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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT01711658
• Collaborator: GlaxoSmithKline (Industry), Novartis (Industry)
• Enrollment: 142
• Locations: 16
• Arms: 2
• Anticipated Duration (Months): 153.6
• Patients Per Site: 8.9
• Patients Per Site Per Month: 0.1

Study Details

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
• 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: Mar 15, 2013
• Actual Primary Completion Date: Dec 1, 2020
• Anticipated Study Completion Date: Jan 1, 2026

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) [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) [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 [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 [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 [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 [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. [3 months, 1 year, and 2 years]

7. Functional Assessment of Cancer Therapy - Head & Neck. [3 months, 1 year, and 2 years.]

8. University of Michigan Xerostomia-Related Quality of Life Scale. [3 months, 1 year, and 2 years.]

9. HER2, EGFR, EMT as Biomarkers of Response. [End of Study]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham Comprehensive Cancer Center	Birmingham	Alabama	United States	35294
2	University of California, San Diego	La Jolla	California	United States	92093
3	Sutter General Hospital	Sacramento	California	United States	95816
4	University of California San Francisco	San Francisco	California	United States	94143
5	Yale University	New Haven	Connecticut	United States	06520
6	Emory University	Atlanta	Georgia	United States	30308
7	James Graham Brown Cancer Center at University of Louisville	Louisville	Kentucky	United States	40202
8	University Hospitals of Cleveland	Cleveland	Ohio	United States	44106
9	Ohio State University Medical Center	Columbus	Ohio	United States	43210
10	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73190
11	Fox Chase Cancer Center Buckingham	Furlong	Pennsylvania	United States	18925
12	University of Texas Southwestern Medical School	Dallas	Texas	United States	75390
13	University of Texas - MD Anderson Cancer Center	Houston	Texas	United States	77030-4009
14	University of Wisconsin Comprehensive Cancer Center	Madison	Wisconsin	United States	53792
15	Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226
16	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)

• Study Protocol and Statistical Analysis Plan - Sep 27, 2016
• Informed Consent Form - Sep 27, 2016

More Information

Publications

• Ang KK, Harris J, Wheeler R, Weber R, Rosenthal DI, Nguyen-Tân 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
• First Posted: Oct 22, 2012
• Last Update Posted: Nov 29, 2021
• Last Verified: Oct 1, 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; Lapatinib

Study Results

Participant Flow

Pre-assignment Detail	After first step registration and prior to randomization, patients with oropharyngeal cancer were tested for p16. Only patients with p16-negative tumors continued to randomization. Patients with larynx or hypopharynx cancer did not require p16 testing. In total, 142 patients were enrolled and 127 were randomized.

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Period Title: Overall Study
STARTED	64	63
Participants Who Started Protocol Treatment	59	60
COMPLETED	64	63
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib	Total
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	Total of all reporting groups
Overall Participants	64	63	127
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	58	57	58
Age, Customized (Count of Participants)
<=65	54 84.4%	56 88.9%	110 86.6%
>65	10 15.6%	7 11.1%	17 13.4%
Sex: Female, Male (Count of Participants)
Female	13 20.3%	16 25.4%	29 22.8%
Male	51 79.7%	47 74.6%	98 77.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 4.7%	1 1.6%	4 3.1%
Not Hispanic or Latino	60 93.8%	61 96.8%	121 95.3%
Unknown or Not Reported	1 1.6%	1 1.6%	2 1.6%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 1.6%	1 1.6%	2 1.6%
Asian	2 3.1%	0 0%	2 1.6%
Native Hawaiian or Other Pacific Islander	2 3.1%	0 0%	2 1.6%
Black or African American	9 14.1%	10 15.9%	19 15%
White	49 76.6%	50 79.4%	99 78%
More than one race	0 0%	1 1.6%	1 0.8%
Unknown or Not Reported	1 1.6%	1 1.6%	2 1.6%
Zubrod performance status (Count of Participants)
0	33 51.6%	27 42.9%	60 47.2%
1	31 48.4%	36 57.1%	67 52.8%
Smoking history: pack-years (pack-years) [Median (Full Range) ]
Median (Full Range) [pack-years]	38	29.5	30
Smoking history: pack-years (Count of Participants)
<=10	13 20.3%	17 27%	30 23.6%
>10	50 78.1%	45 71.4%	95 74.8%
Primary site (Count of Participants)
Oropharynx, p16-negative (central review)	15 23.4%	16 25.4%	31 24.4%
Oropharynx, unknown p16 (central review)	0 0%	1 1.6%	1 0.8%
Hypopharynx	16 25%	7 11.1%	23 18.1%
Larynx	33 51.6%	39 61.9%	72 56.7%
T stage (stratification factor) (Count of Participants)
T1	2 3.1%	0 0%	2 1.6%
T2	9 14.1%	7 11.1%	16 12.6%
T3	35 54.7%	38 60.3%	73 57.5%
T4	18 28.1%	18 28.6%	36 28.3%
N stage (stratification factor) (Count of Participants)
N0	18 28.1%	20 31.7%	38 29.9%
N1	7 10.9%	8 12.7%	15 11.8%
N2a	3 4.7%	2 3.2%	5 3.9%
N2b	19 29.7%	19 30.2%	38 29.9%
N2c	15 23.4%	13 20.6%	28 22%
N3	2 3.1%	1 1.6%	3 2.4%
Overall stage (Count of Participants)
II	1 1.6%	0 0%	1 0.8%
III	18 28.1%	20 31.7%	38 29.9%
IV	45 70.3%	43 68.3%	88 69.3%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Alive Without Progression (Progression-free Survival)
Description	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.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Measure Participants	64	63
Number (95% Confidence Interval) [percentage of participants]	34.6 54.1%	43.1 68.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments	Hazard ratio (lapatinib/placebo) set at 0.65 (35% reduction), 1-sided alpha 0.20 (final test at 0.1803 accounting for 1 interim analysis), logrank test, 80% power, 69 events in 128 randomized (142 total enrolled) patients required. Final analysis at 67 (of 69) events drops power to 79%.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3436
	Comments
	Method	Log Rank
	Comments	One-sided significance level = 0.1803
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.56 to 1.46
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = IMRT + cisplatin + placebo

2. Secondary Outcome

Title	Percentage of Participants Alive (Overall Survival)
Description	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.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Measure Participants	64	63
Number (95% Confidence Interval) [percentage of participants]	55.1 86.1%	49.9 79.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5836
	Comments
	Method	Log Rank
	Comments	One-sided significance level = 0.05
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.61 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = IMRT + cisplatin + placebo

3. Secondary Outcome

Title	Percentage of Participants With Distant Metastases
Description	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.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Measure Participants	64	63
Number (95% Confidence Interval) [percentage of participants]	19.9 31.1%	12.4 19.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1743
	Comments
	Method	Log Rank
	Comments	One-sided significance level = 0.05
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.64
	Confidence Interval	(2-Sided) 95%; 0.25 to 1.65
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = IMRT + cisplatin + placebo

4. Secondary Outcome

Title	Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events
Description	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.
Time Frame	From start of treatment to last follow-up. Maximum follow-up at time of analysis was 7.1 years.

Outcome Measure Data

Analysis Population Description

Participants Who Started Protocol Treatment

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Measure Participants	59	60
Number (95% Confidence Interval) [percentage of participants]	84.7 132.3%	86.7 137.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7989
	Comments
	Method	Fisher Exact
	Comments	Two-sided significance level = 0.05

5. Secondary Outcome

Title	Percentage of Participants Who Complied With Protocol Treatment
Description	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.
Time Frame	From start of treatment to end of treatment (approximately 5 months from randomization).

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Measure Participants	64	63
IMRT	76.6 119.7%	84.1 133.5%
Cisplatin	90.6 141.6%	88.9 141.1%
Pre-IMRT lapatinib/placebo	84.4 131.9%	87.3 138.6%
Concurrent lapatinib/placebo	79.7 124.5%	84.1 133.5%
Maintenance lapatinib/placebo	56.3 88%	49.2 78.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3728
	Comments	IMRT
	Method	Fisher Exact
	Comments	Two-sided significance level = 0.05

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7781
	Comments	Cisplatin
	Method	Fisher Exact
	Comments	Two-sided significance level = 0.05

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.8000
	Comments	Pre-IMRT lapatinib/placebo
	Method	Fisher Exact
	Comments	Two-sided significance level = 0.05

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6459
	Comments	Concurrent lapatinib/placebo
	Method	Fisher Exact
	Comments	Two-sided significance level = 0.05

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4792
	Comments	Maintenance lapatinib/placebo
	Method	Fisher Exact
	Comments	Two-sided significance level = 0.05

6. Secondary Outcome

Title	Percentage of Participants With Local-regional Progression
Description	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.
Time Frame	From randomization to last follow-up. Maximum follow-up at time of analysis was 7.1 years.

Outcome Measure Data

Analysis Population Description

All randomized participants

Arm/Group Title	IMRT + Cisplatin + Placebo	IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
Measure Participants	64	63
Number (95% Confidence Interval) [percentage of participants]	33.7 52.7%	37.7 59.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	IMRT + Cisplatin + Placebo, IMRT + Cisplatin + Lapatinib
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6735
	Comments
	Method	Log Rank
	Comments	One-sided significance level = 0.05
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.62 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments	Reference level = IMRT + cisplatin + placebo

7. Secondary Outcome

Title	Performance Status Scale for Head & Neck Cancer.
Time Frame	3 months, 1 year, and 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	Functional Assessment of Cancer Therapy - Head & Neck.
Time Frame	3 months, 1 year, and 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

9. Secondary Outcome

Title	University of Michigan Xerostomia-Related Quality of Life Scale.
Time Frame	3 months, 1 year, and 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

10. Secondary Outcome

Title	HER2, EGFR, EMT as Biomarkers of Response.
Time Frame	End of Study

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Weekly during radiation therapy, then every 3 months for years 1 and 2, every 6 months for years 3-5, then annually
Adverse Event Reporting Description	All-cause mortality was assessed in all randomized participants. Adverse events were assessed in participants who started protocol treatment
Arm/Group Title	IMRT + Cisplatin + Placebo		IMRT + Cisplatin + Lapatinib
Arm/Group Description	IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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		IMRT: 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 Cisplatin: 100 mg/m^2 administered intravenously on days 8 and 29 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
All Cause Mortality
	IMRT + Cisplatin + Placebo		IMRT + Cisplatin + Lapatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/64 (35.9%)		26/63 (41.3%)
Serious Adverse Events
	IMRT + Cisplatin + Placebo		IMRT + Cisplatin + Lapatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	26/59 (44.1%)		31/60 (51.7%)
Blood and lymphatic system disorders
Anemia	2/59 (3.4%)		2/60 (3.3%)
Febrile neutropenia	2/59 (3.4%)		1/60 (1.7%)
Leukocytosis	0/59 (0%)		1/60 (1.7%)
Cardiac disorders
Atrial fibrillation	1/59 (1.7%)		0/60 (0%)
Cardiac arrest	1/59 (1.7%)		1/60 (1.7%)
Sinus tachycardia	1/59 (1.7%)		0/60 (0%)
Gastrointestinal disorders
Abdominal pain	0/59 (0%)		2/60 (3.3%)
Colitis	1/59 (1.7%)		0/60 (0%)
Diarrhea	0/59 (0%)		3/60 (5%)
Dysphagia	6/59 (10.2%)		4/60 (6.7%)
Esophagitis	1/59 (1.7%)		0/60 (0%)
Gastrointestinal disorders - Other	1/59 (1.7%)		0/60 (0%)
Ileus	1/59 (1.7%)		0/60 (0%)
Mucositis oral	0/59 (0%)		1/60 (1.7%)
Nausea	5/59 (8.5%)		7/60 (11.7%)
Oral hemorrhage	1/59 (1.7%)		0/60 (0%)
Oral pain	1/59 (1.7%)		1/60 (1.7%)
Vomiting	5/59 (8.5%)		6/60 (10%)
General disorders
Death NOS	0/59 (0%)		1/60 (1.7%)
Edema limbs	0/59 (0%)		1/60 (1.7%)
Fatigue	1/59 (1.7%)		0/60 (0%)
Fever	0/59 (0%)		2/60 (3.3%)
Pain	2/59 (3.4%)		1/60 (1.7%)
Sudden death NOS	1/59 (1.7%)		0/60 (0%)
Infections and infestations
Bronchial infection	1/59 (1.7%)		0/60 (0%)
Infections and infestations - Other	1/59 (1.7%)		1/60 (1.7%)
Lung infection	2/59 (3.4%)		1/60 (1.7%)
Sepsis	0/59 (0%)		1/60 (1.7%)
Soft tissue infection	0/59 (0%)		1/60 (1.7%)
Injury, poisoning and procedural complications
Dermatitis radiation	1/59 (1.7%)		0/60 (0%)
Fall	0/59 (0%)		1/60 (1.7%)
Injury to carotid artery	1/59 (1.7%)		0/60 (0%)
Tracheal hemorrhage	1/59 (1.7%)		0/60 (0%)
Investigations
Creatinine increased	2/59 (3.4%)		2/60 (3.3%)
Ejection fraction decreased	0/59 (0%)		1/60 (1.7%)
Lymphocyte count decreased	0/59 (0%)		1/60 (1.7%)
Neutrophil count decreased	0/59 (0%)		2/60 (3.3%)
Weight loss	1/59 (1.7%)		0/60 (0%)
White blood cell decreased	0/59 (0%)		1/60 (1.7%)
Metabolism and nutrition disorders
Anorexia	1/59 (1.7%)		5/60 (8.3%)
Dehydration	8/59 (13.6%)		7/60 (11.7%)
Hyperglycemia	0/59 (0%)		1/60 (1.7%)
Hyperuricemia	0/59 (0%)		1/60 (1.7%)
Hypocalcemia	1/59 (1.7%)		0/60 (0%)
Hypokalemia	2/59 (3.4%)		1/60 (1.7%)
Hyponatremia	1/59 (1.7%)		3/60 (5%)
Musculoskeletal and connective tissue disorders
Chest wall pain	1/59 (1.7%)		0/60 (0%)
Nervous system disorders
Cognitive disturbance	1/59 (1.7%)		1/60 (1.7%)
Depressed level of consciousness	0/59 (0%)		1/60 (1.7%)
Dizziness	1/59 (1.7%)		0/60 (0%)
Stroke	1/59 (1.7%)		0/60 (0%)
Psychiatric disorders
Depression	0/59 (0%)		1/60 (1.7%)
Suicidal ideation	0/59 (0%)		1/60 (1.7%)
Renal and urinary disorders
Acute kidney injury	5/59 (8.5%)		8/60 (13.3%)
Respiratory, thoracic and mediastinal disorders
Aspiration	2/59 (3.4%)		2/60 (3.3%)
Dyspnea	3/59 (5.1%)		1/60 (1.7%)
Laryngeal edema	4/59 (6.8%)		3/60 (5%)
Laryngeal mucositis	2/59 (3.4%)		0/60 (0%)
Laryngeal stenosis	1/59 (1.7%)		0/60 (0%)
Pleural effusion	1/59 (1.7%)		0/60 (0%)
Pneumonitis	0/59 (0%)		1/60 (1.7%)
Respiratory failure	0/59 (0%)		1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders - Other	2/59 (3.4%)		1/60 (1.7%)
Sore throat	0/59 (0%)		1/60 (1.7%)
Stridor	1/59 (1.7%)		0/60 (0%)
Tracheal mucositis	1/59 (1.7%)		0/60 (0%)
Skin and subcutaneous tissue disorders
Rash acneiform	0/59 (0%)		1/60 (1.7%)
Surgical and medical procedures
Surgical and medical procedures - Other	0/59 (0%)		1/60 (1.7%)
Vascular disorders
Hypertension	1/59 (1.7%)		0/60 (0%)
Hypotension	2/59 (3.4%)		4/60 (6.7%)
Thromboembolic event	0/59 (0%)		1/60 (1.7%)
Other (Not Including Serious) Adverse Events
	IMRT + Cisplatin + Placebo		IMRT + Cisplatin + Lapatinib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	59/59 (100%)		60/60 (100%)
Blood and lymphatic system disorders
Anemia	38/59 (64.4%)		36/60 (60%)
Blood and lymphatic system disorders - Other	7/59 (11.9%)		5/60 (8.3%)
Cardiac disorders
Sinus tachycardia	4/59 (6.8%)		1/60 (1.7%)
Ear and labyrinth disorders
Ear pain	14/59 (23.7%)		12/60 (20%)
Hearing impaired	18/59 (30.5%)		15/60 (25%)
Tinnitus	23/59 (39%)		14/60 (23.3%)
Endocrine disorders
Hyperthyroidism	2/59 (3.4%)		3/60 (5%)
Hypothyroidism	17/59 (28.8%)		16/60 (26.7%)
Gastrointestinal disorders
Abdominal pain	4/59 (6.8%)		4/60 (6.7%)
Constipation	32/59 (54.2%)		17/60 (28.3%)
Dental caries	3/59 (5.1%)		0/60 (0%)
Diarrhea	8/59 (13.6%)		24/60 (40%)
Dry mouth	47/59 (79.7%)		46/60 (76.7%)
Dyspepsia	8/59 (13.6%)		8/60 (13.3%)
Dysphagia	53/59 (89.8%)		55/60 (91.7%)
Esophageal pain	4/59 (6.8%)		2/60 (3.3%)
Esophageal stenosis	3/59 (5.1%)		3/60 (5%)
Esophagitis	3/59 (5.1%)		3/60 (5%)
Gastroesophageal reflux disease	8/59 (13.6%)		5/60 (8.3%)
Gastrointestinal disorders - Other	12/59 (20.3%)		18/60 (30%)
Mucositis oral	45/59 (76.3%)		48/60 (80%)
Nausea	32/59 (54.2%)		35/60 (58.3%)
Oral pain	10/59 (16.9%)		13/60 (21.7%)
Salivary duct inflammation	5/59 (8.5%)		6/60 (10%)
Vomiting	20/59 (33.9%)		25/60 (41.7%)
General disorders
Chills	4/59 (6.8%)		4/60 (6.7%)
Edema face	6/59 (10.2%)		6/60 (10%)
Edema limbs	3/59 (5.1%)		5/60 (8.3%)
Fatigue	49/59 (83.1%)		49/60 (81.7%)
Fever	8/59 (13.6%)		0/60 (0%)
General disorders and administration site conditions - Other	7/59 (11.9%)		5/60 (8.3%)
Localized edema	4/59 (6.8%)		8/60 (13.3%)
Neck edema	2/59 (3.4%)		7/60 (11.7%)
Non-cardiac chest pain	4/59 (6.8%)		6/60 (10%)
Pain	22/59 (37.3%)		14/60 (23.3%)
Infections and infestations
Infections and infestations - Other	5/59 (8.5%)		4/60 (6.7%)
Laryngitis	2/59 (3.4%)		3/60 (5%)
Lung infection	3/59 (5.1%)		1/60 (1.7%)
Mucosal infection	9/59 (15.3%)		5/60 (8.3%)
Skin infection	2/59 (3.4%)		4/60 (6.7%)
Upper respiratory infection	0/59 (0%)		3/60 (5%)
Urinary tract infection	3/59 (5.1%)		2/60 (3.3%)
Injury, poisoning and procedural complications
Dermatitis radiation	39/59 (66.1%)		35/60 (58.3%)
Fall	2/59 (3.4%)		4/60 (6.7%)
Investigations
Alanine aminotransferase increased	12/59 (20.3%)		14/60 (23.3%)
Alkaline phosphatase increased	9/59 (15.3%)		4/60 (6.7%)
Aspartate aminotransferase increased	6/59 (10.2%)		7/60 (11.7%)
Blood bilirubin increased	4/59 (6.8%)		10/60 (16.7%)
CD4 lymphocytes decreased	2/59 (3.4%)		3/60 (5%)
Creatinine increased	18/59 (30.5%)		19/60 (31.7%)
Investigations - Other	5/59 (8.5%)		4/60 (6.7%)
Lymphocyte count decreased	22/59 (37.3%)		26/60 (43.3%)
Neutrophil count decreased	22/59 (37.3%)		13/60 (21.7%)
Platelet count decreased	16/59 (27.1%)		14/60 (23.3%)
Weight loss	31/59 (52.5%)		41/60 (68.3%)
White blood cell decreased	25/59 (42.4%)		24/60 (40%)
Metabolism and nutrition disorders
Anorexia	32/59 (54.2%)		34/60 (56.7%)
Dehydration	15/59 (25.4%)		14/60 (23.3%)
Hypercalcemia	4/59 (6.8%)		5/60 (8.3%)
Hyperglycemia	16/59 (27.1%)		18/60 (30%)
Hyperkalemia	5/59 (8.5%)		4/60 (6.7%)
Hypermagnesemia	5/59 (8.5%)		4/60 (6.7%)
Hypernatremia	3/59 (5.1%)		2/60 (3.3%)
Hyperuricemia	3/59 (5.1%)		0/60 (0%)
Hypoalbuminemia	18/59 (30.5%)		20/60 (33.3%)
Hypocalcemia	15/59 (25.4%)		16/60 (26.7%)
Hypoglycemia	0/59 (0%)		4/60 (6.7%)
Hypokalemia	17/59 (28.8%)		23/60 (38.3%)
Hypomagnesemia	16/59 (27.1%)		23/60 (38.3%)
Hyponatremia	26/59 (44.1%)		29/60 (48.3%)
Hypophosphatemia	5/59 (8.5%)		4/60 (6.7%)
Metabolism and nutrition disorders - Other	7/59 (11.9%)		11/60 (18.3%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/59 (5.1%)		3/60 (5%)
Back pain	7/59 (11.9%)		5/60 (8.3%)
Bone pain	1/59 (1.7%)		3/60 (5%)
Fibrosis deep connective tissue	4/59 (6.8%)		3/60 (5%)
Generalized muscle weakness	5/59 (8.5%)		6/60 (10%)
Musculoskeletal and connective tissue disorder - Other	8/59 (13.6%)		11/60 (18.3%)
Neck pain	12/59 (20.3%)		17/60 (28.3%)
Neck soft tissue necrosis	5/59 (8.5%)		2/60 (3.3%)
Superficial soft tissue fibrosis	9/59 (15.3%)		6/60 (10%)
Trismus	5/59 (8.5%)		4/60 (6.7%)
Nervous system disorders
Dizziness	5/59 (8.5%)		8/60 (13.3%)
Dysgeusia	36/59 (61%)		38/60 (63.3%)
Headache	13/59 (22%)		12/60 (20%)
Nervous system disorders - Other	2/59 (3.4%)		5/60 (8.3%)
Neuralgia	0/59 (0%)		3/60 (5%)
Peripheral sensory neuropathy	11/59 (18.6%)		11/60 (18.3%)
Tremor	4/59 (6.8%)		1/60 (1.7%)
Psychiatric disorders
Anxiety	16/59 (27.1%)		14/60 (23.3%)
Confusion	4/59 (6.8%)		1/60 (1.7%)
Depression	10/59 (16.9%)		11/60 (18.3%)
Insomnia	13/59 (22%)		20/60 (33.3%)
Psychiatric disorders - Other	5/59 (8.5%)		3/60 (5%)
Renal and urinary disorders
Acute kidney injury	5/59 (8.5%)		6/60 (10%)
Hematuria	3/59 (5.1%)		1/60 (1.7%)
Proteinuria	4/59 (6.8%)		0/60 (0%)
Urinary retention	3/59 (5.1%)		1/60 (1.7%)
Respiratory, thoracic and mediastinal disorders
Aspiration	8/59 (13.6%)		4/60 (6.7%)
Cough	22/59 (37.3%)		20/60 (33.3%)
Dyspnea	21/59 (35.6%)		16/60 (26.7%)
Hoarseness	29/59 (49.2%)		29/60 (48.3%)
Laryngeal edema	12/59 (20.3%)		12/60 (20%)
Laryngeal inflammation	3/59 (5.1%)		2/60 (3.3%)
Pharyngeal fistula	1/59 (1.7%)		3/60 (5%)
Pharyngeal mucositis	14/59 (23.7%)		11/60 (18.3%)
Pharyngolaryngeal pain	5/59 (8.5%)		4/60 (6.7%)
Pneumonitis	3/59 (5.1%)		1/60 (1.7%)
Productive cough	8/59 (13.6%)		5/60 (8.3%)
Respiratory, thoracic and mediastinal disorders - Other	10/59 (16.9%)		10/60 (16.7%)
Sore throat	21/59 (35.6%)		25/60 (41.7%)
Voice alteration	12/59 (20.3%)		10/60 (16.7%)
Skin and subcutaneous tissue disorders
Alopecia	1/59 (1.7%)		7/60 (11.7%)
Dry skin	2/59 (3.4%)		4/60 (6.7%)
Pruritus	3/59 (5.1%)		1/60 (1.7%)
Rash acneiform	4/59 (6.8%)		7/60 (11.7%)
Rash maculo-papular	2/59 (3.4%)		5/60 (8.3%)
Skin and subcutaneous tissue disorders - Other	7/59 (11.9%)		9/60 (15%)
Skin hyperpigmentation	5/59 (8.5%)		7/60 (11.7%)
Telangiectasia	3/59 (5.1%)		4/60 (6.7%)
Vascular disorders
Hot flashes	3/59 (5.1%)		0/60 (0%)
Hypertension	8/59 (13.6%)		11/60 (18.3%)
Hypotension	11/59 (18.6%)		4/60 (6.7%)
Lymphedema	6/59 (10.2%)		6/60 (10%)

Limitations/Caveats

A total of 69 progression-free survival (PFS) were required. As of September 13, 2020, the number of observed PFS events was 66. At the Radiation Therapy Oncology Group Foundation Data Monitoring Committee meeting on October 22, 2020, a decision was made to report the final results using data through November 30, 2020. This decision has a minor impact (<1%) on the power given that 67 PFS events are included in the final analysis of this trial.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.