A Study of Palifermin for the Reduction of Oral Mucositis in Patients With Locally Advanced Head and Neck Cancer Receiving Postoperative Radiotherapy and Concurrent Chemotherapy

Study Overview
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Brief Summary
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Oral Mucositis associated with adjuvant radiation and concurrent chemotherapy in postoperative Head and Neck setting

Detailed Description
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This study consisted of 2 phases. The acute oral mucositis (OM) evaluation phase includes the time from randomization to the time of severe OM (WHO Grade 3 or 4) resolution (up to Week 12 or up to Week 15 for participants whose severe OM is not resolved at Week 12). In the acute OM evaluation phase, participants were randomized to receive either a single IV bolus dose of palifermin or placebo at 120 μg/kg, 3 days before the start of radiotherapy, plus 7 once-weekly palifermin or placebo doses at the same dose level during a 7-week radio/chemotherapy course. In the long-term follow up phase, participants are followed until death, withdrawal of consent, or loss to follow-up. The long-term follow up phase is still ongoing.

Official Title
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A Phase 1/2 Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics and Preliminary Efficacy of Weekly Doses of Palifermin (rHuKGF) for the Reduction of Oral Mucositis in Subjects With Locally Advanced Head and Neck Cancer (HNC) Receiving Postoperative Radiotherapy With Concurrent Chemotherapy

Conditions
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Mucositis, Head and Neck Cancer

Intervention / Treatment
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* Drug: Placebo
* Drug: palifermin
* Radiation: Radiotherapy
* Drug: Cisplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: History of newly diagnosed histologically confirmed squamous cell carcinoma (American Joint Committee on Cancer [AJCC] Stage II, III, IVA, or IVB) involving either the oral cavity, oropharynx, nasopharynx, hypopharynx, or larynx, post surgical resection (R0, R1) Scheduled to receive adjuvant concurrent chemoradiation treatment within 12 weeks of surgery High-risk subject defined by presence of at least one of the following: R1 resection margins; T3 or T4 tumor stage; 3 or more positive lymph node metastases; <3 lymph node metastases with extracapsular extension of the disease Radiation treatment field to receive planned dose of at least 50Gy to areas of the oral cavity/oropharynx mucosa that can be visualized Exclusion Criteria: Tumors of the lips, paranasal sinuses, salivary glands, or of unknown primary tumors Metastatic disease (M1) / Stage IV C Presence or history of any other primary malignancy History of pancreatitis Prior radiotherapy to the site of disease Prior chemotherapy Other investigational procedures Thirty days or less since receiving an investigational product or device in another clinical trial. Current enrollment in another clinical trial is not permitted unless the sole purpose of the trial is for long-term follow-up/survival data

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Three days before the start of radiotherapy (Day -3), participants received a single intravenous (IV) bolus injection of matching placebo. During radiotherapy (beginning on Day 1), participants received a weekly single IV bolus injection of matching placebo after the last radiation fraction of that week (usually on Fridays) until grade ≥3 oral mucositis occurred, or for a maximum 8 doses (completion of radiotherapy). Participants also received cisplatin 100 mg/m^2 on days 1, 22 and 43. | Drug: Placebo<br>* Administered by intravenous (IV) bolus injection<br>Radiation: Radiotherapy<br>* Once daily irradiation of 20 centigray (cGy)/day x 33 fractions for a total target dose of 6600 cGy (conventional radiation therapy using standard fractionation [one fraction per day])<br>Drug: Cisplatin<br>* 100 mg/m^2 intravenously (IV) on days 1, 22 and 43.<br>|
| Experimental: Palifermin<br>Three days before the start of radiotherapy (Day -3), participants received a single intravenous (IV) bolus injection of palifermin at 120 μg/kg. During radiotherapy (beginning on Day 1), participants received a weekly single IV bolus injection of palifermin at 120 μg/kg after the last radiation fraction of that week (usually on Fridays) until grade ≥3 oral mucositis occurred, or for a maximum 8 doses (completion of radiotherapy). Participants also received cisplatin 100 mg/m^2 on days 1, 22 and 43. | Drug: palifermin<br>* Administered by intravenous (IV) bolus injection<br>Radiation: Radiotherapy<br>* Once daily irradiation of 20 centigray (cGy)/day x 33 fractions for a total target dose of 6600 cGy (conventional radiation therapy using standard fractionation [one fraction per day])<br>Drug: Cisplatin<br>* 100 mg/m^2 intravenously (IV) on days 1, 22 and 43.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events (AEs) | An adverse event is an undesirable medical occurrence (sign, symptom, or diagnosis) or worsening of a pre-existing medical condition occurring after start of study drug up to the end of acute oral mucositis (OM) evaluation phase, whether or not considered to be study drug related. If severe OM was not resolved by Week 12, AEs were documented until resolution of severe OM or Week 15, whichever occurred first. A serious AE is any event that is fatal, life threatening, requires or prolongs hospitalization, is a persistent or significant disability/incapacity or is a congenital anomaly/birth defect. The intensity of AEs was graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3 based on the following: 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. A Protocol-specific Limiting Toxicity (PSLT) is any non-hematologic Grade 3 or 4 AE considered related to study drug. | Up to Week 12 (or Week 15 for participants with severe OM was not resolved by Week 12) | 
| Ratio of Ki67-positive Cells Before and After Palifermin Treatment | The effect of palifermin on cell proliferation was to be assayed by staining for the cell cycle proliferation marker Ki67 in buccal mucosal biopsy samples taken prior to the first dose and either 24 or 48 hours after the first dose. Due to the small sample size, this analysis was not performed. | Day -3 predose and 24 or 48 hours post-dose | 
| Pharmacokinetics of Palifermin | Due to the small sample size this analysis was not performed. | Day -3, predose and at 2, 5, 15, 30, 60, and 90 minutes and 2, 4, 6, 8, 10, 12, 24 and 48 hours after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Severe Oral Mucositis (OM) (Adapted RTOG/EORTC Grade ≥3) | The adapted RTOG/EORTC mucositis assessment scale as follows: Grade 0 = no change; Grade 1 = mild enanthema, mild pain; Grade 2 = patchy mucositis, moderate edema, moderate pain; Grade 3 = confluent fibrinous mucositis, massive edema, massive pain; Grade 4 = extensive ulceration, confluent necrosis, massive hemorrhage. Due to the small sample size this analysis was not performed. | Assessed daily up to Week 12 (or Week 15 if severe oral mucositis not resolved ≤ adapted RTOG/EORTC Grade 2 by Week 12). | 
| Patient-Reported Mouth and Throat Soreness Score | The average patient-reported mouth and throat soreness (MTS) score as reported on question 3 of the Oral Mucositis Questionnaire for Head and Neck Cancer [OMQ-HN]): How much mouth and throat soreness did you experience in the past 24 hours? Participants answered on a scale from 0 (no soreness) to 4 (extreme soreness). Due to the small sample size this analysis was not performed. | Assessed daily up to Week 12 (or Week 15 if severe oral mucositis not resolved ≤ adapted RTOG/EORTC Grade 2 by Week 12). | 
| Number of Participants With Disease Progression by Week 12 | Disease progression was determined by clinical examination and histopathologic examination by the Investigator. | Up to Week 12 | 
| Overall Survival | Deaths during long-term follow up of subject participating in the acute phase of the study receiving placebo or Palifermin. | During long-term follow-up phase, until December 2015 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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palifermin, Clinical Trial, Oncology, Head & Neck