TRYHARD: Radiation Therapy Plus Cisplatin With or Without Lapatinib in Treating Patients With Head and Neck Cancer. (TRYHARD)

• ClinicalTrials.gov Identifier: NCT01711658
• Recruitment Status: Completed
• First Posted: October 22, 2012
• Results First Posted: November 29, 2021
• Last Update Posted: October 17, 2023
• Sponsor: Radiation Therapy Oncology Group
• Collaborators: GlaxoSmithKline; Novartis
• Information provided by (Responsible Party): Radiation Therapy Oncology Group

Study Description

Brief Summary:

PURPOSE: This trial is studying if and how well lapatinib adds to the effectiveness of radiation therapy plus cisplatin in patients who have head and neck cancer that is not related to the human papillomavirus (HPV).

Condition or disease	Intervention/treatment	Phase
Non-HPV Locally Advanced Head and Neck Cancer	Radiation: IMRT; Drug: Cisplatin; Drug: placebo; Drug: Lapatinib	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 142 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: TRYHARD: A Phase II, Randomized, Double Blind, Placebo-Controlled Study of Lapatinib (Tykerb®) for Non-HPV Locally Advanced Head and Neck Cancer With Concurrent Chemoradiation
• Actual Study Start Date: March 15, 2013
• Actual Primary Completion Date: December 1, 2020
• Actual Study Completion Date: September 21, 2022

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: IMRT + cisplatin + placebo; Intensity Modulated Radiation Therapy (IMRT) with cisplatin and placebo	Radiation: IMRT; Intensity modulated radiation therapy (IMRT), 35 fractions over 6 weeks, 6 fractions per week for 5 weeks and 5 fractions per week for 1 week, 2 Gy per fraction to total dose of 70 Gy; Drug: Cisplatin; 100 mg/m^2 administered intravenously on days 8 and 29; Drug: placebo; 1500 mg placebo daily by mouth or by feeding tube starting 7 days before IMRT for 7 weeks prior to and during IMRT and 3 months after completion of IMRT
Active Comparator: IMRT + cisplatin + lapatinib; IMRT with cisplatin and lapatinib	Radiation: IMRT; Intensity modulated radiation therapy (IMRT), 35 fractions over 6 weeks, 6 fractions per week for 5 weeks and 5 fractions per week for 1 week, 2 Gy per fraction to total dose of 70 Gy; Drug: Cisplatin; 100 mg/m^2 administered intravenously on days 8 and 29; Drug: Lapatinib; 1500 mg lapatinib by mouth or by feeding tube daily starting 7 days before IMRT for 7 weeks prior to and during IMRT and 3 months after completion of IMRT

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants Alive Without Progression (Progression-free Survival) [ Time Frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years. ]
   An event for progression-free survival is local, regional, or distant disease progression or death due to any cause. Progression-free survival time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of survival times be compared between the arms, which is reported in the statistical analysis results. Five-year rates are provided. Analysis occurred after 67 progressions or deaths were reported.

Secondary Outcome Measures :

1. Percentage of Participants Alive (Overall Survival) [ Time Frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years. ]
   An event for overall survival is death due to any cause. Overall survival time is defined as time from randomization to the date of death or last known follow-up (censored). Rates are estimated by the Kaplan-Meier method. The protocol specifies that the distributions of survival times be compared between the arms, which is reported in the statistical analysis results. Five-year rates are provided.
2. Percentage of Participants With Distant Metastases [ Time Frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years. ]
   Failure for distant metastasis endpoint was defined as distant progression; local-regional failure and death due to any cause were considered competing risks. Distant metastasis time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Rates are estimated by the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Five-year rates are provided.
3. Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events [ Time Frame: From start of treatment to last follow-up. Maximum follow-up at time of analysis was 7.1 years. ]
   Adverse events (AE) were graded using the Common Terminology Criteria for Adverse Events (CTCAE) v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild, Grade 2 Moderate, Grade 3 Severe, Grade 4 Life-threatening or disabling, Grade 5 Death related to adverse event. "Treatment-related" is defined definitely, probably, or possibly related to treatment.
4. Percentage of Participants Who Complied With Protocol Treatment [ Time Frame: From start of treatment to end of treatment (approximately 5 months from randomization). ]
   Compliance with protocol treatment is defined as "per protocol" or "acceptable variation" per study chair review for IMRT, cisplatin, pre-IMRT lapatinib/placebo, concurrent lapatinib/placebo, and maintenance lapatinib/placebo. Rates of treatment compliance were compared between groups by a 2-sided Fisher's exact test.
5. Percentage of Participants With Local-regional Progression [ Time Frame: From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years. ]
   Failure for local-regional control endpoint was defined as local or regional progression, salvage surgery of the primary tumor with tumor present/unknown, salvage neck dissection with tumor present/unknown > 20 weeks after the end of radiation therapy, death due to study cancer without documented progression, or death due to unknown causes without documented progression; distant metastasis and death due to other causes were considered competing risks. Local-regional failure time is defined as time from randomization to the date of progression/death or last known follow-up (censored). Failure rates are estimated by the cumulative incidence method. The protocol specifies that the distributions of failure times be compared between the arms, which is reported in the statistical analysis results. Five-year rates are provided.
6. Performance Status Scale for Head & Neck Cancer. [ Time Frame: 3 months, 1 year, and 2 years ]
7. Functional Assessment of Cancer Therapy - Head & Neck. [ Time Frame: 3 months, 1 year, and 2 years. ]
8. University of Michigan Xerostomia-Related Quality of Life Scale. [ Time Frame: 3 months, 1 year, and 2 years. ]
9. HER2, EGFR, EMT as Biomarkers of Response. [ Time Frame: End of Study ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion criteria:

• Patients must have histologically or cytologically confirmed diagnosis (from primary lesion and/or lymph nodes) of Squamous Cell Cancer of the oropharynx, hypopharynx or larynx (For patients with oropharynx primary, the tumor must be negative for p16 by immunohistochemistry).
• Patients with selected Stage III or IV disease (T2 N2-3 M0, T3-4 any N M0, T1 N2b, N2c or N3 p16 negative oropharynx cancer or T1-2 any N+ hypopharynx cancer) including no distant metastases.
• History/Physical examination by a Radiation Oncologist and Medical oncologist prior to entering the study.
• Examination by an ears, nose, throat (ENT) or Head & Neck Surgeon including laryngopharyngoscopy prior to entering the study.
• Patients must have a chest CT scan, or positron emission tomography (PET)/CT scan to rule out metastatic disease
• Patients must have a contrast enhanced CT scan or MRI or PET/CT scan of the tumor site and neck nodes prior to entering the study.
• Patients must have an EKG and echocardiogram (ECHO) or multigated acquisition (MUGA) scan prior to entering the study.
• Patients must have Zubrod Performance Status of 0-1.
• Patients must be ≥ 18 years of age.

• Patients must have normal organ and marrow function as defined below:

  • Absolute neutrophil count (ANC) ≥ 1,500 cells/mm3
  • Platelets ≥ 100,000 cells/mm3
  • Hemoglobin ≥ 8.0 g/dl
  • Serum creatinine < 1.5 mg/dl or creatinine clearance (CC) ≥ 50 ml/min
  • Total bilirubin < 2 x the institutional upper limit of normal
  • Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤ 3 x the institutional upper limit of normal
• Patient must have magnesium, calcium, glucose, potassium and sodium levels within normal limits
• Women of childbearing potential must have a negative pregnancy test prior to registration.
• Patients of reproductive potential must practice effective contraception while on study and for at least 60 calendar days following treatment.
• All patients must sign an informed consent prior to enrollment.
• Patients must comply with the treatment plan and follow-up schedule.

Exclusion criteria:

• Patients with simultaneous primaries or bilateral tumors.
• Patients who have had gross total excision of the primary tumor.
• Patients with initial surgical treatment, radical or modified neck dissection.
• Patients who received prior systemic chemotherapy for the study cancer.
• Patients who received prior radiotherapy to the region of the study cancer that would result in overlap of radiation therapy fields.
• Patients with primary tumor of oral cavity, nasopharynx, sinuses or salivary glands.
• Prior allergic reaction to the study drugs.
• Patients who have had prior therapy that specifically and directly targets the epidermal growth factor receptor (EGFR)/human epidermal growth factor receptor 2 (HER2) pathway.
• Patients who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment);
• Pregnant women or sexually active patients not willing or able to use medically acceptable forms of contraceptive method while on treatment.

• Patients with severe, active co-morbidity, defined as follows:

  • Uncontrolled cardiac disease, such as uncontrolled hypertension, unstable angina, and/or congestive heart failure requiring hospitalization within the last 6 months
  • Transmural myocardial infarction within the last 6 months
  • Left ventricular ejection fraction < 45%
  • Acute bacterial or fungal infection requiring intravenous antibiotics at the time of registration
  • Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy within 30 calendar days prior to registration
  • Hepatic insufficiency resulting in clinical jaundice and/or Coagulation defects
  • Acquired Immune Deficiency Syndrome (AIDS) based upon current Centers for Disease Control and Prevention (CDC) definition

Contacts and Locations

Locations

United States, Alabama

University of Alabama at Birmingham Comprehensive Cancer Center

Birmingham, Alabama, United States, 35294

United States, California

University of California, San Diego

La Jolla, California, United States, 92093

Sutter General Hospital

Sacramento, California, United States, 95816

University of California San Francisco

San Francisco, California, United States, 94143

United States, Connecticut

Yale University

New Haven, Connecticut, United States, 06520

United States, Georgia

Emory University

Atlanta, Georgia, United States, 30308

United States, Kentucky

James Graham Brown Cancer Center at University of Louisville

Louisville, Kentucky, United States, 40202

United States, Ohio

University Hospitals of Cleveland

Cleveland, Ohio, United States, 44106

Ohio State University Medical Center

Columbus, Ohio, United States, 43210

United States, Oklahoma

University of Oklahoma Health Sciences Center

Oklahoma City, Oklahoma, United States, 73190

United States, Pennsylvania

Fox Chase Cancer Center Buckingham

Furlong, Pennsylvania, United States, 18925

United States, Texas

University of Texas Southwestern Medical School

Dallas, Texas, United States, 75390

University of Texas - MD Anderson Cancer Center

Houston, Texas, United States, 77030-4009

United States, Wisconsin

University of Wisconsin Comprehensive Cancer Center

Madison, Wisconsin, United States, 53792

Medical College of Wisconsin

Milwaukee, Wisconsin, United States, 53226

Canada, Quebec

McGill Cancer Centre at McGill University

Montreal, Quebec, Canada, H2W 1S6

Sponsors and Collaborators

Radiation Therapy Oncology Group

GlaxoSmithKline

Novartis

Investigators

• Principal Investigator: Stuart Wong, MD; Medical College of Wisconsin

  Study Documents (Full-Text)

Documents provided by Radiation Therapy Oncology Group:

Study Protocol and Statistical Analysis Plan  [PDF] September 27, 2016

Informed Consent Form  [PDF] September 27, 2016

More Information

Publications:

Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tan PF, Westra WH, Chung CH, Jordan RC, Lu C, Kim H, Axelrod R, Silverman CC, Redmond KP, Gillison ML. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010 Jul 1;363(1):24-35. doi: 10.1056/NEJMoa0912217. Epub 2010 Jun 7.

Harrington K. et al. Phase II study of oral Lapatinib, a dual-tyrosine kinase inhibitor, combined with chemoradiotherapy (CRT) in patients with advanced squamous cell carcinoma of the head and neck (SCCHN). J Clin Oncol. 28:15s, 2010 suppl. Abstract 5505. GSK study 884

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01711658
• Other Study ID Numbers: RF-3501; LAP116153 ( Other Identifier: GlaxoSmith Kline, LLC )
• First Posted: October 22, 2012
• Results First Posted: November 29, 2021
• Last Update Posted: October 17, 2023
• Last Verified: October 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Head and Neck Neoplasms; Neoplasms by Site; Neoplasms; Lapatinib; Antineoplastic Agents; Tyrosine Kinase Inhibitors; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action