimum diagnostic workup: 4.1 History/physical examination, including documentation of tobacco/alcohol use and current medications (including opioids/dosing), within 8 weeks prior to registration; 4.2 Chest x-ray (or Chest CT scan) within 6 weeks prior to registration; 4.3 MRI or CT scan with contrast of tumor site within 6 weeks prior to registration; 4.4 Assessment of mucositis and xerostomia within 2 weeks prior to registration; Zubrod Performance Status 0-1; Age > 18; Adequate bone marrow function, defined as follows: 7.1 Absolute neutrophil count (ANC) > 1,800 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to registration on study 7.2 Platelets > 100,000 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to registration on study 7.3 Hemoglobin > 8.0 g/dl based upon CBC/differential obtained within 2 weeks prior to registration on study (Note: The use of transfusion or other intervention to achieve Hgb > 8.0 g/dl is acceptable.) Adequate hepatic function with bilirubin < 1.5 mg/dl, AST or ALT < 2 x ULN within 2 weeks prior to registration; Adequate renal function with serum creatinine < 1.5 mg/dl and creatinine clearance (CC) ≥ 50 ml/min within 2 weeks prior to registration determined by 24-hour collection or estimated by Cockcroft-Gault formula: CCr male = [(140 - age) x (wt in kg)]/[(Serum Cr mg/dl) x (72)] CCr female = 0.85 x (CrCl male) Normal serum calcium or normal corrected serum calcium within 2 weeks prior to registration; formula for corrected calcium if albumin valued is below normal range: Corrected calcium (mg/dl) = (4 - [patient's albumin (g/dl)] x 0.8) + patient's measured calcium (mg/dl); Serum pregnancy test for women of childbearing potential within 2 weeks prior to registration; Women of childbearing potential and male participants must practice adequate contraception. Patient agrees to refrain from using all products listed in Section 9.2, Non-permitted Supportive Therapy; Patient must sign study specific informed consent prior to study entry. Exclusion Criteria: Patients with a history of prior head and neck squamous cancer are ineligible; Stage IVC (AJCC, 6th edition) [Any T, Any N, M1] or distant metastases at protocol study entry; T1N1M0 patients are excluded. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable. See Sections 1 and 3. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields; Initial surgical treatment, excluding diagnostic biopsy of the primary site or nodal sampling of neck disease; radical or modified neck dissection is not permitted. Severe, active co-morbidity, defined as follows: 7.1 Symptomatic and/or uncontrolled cardiac disease, New York Heart Association Classification III or IV (see Appendix II); 7.2 Transmural myocardial infarction within the last 6 months; 7.3 Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration; 7.4 Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy at the time of registration. 7.5 Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects; 7.6 Patients known to be sero-positive for hepatitis B virus (HBV) or hepatitis C virus (HCV); 7.7 Patients known to be sero-positive for human immunodeficiency virus (HIV) or patients with Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition; note, however, that HIV testing is not required for entry into this protocol. The need to exclude patients with HIV or AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive. 7.8 A history of pancreatitis. Collagen vascular disease, such as scleroderma, as this disease is thought to predispose patients to increased risk for radiation-associated toxicities; Previous treatment with palifermin or other keratinocyte growth factors, such as velafermin or repifermin; Prior allergic reaction or known sensitivity to any of the agents administered during dosing, including E. coli-derived products, such as Nutropin®, Neupogen®, Humulin®, Roferon®; Neumega®, Neulasta®), IntronA®, Betaseron®; Pregnancy or women of childbearing potential and men who are sexually active and not willing/able to use medically acceptable forms of contraception; this exclusion is necessary because the treatment involved in this study may be significantly teratogenic.

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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Palifermin<br>Concurrent radiation therapy, cisplatin, and palifermin followed by neck dissection for indicated patients. | Biological: palifermin<br>* Four doses of palifermin, 180ųg/kg, administered as an i.v. bolus injection over 30-60 seconds. Starting on day -3 (Friday) prior to radiation therapy / chemotherapy and then once weekly, on days 5, 12, and 19.<br>Drug: cisplatin<br>* Patients will receive cisplatin (100 mg/m2) administered intravenously on days 1, 22, and 43 of the treatment course.<br>Procedure: neck dissection<br>* A neck dissection is required for patients with persistent nodal disease, any stage, if a palpable abnormality or worrisome radiographic abnormality persists in the neck 8-9 weeks after completion of therapy. A neck dissection is optional for patients with multiple positive lymph nodes or with lymph nodes exceeding 3 cm in diameter at pre-treatment (N2a, N2b, N3) who achieve a complete clinical and radiographic response in the neck. All patients will be assessed at approximately 8 weeks post-treatment with CT scan or MRI by the same technique used at baseline.<br>Radiation: radiation therapy<br>* A radiation dose of 70 Gy with at least 66 Gy to at least 2 mucosal sites of the oral cavity/oropharynx mucosa. Radiation therapy can be given with 3D conformal (3D-CRT) or with intensity modulated RT (IMRT) techniques; however, the chosen modality must be used for the entire course of treatment.<br>|
| Placebo Comparator: Placebo<br>Concurrent radiation therapy, cisplatin, and placebo followed by neck dissection for indicated patients. | Drug: cisplatin<br>* Patients will receive cisplatin (100 mg/m2) administered intravenously on days 1, 22, and 43 of the treatment course.<br>Other: placebo<br>* Four doses of placebo, 180ųg/kg, administered as an i.v. bolus injection over 30-60 seconds. Starting on day -3 (Friday) prior to radiation therapy / chemotherapy and then once weekly, on days 5, 12, and 19.<br>Procedure: neck dissection<br>* A neck dissection is required for patients with persistent nodal disease, any stage, if a palpable abnormality or worrisome radiographic abnormality persists in the neck 8-9 weeks after completion of therapy. A neck dissection is optional for patients with multiple positive lymph nodes or with lymph nodes exceeding 3 cm in diameter at pre-treatment (N2a, N2b, N3) who achieve a complete clinical and radiographic response in the neck. All patients will be assessed at approximately 8 weeks post-treatment with CT scan or MRI by the same technique used at baseline.<br>Radiation: radiation therapy<br>* A radiation dose of 70 Gy with at least 66 Gy to at least 2 mucosal sites of the oral cavity/oropharynx mucosa. Radiation therapy can be given with 3D conformal (3D-CRT) or with intensity modulated RT (IMRT) techniques; however, the chosen modality must be used for the entire course of treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Oral Mucositis as Measured in Terms of Days | Duration in days of World Heath Organization (WHO) Grades 3 and 4 oral mucositis during the acute period (defined to be 105 days [15 weeks] or less from the start of treatment); duration is calculated from the onset of a Grade 3 or 4 oral mucositis to the day when an oral mucositis of ≤ Grade 2 is reported after the last oral mucositis of Grade 3 or 4. Patients with grade 0-2 mucositis have a duration of 0. This study required 298 patients to detect via two-sided t-test a reduction of mean duration of at least 9 days from 29 days (standard deviation = 23 days) on the placebo arm with 90% power and alpha = 0.05. Statistical testing was not done due to the small sample size. | Twice-weekly from start of treatment up to 15 weeks after the start of treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Grade 3 or 4 Mucositis as Measured by the World Heath Organization (WHO) Scale | Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | Twice-weekly from start of treatment up to 15 weeks after the start of treatment. | 
| Time to Onset of Grade 3 or 4 Oral Mucositis as Measured by the World Heath Organization (WHO) Scale | Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. | Twice-weekly from start of treatment up to 15 weeks after the start of treatment. | 
| Overall Survival | An event is death from any cause. Overall survival was not calculated due to the limited number of events. Number of patients with an event is reported. | From randomization to maximum follow-up at time of analysis of 21 months | 
| Progression-free Survival | An event is defined as the first occurrence of local, regional, distant disease. Progression-free survival is calculated at the time from registration to the death of progression, death in the absence of progression, or last follow-up. Progression-free survival was not calculated due to the limited number of events. Number of patients with an event is reported. | From randomization to maximum follow-up at time of analysis of 21 months | 
| Time to Second Primary Tumor | An event is occurrence of a second primary other than basal cell. Time to second primary tumor was not calculated because there were no events. Number of patients with an event is reported. | From randomization to maximum follow-up at time of analysis of 21 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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mucositis, pain, radiation toxicity, stage III squamous cell carcinoma of the hypopharynx, stage IV squamous cell carcinoma of the hypopharynx, stage III squamous cell carcinoma of the larynx, stage IV squamous cell carcinoma of the larynx, stage III squamous cell carcinoma of the lip and oral cavity, stage IV squamous cell carcinoma of the lip and oral cavity, stage III squamous cell carcinoma of the oropharynx, stage IV squamous cell carcinoma of the oropharynx