Clinical trial NCT00360971: Palifermin in Lessening Oral Mucositis in Patients Undergoing Radiation Therapy and Chemotherapy for Locally Advanced Head and Neck Cancer
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Head and Neck Cancer
Mucositis
Pain
Radiation Toxicity
Keywords: 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
Lead sponsor: Radiation Therapy Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-08-07
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SUPPORTIVE_CARE

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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;
2. 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;
3. 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.
4. 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;
5. Zubrod Performance Status 0-1;
6. Age \> 18;
7. 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.)
8. Adequate hepatic function with bilirubin \< 1.5 mg/dl, AST or ALT \< 2 x ULN within 2 weeks prior to registration;
9. 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)
10. 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);
11. Serum pregnancy test for women of childbearing potential within 2 weeks prior to registration;
12. Women of childbearing potential and male participants must practice adequate contraception.
13. Patient agrees to refrain from using all products listed in Section 9.2, "Non-permitted Supportive Therapy";
14. Patient must sign study specific informed consent prior to study entry.

Exclusion Criteria:

1. Patients with a history of prior head and neck squamous cancer are ineligible;
2. Stage IVC (AJCC, 6th edition) \[Any T, Any N, M1\] or distant metastases at protocol study entry; T1N1M0 patients are excluded.
3. Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years;
4. Prior systemic chemotherapy for the study cancer; note that prior chemotherapy for a different cancer is allowable. See Sections 1 and 3.
5. Prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields;
6. Initial surgical treatment, excluding diagnostic biopsy of the primary site or nodal sampling of neck disease; radical or modified neck dissection is not permitted.
7. 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.
8. Collagen vascular disease, such as scleroderma, as this disease is thought to predispose patients to increased risk for radiation-associated toxicities;
9. Previous treatment with palifermin or other keratinocyte growth factors, such as velafermin or repifermin;
10. 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®;
11. 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.

Primary outcomes:
measure: Duration of Oral Mucositis as Measured in Terms of Days
timeFrame: Twice-weekly from start of treatment up to 15 weeks after the start of treatment.
Secondary outcomes:
measure: Number of Patients With Grade 3 or 4 Mucositis as Measured by the World Heath Organization (WHO) Scale
timeFrame: Twice-weekly from start of treatment up to 15 weeks after the start of treatment.
measure: Time to Onset of Grade 3 or 4 Oral Mucositis as Measured by the World Heath Organization (WHO) Scale
timeFrame: Twice-weekly from start of treatment up to 15 weeks after the start of treatment.
measure: Overall Survival
timeFrame: From randomization to maximum follow-up at time of analysis of 21 months
measure: Progression-free Survival
timeFrame: From randomization to maximum follow-up at time of analysis of 21 months
measure: Time to Second Primary Tumor
timeFrame: From randomization to maximum follow-up at time of analysis of 21 months
Other outcomes:
Locations:
city: Scottsdale
country: United States
facility: Mayo Clinic Scottsdale
state: Arizona
city: Auburn
country: United States
facility: Auburn Radiation Oncology
state: California
city: Burbank
country: United States
facility: Providence Saint Joseph Medical Center - Burbank
state: California
city: Cameron Park
country: United States
facility: Radiation Oncology Centers - Cameron Park
state: California
city: Carmichael
country: United States
facility: Mercy Cancer Center at Mercy San Juan Medical Center
state: California
city: Chico
country: United States
facility: Enloe Cancer Center at Enloe Medical Center
state: California
city: Duarte
country: United States
facility: City of Hope Comprehensive Cancer Center
state: California
city: Los Angeles
country: United States
facility: USC/Norris Comprehensive Cancer Center and Hospital
state: California
city: Roseville
country: United States
facility: Radiation Oncology Center - Roseville
state: California
city: Sacramento
country: United States
facility: Radiological Associates of Sacramento Medical Group, Incorporated
state: California
city: Sacramento
country: United States
facility: Mercy General Hospital
state: California
city: Torrance
country: United States
facility: Torrance Memorial Medical Center
state: California
city: Vacaville
country: United States
facility: Solano Radiation Oncology Center
state: California
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Anderson
country: United States
facility: Saint John's Cancer Center at Saint John's Medical Center
state: Indiana
city: Baltimore
country: United States
facility: St. Agnes Hospital Cancer Center
state: Maryland
city: Detroit
country: United States
facility: Barbara Ann Karmanos Cancer Institute
state: Michigan
city: Iron Mountain
country: United States
facility: Dickinson County Healthcare System
state: Michigan
city: Kalamazoo
country: United States
facility: Borgess Medical Center
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Kalamazoo
country: United States
facility: Bronson Methodist Hospital
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital - Royal Oak Campus
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic Cancer Center
state: Minnesota
city: Saint Cloud
country: United States
facility: CentraCare Clinic - River Campus
state: Minnesota
city: Pascagoula
country: United States
facility: Regional Cancer Center at Singing River Hospital
state: Mississippi
city: Great Falls
country: United States
facility: Great Falls Clinic - Main Facility
state: Montana
city: Camden
country: United States
facility: Cancer Institute of New Jersey at Cooper University Hospital - Camden
state: New Jersey
city: Vineland
country: United States
facility: Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare
state: New Jersey
city: Voorhees
country: United States
facility: Cancer Institute of New Jersey at Cooper - Voorhees
state: New Jersey
city: Durham
country: United States
facility: Duke Comprehensive Cancer Center
state: North Carolina
city: Greenville
country: United States
facility: Leo W. Jenkins Cancer Center at ECU Medical School
state: North Carolina
city: Akron
country: United States
facility: McDowell Cancer Center at Akron General Medical Center
state: Ohio
city: Akron
country: United States
facility: Summa Center for Cancer Care at Akron City Hospital
state: Ohio
city: Salem
country: United States
facility: Cancer Research UK Medical Oncology Unit at Churchill Hospital & Weatherall Institute of Molecular Medicine - Oxford
state: Ohio
city: Wooster
country: United States
facility: Cancer Treatment Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma University Cancer Institute
state: Oklahoma
city: Hermitage
country: United States
facility: Sharon Regional Cancer Care Center- Hermitage
state: Pennsylvania
city: Monroeville
country: United States
facility: Intercommunity Cancer Center
state: Pennsylvania
city: Natrona Heights
country: United States
facility: Alle-Kiski Medical Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Allegheny Cancer Center at Allegheny General Hospital
state: Pennsylvania
city: Somerset
country: United States
facility: Somerset Oncology Center
state: Pennsylvania
city: State College
country: United States
facility: Mount Nittany Medical Center
state: Pennsylvania
city: Johnson City
country: United States
facility: Johnson City Medical Center Hospital
state: Tennessee
city: Houston
country: United States
facility: M. D. Anderson Cancer Center at University of Texas
state: Texas
city: Wheeling
country: United States
facility: Schiffler Cancer Center at Wheeling Hospital
state: West Virginia
city: Green Bay
country: United States
facility: St. Vincent Hospital Regional Cancer Center
state: Wisconsin
city: Marinette
country: United States
facility: Bay Area Cancer Care Center at Bay Area Medical Center
state: Wisconsin
city: Edmonton
country: Canada
facility: Cross Cancer Institute at University of Alberta
state: Alberta
Study officials:
affiliation: M.D. Anderson Cancer Center
name: David I. Rosenthal, MD
role: STUDY_CHAIR
References: