Transoral Surgery Followed by Low-Dose or Standard-Dose Radiation Therapy with or without Chemotherapy in Treating Patients with HPV Positive Stage III-IVA Oropharyngeal Cancer

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 and overE3311
NCI-2013-00814, ECOG-E3311, NCT01898494

Trial Description

Summary

This randomized phase II trial studies how well transoral surgery followed by low-dose or standard-dose radiation therapy works in treating patients with human papilloma virus (HPV) positive stage III-IVA oropharyngeal cancer. Radiation therapy uses high-energy x-rays to kill tumor cells. Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving radiation therapy with chemotherapy may kill any tumor cells that remain after surgery. It is not yet known how much extra treatment needs to be given after surgery.

Further Study Information

PRIMARY OBJECTIVES:

I. Accrual, risk distribution, and surgical quality will be used to determine the feasibility of a prospective multi-institutional study of transoral surgery for HPV positive (+) oropharynx cancer followed by risk-adjusted adjuvant therapy.

II. To assess the oncologic efficacy following transoral resection and adjuvant therapy in patients determined to be at “intermediate risk” after surgical excision, the 2-year progression free survival (PFS) rate will be examined.

SECONDARY OBJECTIVES:

I. To estimate the patient distribution with various histologic risk features.

II. To assess and compare early and late toxicities associated with transoral surgery (TOS) and the different doses of adjuvant postoperative radiotherapy (PORT).

III. To evaluate swallowing function before and after TOS and risk-adjusted adjuvant therapy.

IV. To evaluate quality of life (QOL), swallowing perception and performance, voice outcomes, and head and neck symptoms.

TERTIARY OBJECTIVES:

I. To correlate tumor protein 53 (TP53) mutation and other associated mutation profile with pathologic findings, with PFS and other outcome parameters in patients with resectable HPV-associated oropharyngeal squamous cell carcinoma (OPSCC) after the above treatments.

II. To evaluate radiation resistance markers, including excision repair cross complementing 1 (ERCC1) single nucleotide polymorphism and protein expression, and correlate them with treatment efficacy.

III. To investigate the usefulness of biomarkers in predicting progression-free survival and biomarkers, including tumor ERCC1, epidermal growth factor receptor (EGFR), plasma cytokine/chemokines, cellular immunity to HPV, and oral HPV deoxyribonucleic acid (DNA).

OUTLINE: Patients are classified by risk status (low risk, intermediate risk, or high risk) and assigned to the appropriate treatment group. Patients classified as intermediate risk are randomized to 1 or 2 treatment arms.

ARM A (low risk): Patients undergo transoral surgical resection of the oropharyngeal tumor.

ARM B (intermediate risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo low-dose intensity modulated radiation therapy (IMRT) once daily (QD) five days a week for 5 weeks.

ARM C (intermediate or unknown risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6 weeks.

ARM D (high risk): Patients undergo transoral surgical resection of the oropharyngeal tumor. Patients then undergo standard-dose IMRT QD five days a week for 6-7 weeks. Patients also receive cisplatin intravenously (IV) over 60 minutes or carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43 during radiation therapy.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 1 year, and then every 12 months for 2 years.

Eligibility Criteria

Inclusion Criteria:

Patient must be registered/randomized to Step 2 within 5-7 weeks following surgery

Women of childbearing potential and sexually active males are strongly advised to use an accepted and effective method of contraception

Patient must be stratified/classified into one of the following risk categories:

The highest risk feature assessed pathologically will determine the patient's category/treatment arm assignment

  • Low risk: T1-T2, N0-N1 AND clear (> 3 mm) margins, AND no extra-capsular extension (ECE) or peri-neural invasion (PNI)/lympho-vascular invasion (LVI)
  • High risk: any of the following features: one or more positive margin(s) with any T stage, OR “extensive” (> 1 mm) ECE, OR >= 5 metastatic lymph nodes (regardless of primary tumor margin status)

Intermediate risk: any of the following features: one or more “close” (< 3 mm) margin(s), OR “minimal” (=< 1 mm) ECE, OR 2-4 metastatic lymph nodes (regardless of primary tumor margin status), OR with perineural invasion or lymphovascular invasion

  • Unknown risk: patients found to have N2C or N3 disease on final pathologic analysis are at unknown risk for recurrence, but are not candidates for deintensified adjuvant therapy in this trial; these patients will be treated on Arm C

Histopathologic assessment of surgical pathology must include examination for perineural invasion (PNI) and lymphovascular invasion (LVI) and reported as absent or present; the absence or presence of extracapsular extension (ECE) requires gross and microscopic assessment and is defined to be:

Absent (negative or nodal metastasis with smooth/rounded leading edge confined to thickened capsule/pseudocapsule),

Present - minimal (tumor extends =< 1 mm beyond the lymph node capsule), or

Present - extensive (gross, tumor extends > 1 mm beyond the lymph node capsule [includes soft tissue metastasis])

REGISTRATION/RANDOMIZATION TO STEP 2 - ARMS A, B, C AND D

Patients must not have uncontrolled diabetes, uncontrolled infection despite antibiotics or uncontrolled hypertension within 30 days prior to pre-registration

Patient must not have an intercurrent illness likely to interfere with protocol therapy or prevent surgical resection

Women must not be pregnant or breast-feeding; all females of childbearing potential must have a blood test or urine study within 2 weeks prior to registration to rule out pregnancy; a female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months)

Calculated creatinine clearance must be > 60 ml/min using the Cockcroft-Gault formula

Total bilirubin =< the upper limit of normal (ULN)

Absolute neutrophil count >= 1,500/mm^3

Patients must not have evidence of extensive or “matted/fixed” pathologic adenopathy on preoperative imaging

Patients with the following within the last 6 months prior to pre-registration must be evaluated by a cardiologist and/or neurologist prior to entry into the study

Patients with a history of a curatively treated malignancy must be disease-free for at least two years except for carcinoma in situ of cervix and/or non-melanomatous skin cancer

No prior radiation above the clavicles

Carcinoma of the oropharynx associated with HPV as determined by p16 protein expression using immunohistochemistry (IHC) performed by a Clinical Laboratory Improvement Amendments (CLIA) approved laboratory; using p16 antibody obtained from Roche mtm laboratories AG (CINtec, clone E6H4) is recommended

Patients must have biopsy-proven cyclin-dependent kinase inhibitor 2A (p16)+ oropharynx cancer; the histologic evidence of invasive squamous cell carcinoma may have been obtained from the primary tumor or metastatic lymph node; it is required that patients have a positive p16 immunohistochemistry (IHC) (as surrogate for HPV) status from either the primary tumor or metastatic lymph node

Patients must have American Joint Committee on Cancer (AJCC) TNM tumor stage III, IV a, or IV b (with no evidence of distant metastases) as determined by imaging studies (performed < 30 days prior to pre-registration) and complete neck exam from the skull base to the clavicles; the following imaging is required: computed tomography (CT) scan with IV contrast or magnetic resonance imaging (MRI); the primary tumor should be cT1 or T2 and cervical nodes cN1, N2a, or N2b based on clinical or radiographic criteria

Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

Platelets >= 100,000/mm^3

Patients must have newly diagnosed, histologically or cytologically confirmed squamous cell carcinoma or undifferentiated carcinoma of the oropharynx; patients must have been determined to have resectable oropharyngeal disease; patients with primary tumor or nodal metastasis fixed to the carotid artery, skull base or cervical spine are not eligible

Patients must register to Step 1 prior to surgery

REGISTRATION TO SURGERY (ARM S)

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

ECOG-ACRIN Cancer Research Group

  • National Cancer Institute
Robert Louis Ferris, Principal Investigator

Trial Sites

U.S.A.

Alabama
Birmingham

University of Alabama at Birmingham Cancer Center

Sharon A. Spencer
Ph: 205-934-0309

Sharon A. Spencer
Principal Investigator

Arizona
Scottsdale

Mayo Clinic in Arizona

Michael L. Hinni
Ph: 507-538-7623

Michael L. Hinni
Principal Investigator

Arkansas
Little Rock

University of Arkansas for Medical Sciences

Rangaswamy Govindarajan
Ph: 501-686-8274

Rangaswamy Govindarajan
Principal Investigator

California
Oakland

Kaiser Permanente Oakland-Broadway

Samantha Andrews Seaward
Ph: 626-564-3455

Samantha Andrews Seaward
Principal Investigator

Palo Alto

Stanford Cancer Institute

Floyd Christopher Holsinger
Ph: 650-498-7061
Email: ccto-office@stanford.edu

Floyd Christopher Holsinger
Principal Investigator

Colorado
Boulder

Rocky Mountain Cancer Centers-Boulder

Keren Sturtz
Ph: 888-785-6789

Keren Sturtz
Principal Investigator

Colorado Springs

Penrose-Saint Francis Healthcare

Keren Sturtz
Ph: 888-785-6789

Keren Sturtz
Principal Investigator

Rocky Mountain Cancer Centers-Penrose

Keren Sturtz
Ph: 888-785-6789

Keren Sturtz
Principal Investigator

Denver

Porter Adventist Hospital

Keren Sturtz
Ph: 888-785-6789

Keren Sturtz
Principal Investigator

Connecticut
New Haven

Yale University

Benjamin L. Judson
Ph: 203-785-5702

Benjamin L. Judson
Principal Investigator

Florida
Deerfield Beach

University of Miami Sylvester Comprehensive Cancer Center at Deerfield Beach

Giovana R. Thomas
Ph: 866-574-5124
Email: Sylvester@emergingmed.com

Giovana R. Thomas
Principal Investigator

Miami

University of Miami Miller School of Medicine-Sylvester Cancer Center

Giovana R. Thomas
Ph: 866-574-5124
Email: Sylvester@emergingmed.com

Giovana R. Thomas
Principal Investigator

Orlando

Florida Hospital Orlando

Lee M. Zehngebot
Ph: 407-303-5623

Lee M. Zehngebot
Principal Investigator

Georgia
Atlanta

Emory University Hospital Midtown

Nabil F. Saba
Ph: 404-778-1868

Nabil F. Saba
Principal Investigator

Emory University/Winship Cancer Institute

Nabil F. Saba
Ph: 404-778-1868

Nabil F. Saba
Principal Investigator

Iowa
Iowa City

University of Iowa/Holden Comprehensive Cancer Center

Daniel Alberto Vaena
Ph: 800-237-1225

Daniel Alberto Vaena
Principal Investigator

Kansas
Kansas City

University of Kansas Cancer Center

Yelizaveta Shnayder
Ph: 913-945-7552
Email: ctnursenav@kumc.edu

Yelizaveta Shnayder
Principal Investigator

Kentucky
Lexington

University of Kentucky/Markey Cancer Center

Thomas J. Gal
Ph: 859-257-3379

Thomas J. Gal
Principal Investigator

Maryland
Baltimore

Greater Baltimore Medical Center

Marshall A. Levine
Ph: 443-849-3706

Marshall A. Levine
Principal Investigator

Johns Hopkins University/Sidney Kimmel Cancer Center

Jeremy David Richmon
Ph: 410-955-8804
Email: jhcccro@jhmi.edu

Jeremy David Richmon
Principal Investigator

Massachusetts
Boston

Boston Medical Center

Scharukh Jalisi
Ph: 617-638-8265

Scharukh Jalisi
Principal Investigator

Brigham and Women's Hospital

Tom Thomas
Ph: 617-724-5200

Tom Thomas
Principal Investigator

Dana-Farber Cancer Institute

Tom Thomas
Ph: 617-724-5200

Tom Thomas
Principal Investigator

Michigan
Detroit

Henry Ford Hospital

Robert Anthony Chapman
Ph: 313-916-1784

Robert Anthony Chapman
Principal Investigator

Missouri
Springfield

Mercy Hospital Springfield

Jay W. Carlson
Ph: 800-821-7532

Jay W. Carlson
Principal Investigator

Nebraska
Omaha

Nebraska Methodist Hospital

Russell B. Smith
Ph: 402-354-5144

Russell B. Smith
Principal Investigator

University of Nebraska Medical Center

Apar Kishor Ganti
Ph: 402-559-6941
Email: unmcrsa@unmc.edu

Apar Kishor Ganti
Principal Investigator

New Mexico
Albuquerque

University of New Mexico

Andrew T. Cowan
Ph: 505-272-6972

Andrew T. Cowan
Principal Investigator

New York
Bronx

Montefiore Medical Center - Moses Campus

Missak Haigentz
Ph: 718-904-2730
Email: aecc@aecom.yu.edu

Missak Haigentz
Principal Investigator

New York

Memorial Sloan-Kettering Cancer Center

Luc G.T. Morris
Ph: 212-639-7202

Luc G.T. Morris
Principal Investigator

North Carolina
Durham

Duke University Medical Center

Walter Tsong Lee
Ph: 888-275-3853

Walter Tsong Lee
Principal Investigator

Ohio
Cleveland

Case Western Reserve University

David J. Adelstein
Ph: 866-223-8100

David J. Adelstein
Principal Investigator

Cleveland Clinic Foundation

David J. Adelstein
Ph: 866-223-8100

David J. Adelstein
Principal Investigator

Columbus

Ohio State University Comprehensive Cancer Center

Enver Ozer
Ph: 800-293-5066
Email: Jamesline@osumc.edu

Enver Ozer
Principal Investigator

Oregon
Portland

Oregon Health and Science University

Peter E. Andersen
Ph: 503-494-1080
Email: trials@ohsu.edu

Peter E. Andersen
Principal Investigator

Providence Portland Medical Center

Alison Katherine Conlin
Ph: 503-215-6412

Alison Katherine Conlin
Principal Investigator

Pennsylvania
Harrisburg

PinnacleHealth Cancer Center-Community Campus

Brij M. Sood
Ph: 717-724-6765
Email: klitchfield@PINNACLEHEALTH.org

Brij M. Sood
Principal Investigator

Philadelphia

Fox Chase Cancer Center

Miriam N. Lango
Ph: 215-728-4790

Miriam N. Lango
Principal Investigator

Thomas Jefferson University Hospital

David Michael Cognetti
Ph: 215-955-6084

David Michael Cognetti
Principal Investigator

University of Pennsylvania/Abramson Cancer Center

Gregory S. Weinstein
Ph: 800-474-9892

Gregory S. Weinstein
Principal Investigator

Pittsburgh

University of Pittsburgh Cancer Institute (UPCI)

Robert Louis Ferris
Ph: 412-647-8073

Robert Louis Ferris
Principal Investigator

South Carolina
Charleston

Medical University of South Carolina

Terry A. Day
Ph: 843-792-9321

Terry A. Day
Principal Investigator

Tennessee
Nashville

Vanderbilt University/Ingram Cancer Center

James Lee Netterville
Ph: 800-811-8480

James Lee Netterville
Principal Investigator

Texas
Dallas

UT Southwestern/Simmons Cancer Center-Dallas

Baran Devrim Sumer
Ph: 214-648-7097

Baran Devrim Sumer
Principal Investigator

Houston

M D Anderson Cancer Center

Michael E. Kupferman
Ph: 713-792-3245

Michael E. Kupferman
Principal Investigator

Virginia
Falls Church

Inova Fairfax Hospital

John Frederick Deeken
Ph: 202-444-0381

John Frederick Deeken
Principal Investigator

Hampton

Sentara Cancer Institute at Sentara CarePlex Hospital

Scott S. Williams
Ph: 757-388-2406

Scott S. Williams
Principal Investigator

Norfolk

Sentara Hospitals

Scott S. Williams
Ph: 757-388-2406

Scott S. Williams
Principal Investigator

Virginia Beach

Sentara Virginia Beach General Hospital

Scott S. Williams
Ph: 757-388-2406

Scott S. Williams
Principal Investigator

Washington
Seattle

University of Washington Medical Center

Eduardo Mendez
Ph: 206-616-8289

Eduardo Mendez
Principal Investigator

Wisconsin
Madison

University of Wisconsin Hospital and Clinics

Paul Maurice Harari
Ph: 877-405-6866

Paul Maurice Harari
Principal Investigator

Milwaukee

Froedtert and the Medical College of Wisconsin

Stuart J. Wong
Ph: 414-805-4380

Stuart J. Wong
Principal Investigator

Zablocki Veterans Administration Medical Center

Elizabeth M. Gore
Ph: 414-805-4380

Elizabeth M. Gore
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01898494

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.