Clinical trial NCT01084083: Induction Chemotherapy Followed By Cetuximab and Radiation in HPV-Associated Resectable Stage III/IV Oropharynx Cancer
Official title: A Phase II Trial of Induction Chemotherapy Followed by Cetuximab (Erbitux) With Low Dose vs. Standard Dose IMRT in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Head and Neck Cancer
Precancerous Condition
Keywords: human papilloma virus infection
stage III squamous cell carcinoma of the oropharynx
stage IV squamous cell carcinoma of the oropharynx
tongue cancer
Lead sponsor: Eastern Cooperative Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-03-10
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: RATIONALE: Drugs used in chemotherapy, such as paclitaxel and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Radiation therapy uses high energy x-rays to kill tumor cells. Giving paclitaxel, cisplatin, and cetuximab together with radiation therapy may kill more tumor cells.

PURPOSE: This phase II trial is studying paclitaxel, cisplatin, and cetuximab to see how well they work when followed by cetuximab and two different doses of intensity-modulated radiation therapy in treating patients with HPV-associated stage III or stage IV cancer of the oropharynx that can be removed by surgery.

Detailed description: OBJECTIVES:

Primary

* To evaluate the efficacy of induction therapy comprising paclitaxel, cisplatin, and cetuximab followed by cetuximab in combination with low-dose or standard-dose intensity-modulated radiotherapy, as measured by 2-year progression-free survival (PFS), in patients with human papillomavirus(HPV)-associated resectable stage III-IVB squamous cell carcinoma of the oropharynx.

Secondary

* To assess overall survival.
* To evaluate the objective response, local control, and metastatic rate.
* To evaluate early and late toxicities of treatment.

Tertiary

* To evaluate quality of life and speech and swallowing function as measured by Functional Assessment of Cancer Therapy - General (FACT-G), Functional Assessment of Cancer Therapy-Head and Neck (FACT-HN), and Vanderbilt Head and Neck Symptom Survey (VHNSS).
* To assess the effect of treatment-induced fatigue on general physical functioning in patients with head and neck cancer.
* To correlate functional decline with clinical, physical, and biologic correlatives.
* To evaluate radiation-resistance markers, including ERCC1 single nucleotide polymorphism and protein expression, and to correlate them with treatment efficacy.
* To demonstrate the usefulness of biomarkers, including ERCC1, epidermal growth factor receptor (EGFR), cytokine and chemokine markers, and plasma transforming growth factor alpha (TGFA) and transforming growth factor beta (TGFB) levels, in predicting progression-free survival (PFS) and other outcome parameters.
* To evaluate the correlation between the efficacy of cetuximab and polymorphisms in FcγR-receptors.
* To evaluate functional outcome and biological parameters, including telomere length, angiotensin-converting enzyme polymorphism, and C-reactive protein level.

OUTLINE: This is a multicenter study.

* Induction therapy: Patients receive cisplatin intravenously (IV) over 1 hour on day 1 and paclitaxel IV over 3 hours and cetuximab IV over 1-2 hours on days 1, 8, and 15. Treatment repeats every 21 days for 3 courses. Patients then undergo evaluation of response to induction therapy. Patients with a clinical complete response (CR) at the primary tumor site proceed to group 1 of concurrent radiotherapy and cetuximab. Patients with a clinical partial response (PR) or stable disease (SD) at the primary tumor site or those with grossly positive disease at the primary tumor site proceed to group 2 of concurrent radiotherapy and cetuximab.
* Concurrent radiotherapy and cetuximab: Treatment begins 14-21 days after the last day of induction therapy.

  * Group 1 (CR): Patients undergo low-dose intensity-modulated radiotherapy (IMRT) 5 days per week for approximately 5 weeks (27 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 6 weeks.
  * Group 2 (PR, SD, or grossly positive disease): Patients undergo standard-dose IMRT 5 days per week for approximately 6 weeks (33 fractions). Patients also receive cetuximab IV over 1-2 hours once weekly for 7 weeks.

Patients complete questionnaires assessing fatigue, physical function, weight loss, quality of life, head and neck symptom burden, and speech and swallowing function at baseline and at 1, 6, 12, and 24 months after completion of study treatment.

Tumor tissue and serum samples may be collected periodically for correlative laboratory studies.

After completion of study treatment, patients are followed up periodically for 3 years.

PROJECTED ACCRUAL: 83 patients

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed squamous cell carcinoma of the oropharynx as determined by Hematoxylin and eosin (H\&E) staining

  * Newly diagnosed disease
  * Resectable disease OR disease that is expected to become resectable after study treatment
  * Stage III, IVA, or IVB disease as determined by imaging studies (computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI) required) and a complete head and neck exam
* Paraffin-embedded tumor specimen available for central confirmation of HPV-associated disease as determined by H\&E staining and in-situ hybridization (ISH) for HPV-16 and immunohistochemistry (IHC) for p16

  * HPV-associated disease is defined as p16 IHC-positive and/or HPV-16 ISH-positive
  * Non-HPV-associated disease is defined as p16 IHC-negative
  * NOTE: If there is limited tumor material, p16 IHC will be performed before HPV-16 ISH
* Measurable disease of the primary tumor or nodes by clinical and radiographic methods, defined as a lesion that is ≥ 2 cm in at least one dimension by clinical exam AND by radiographic exam with CT scan or MRI (or a lesion that is ≥ 1 cm in at least one dimension if the radiographic exam utilizes spiral CT scan)
* No primary tumor or nodal metastasis fixed to the carotid artery, skull base, or cervical spine
* No evidence of distant metastases
* Eastern Cooperative Oncology Group performance status 0-1
* Granulocytes ≥ 1,000/mm\^3
* Platelet count ≥ 100,000/mm\^3
* Total serum bilirubin ≤ 1.5 mg/dL
* Creatinine clearance ≥ 60 mL/min
* Negative pregnancy test
* Fertile patients must use effective contraception
* No history of another malignancy (except for carcinoma in situ of the cervix and/or nonmelanomatous skin cancer) unless it has been curatively treated and the patient has been disease-free for ≥ 2 years
* Patients with any of the following within the past 6 months are eligible provided they have been evaluated by a cardiologist and/or neurologist before study entry:

  * New York Heart Association (NYHA) class III-IV congestive heart failure
  * Cerebrovascular accident or transient ischemic attack
  * Unstable angina
  * Myocardial infarction (with or without ST elevation)

Exclusion Criteria:

* Prior chemotherapy
* Prior radiotherapy above the clavicles
* Prior surgery with curative intent for this disease (complete head and neck exam with biopsy allowed)
* Prior therapy specifically and directly targeting the EGFR pathway
* Prior severe infusion reaction to a monoclonal antibody
* Uncontrolled diabetes, uncontrolled infection despite antibiotics, or uncontrolled hypertension within the past 30 days
* Concurrent illness likely to interfere with study therapy or to prevent surgical resection
* Pregnant or nursing

Primary outcomes:
measure: 24-month Progression-free Survival
timeFrame: assessed within 14 days after delivery of the third cycle of induction therapy, and 8 weeks and 6 months after completion of concurrent therapy, then every 6 months until progression or until 3 years from study entry
Secondary outcomes:
measure: 24-months Overall Survival
timeFrame: assessed within 14 days after delivery of the third cycle of induction therapy, and 8 weeks and 6 months after completion of concurrent therapy, then every 6 months until progression or until 3 years from study entry
measure: Primary Clinical Response Rate
timeFrame: assessed within 14 days after delivery of the third cycle of induction therapy
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: UAB Comprehensive Cancer Center
state: Alabama
city: Greenbrae
country: United States
facility: California Cancer Care, Incorporated - Greenbrae
state: California
city: Palo Alto
country: United States
facility: Veterans Affairs Medical Center - Palo Alto
state: California
city: Stanford
country: United States
facility: Stanford Cancer Center
state: California
city: Aurora
country: United States
facility: Aurora Presbyterian Hospital
state: Colorado
city: Boulder
country: United States
facility: Boulder Community Hospital
state: Colorado
city: Colorado Springs
country: United States
facility: Penrose Cancer Center at Penrose Hospital
state: Colorado
city: Denver
country: United States
facility: St. Anthony Central Hospital
state: Colorado
city: Denver
country: United States
facility: Porter Adventist Hospital
state: Colorado
city: Denver
country: United States
facility: Presbyterian - St. Luke's Medical Center
state: Colorado
city: Denver
country: United States
facility: St. Joseph Hospital
state: Colorado
city: Denver
country: United States
facility: Rose Medical Center
state: Colorado
city: Denver
country: United States
facility: CCOP - Colorado Cancer Research Program
state: Colorado
city: Englewood
country: United States
facility: Swedish Medical Center
state: Colorado
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Fort Collins
country: United States
facility: Front Range Cancer Specialists
state: Colorado
city: Grand Junction
country: United States
facility: St. Mary's Regional Cancer Center at St. Mary's Hospital and Medical Center
state: Colorado
city: Greeley
country: United States
facility: North Colorado Medical Center
state: Colorado
city: Lone Tree
country: United States
facility: Sky Ridge Medical Center
state: Colorado
city: Longmont
country: United States
facility: Hope Cancer Care Center at Longmont United Hospital
state: Colorado
city: Loveland
country: United States
facility: McKee Medical Center
state: Colorado
city: Pueblo
country: United States
facility: St. Mary - Corwin Regional Medical Center
state: Colorado
city: Thornton
country: United States
facility: North Suburban Medical Center
state: Colorado
city: Wheat Ridge
country: United States
facility: Exempla Lutheran Medical Center
state: Colorado
city: New Britain
country: United States
facility: George Bray Cancer Center at the Hospital of Central Connecticut - New Britain Campus
state: Connecticut
city: Lewes
country: United States
facility: Tunnell Cancer Center at Beebe Medical Center
state: Delaware
city: Newark
country: United States
facility: CCOP - Christiana Care Health Services
state: Delaware
city: Evanston
country: United States
facility: Evanston Hospital
state: Illinois
city: Clive
country: United States
facility: Medical Oncology and Hematology Associates - West Des Moines
state: Iowa
city: Des Moines
country: United States
facility: CCOP - Iowa Oncology Research Association
state: Iowa
city: Des Moines
country: United States
facility: John Stoddard Cancer Center at Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates at John Stoddard Cancer Center
state: Iowa
city: Des Moines
country: United States
facility: Medical Oncology and Hematology Associates at Mercy Cancer Center
state: Iowa
city: Des Moines
country: United States
facility: Mercy Cancer Center at Mercy Medical Center - Des Moines
state: Iowa
city: Des Moines
country: United States
facility: John Stoddard Cancer Center at Iowa Lutheran Hospital
state: Iowa
city: Sioux City
country: United States
facility: Siouxland Hematology-Oncology Associates, LLP
state: Iowa
city: Sioux City
country: United States
facility: Mercy Medical Center - Sioux City
state: Iowa
city: Sioux City
country: United States
facility: St. Luke's Regional Medical Center
state: Iowa
city: Chanute
country: United States
facility: Cancer Center of Kansas, PA - Chanute
state: Kansas
city: Dodge City
country: United States
facility: Cancer Center of Kansas, PA - Dodge City
state: Kansas
city: El Dorado
country: United States
facility: Cancer Center of Kansas, PA - El Dorado
state: Kansas
city: Kingman
country: United States
facility: Cancer Center of Kansas, PA - Kingman
state: Kansas
city: Lawrence
country: United States
facility: Lawrence Memorial Hospital
state: Kansas
city: Liberal
country: United States
facility: Cancer Center of Kansas, PA - Liberal
state: Kansas
city: Newton
country: United States
facility: Cancer Center of Kansas, PA - Newton
state: Kansas
city: Parsons
country: United States
facility: Cancer Center of Kansas, PA - Parsons
state: Kansas
city: Pratt
country: United States
facility: Cancer Center of Kansas, PA - Pratt
state: Kansas
city: Salina
country: United States
facility: Cancer Center of Kansas, PA - Salina
state: Kansas
city: Wellington
country: United States
facility: Cancer Center of Kansas, PA - Wellington
state: Kansas
city: Wichita
country: United States
facility: Associates in Womens Health, PA - North Review
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, PA - Medical Arts Tower
state: Kansas
city: Wichita
country: United States
facility: Cancer Center of Kansas, PA - Wichita
state: Kansas
city: Wichita
country: United States
facility: CCOP - Wichita
state: Kansas
city: Wichita
country: United States
facility: Via Christi Cancer Center at Via Christi Regional Medical Center
state: Kansas
city: Winfield
country: United States
facility: Cancer Center of Kansas, PA - Winfield
state: Kansas
city: Baton Rouge
country: United States
facility: Mary Bird Perkins Cancer Center - Baton Rouge
state: Louisiana
city: New Orleans
country: United States
facility: MBCCOP - LSU Health Sciences Center
state: Louisiana
city: New Orleans
country: United States
facility: Medical Center of Louisiana - New Orleans
state: Louisiana
city: Baltimore
country: United States
facility: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
state: Maryland
city: Elkton
country: United States
facility: Union Hospital of Cecil County
state: Maryland
city: Adrian
country: United States
facility: Hickman Cancer Center at Bixby Medical Center
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: Monroe
country: United States
facility: Community Cancer Center of Monroe
state: Michigan
city: Monroe
country: United States
facility: Mercy Memorial Hospital - Monroe
state: Michigan
city: Burnsville
country: United States
facility: Fairview Ridges Hospital
state: Minnesota
city: Coon Rapids
country: United States
facility: Mercy and Unity Cancer Center at Mercy Hospital
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Fergus Falls
country: United States
facility: Fergus Falls Medical Group, PA
state: Minnesota
city: Fridley
country: United States
facility: Mercy and Unity Cancer Center at Unity Hospital
state: Minnesota
city: Hutchinson
country: United States
facility: Hutchinson Area Health Care
state: Minnesota
city: Maplewood
country: United States
facility: HealthEast Cancer Care at St. John's Hospital
state: Minnesota
city: Maplewood
country: United States
facility: Minnesota Oncology Hematology, PA - Maplewood
state: Minnesota
city: Minneapolis
country: United States
facility: Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Hennepin County Medical Center - Minneapolis
state: Minnesota
city: Robbinsdale
country: United States
facility: Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
state: Minnesota
city: Saint Louis Park
country: United States
facility: CCOP - Metro-Minnesota
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Cancer Center
state: Minnesota
city: Saint Paul
country: United States
facility: Regions Hospital Cancer Care Center
state: Minnesota
city: Saint Paul
country: United States
facility: United Hospital
state: Minnesota
city: Shakopee
country: United States
facility: St. Francis Cancer Center at St. Francis Medical Center
state: Minnesota
city: Waconia
country: United States
facility: Ridgeview Medical Center
state: Minnesota
city: Willmar
country: United States
facility: Willmar Cancer Center at Rice Memorial Hospital
state: Minnesota
city: Woodbury
country: United States
facility: Minnesota Oncology Hematology, PA - Woodbury
state: Minnesota
city: Voorhees
country: United States
facility: Cancer Institute of New Jersey at Cooper - Voorhees
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Stony Brook
country: United States
facility: Stony Brook University Cancer Center
state: New York
city: Fargo
country: United States
facility: CCOP - MeritCare Hospital
state: North Dakota
city: Bowling Green
country: United States
facility: Wood County Oncology Center
state: Ohio
city: Clyde
country: United States
facility: North Coast Cancer Care - Clyde
state: Ohio
city: Elyria
country: United States
facility: Community Cancer Center
state: Ohio
city: Elyria
country: United States
facility: Hematology Oncology Center
state: Ohio
city: Lima
country: United States
facility: Lima Memorial Hospital
state: Ohio
city: Maumee
country: United States
facility: Northwest Ohio Oncology Center
state: Ohio
city: Norwalk
country: United States
facility: Fisher-Titus Medical Center
state: Ohio
city: Oregon
country: United States
facility: St. Charles Mercy Hospital
state: Ohio
city: Oregon
country: United States
facility: Toledo Clinic - Oregon
state: Ohio
city: Sandusky
country: United States
facility: North Coast Cancer Care, Incorporated
state: Ohio
city: Sylvania
country: United States
facility: Flower Hospital Cancer Center
state: Ohio
city: Tiffin
country: United States
facility: Mercy Hospital of Tiffin
state: Ohio
city: Toledo
country: United States
facility: Toledo Hospital
state: Ohio
city: Toledo
country: United States
facility: St. Vincent Mercy Medical Center
state: Ohio
city: Toledo
country: United States
facility: Medical University of Ohio Cancer Center
state: Ohio
city: Toledo
country: United States
facility: CCOP - Toledo Community Hospital
state: Ohio
city: Toledo
country: United States
facility: St. Anne Mercy Hospital
state: Ohio
city: Toledo
country: United States
facility: Toledo Clinic, Incorporated - Main Clinic
state: Ohio
city: Wauseon
country: United States
facility: Fulton County Health Center
state: Ohio
city: Tulsa
country: United States
facility: Natalie Warren Bryant Cancer Center at St. Francis Hospital
state: Oklahoma
city: Butler
country: United States
facility: Butler Memorial Hospital
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center - Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: UPMC Cancer Centers
state: Pennsylvania
city: Franklin
country: United States
facility: Vanderbilt-Ingram Cancer Center - Cool Springs
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt-Ingram Cancer Center
state: Tennessee
city: Fredericksburg
country: United States
facility: Fredericksburg Oncology, Incorporated
state: Virginia
city: Green Bay
country: United States
facility: St. Vincent Hospital Regional Cancer Center
state: Wisconsin
city: Manitowoc
country: United States
facility: Holy Family Memorial Medical Center Cancer Care Center
state: Wisconsin
city: Marinette
country: United States
facility: Bay Area Cancer Care Center at Bay Area Medical Center
state: Wisconsin
city: Oconomowoc
country: United States
facility: Regional Cancer Center at Oconomowoc Memorial Hospital
state: Wisconsin
city: Sheboygan
country: United States
facility: St. Nicholas Hospital
state: Wisconsin
city: Waukesha
country: United States
facility: Waukesha Memorial Hospital Regional Cancer Center
state: Wisconsin
Study officials:
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
name: Shanthi Marur, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Marur S, Li S, Cmelak AJ, Gillison ML, Zhao WJ, Ferris RL, Westra WH, Gilbert J, Bauman JE, Wagner LI, Trevarthen DR, Balkrishna J, Murphy BA, Agrawal N, Colevas AD, Chung CH, Burtness B. E1308: Phase II Trial of Induction Chemotherapy Followed by Reduced-Dose Radiation and Weekly Cetuximab in Patients With HPV-Associated Resectable Squamous Cell Carcinoma of the Oropharynx- ECOG-ACRIN Cancer Research Group. J Clin Oncol. 2017 Feb 10;35(5):490-497. doi: 10.1200/JCO.2016.68.3300. Epub 2016 Dec 28.
citation: Psyrri A, Rampias T, Vermorken JB. The current and future impact of human papillomavirus on treatment of squamous cell carcinoma of the head and neck. Ann Oncol. 2014 Nov;25(11):2101-2115. doi: 10.1093/annonc/mdu265. Epub 2014 Jul 23.