Non-HPV Locally Advanced Head and Neck Cancer
Conditions
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).
Interventions
RADIATIONIMRT
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
DRUGCisplatin
100 mg/m\^2 administered intravenously on days 8 and 29
DRUGplacebo
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
DRUGLapatinib
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
Sponsors
GlaxoSmithKline
Novartis
Radiation Therapy Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
| Functional Assessment of Cancer Therapy - Head & Neck. | 3 months, 1 year, and 2 years. | — |
| University of Michigan Xerostomia-Related Quality of Life Scale. | 3 months, 1 year, and 2 years. | — |
| HER2, EGFR, EMT as Biomarkers of Response. | End of Study | — |
| Performance Status Scale for Head & Neck Cancer. | 3 months, 1 year, and 2 years | — |
Countries
Canada, United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| IMRT + Cisplatin + Placebo 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 | 64 |
| IMRT + Cisplatin + Lapatinib 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 | 63 |
| Total | 127 |
Baseline characteristics
| Characteristic | IMRT + Cisplatin + Lapatinib | Total | IMRT + Cisplatin + Placebo |
|---|---|---|---|
| Age, Continuous | 57 years | 58 years | 58 years |
| Age, Customized <=65 | 56 Participants | 110 Participants | 54 Participants |
| Age, Customized >65 | 7 Participants | 17 Participants | 10 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 4 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 121 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| N stage (stratification factor) N0 | 20 Participants | 38 Participants | 18 Participants |
| N stage (stratification factor) N1 | 8 Participants | 15 Participants | 7 Participants |
| N stage (stratification factor) N2a | 2 Participants | 5 Participants | 3 Participants |
| N stage (stratification factor) N2b | 19 Participants | 38 Participants | 19 Participants |
| N stage (stratification factor) N2c | 13 Participants | 28 Participants | 15 Participants |
| N stage (stratification factor) N3 | 1 Participants | 3 Participants | 2 Participants |
| Overall stage II | 0 Participants | 1 Participants | 1 Participants |
| Overall stage III | 20 Participants | 38 Participants | 18 Participants |
| Overall stage IV | 43 Participants | 88 Participants | 45 Participants |
| Primary site Hypopharynx | 7 Participants | 23 Participants | 16 Participants |
| Primary site Larynx | 39 Participants | 72 Participants | 33 Participants |
| Primary site Oropharynx, p16-negative (central review) | 16 Participants | 31 Participants | 15 Participants |
| Primary site Oropharynx, unknown p16 (central review) | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants | 19 Participants | 9 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) White | 50 Participants | 99 Participants | 49 Participants |
| Sex: Female, Male Female | 16 Participants | 29 Participants | 13 Participants |
| Sex: Female, Male Male | 47 Participants | 98 Participants | 51 Participants |
| Smoking history: pack-years <=10 | 17 Participants | 30 Participants | 13 Participants |
| Smoking history: pack-years >10 | 45 Participants | 95 Participants | 50 Participants |
| Smoking history: pack-years | 29.5 pack-years | 30 pack-years | 38 pack-years |
| T stage (stratification factor) T1 | 0 Participants | 2 Participants | 2 Participants |
| T stage (stratification factor) T2 | 7 Participants | 16 Participants | 9 Participants |
| T stage (stratification factor) T3 | 38 Participants | 73 Participants | 35 Participants |
| T stage (stratification factor) T4 | 18 Participants | 36 Participants | 18 Participants |
| Zubrod performance status 0 | 27 Participants | 60 Participants | 33 Participants |
| Zubrod performance status 1 | 36 Participants | 67 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 23 / 64 | 26 / 63 |
| other Total, other adverse events | 59 / 59 | 60 / 60 |
| serious Total, serious adverse events | 26 / 59 | 31 / 60 |
Outcome results
Primary
Percentage of Participants Alive Without Progression (Progression-free Survival)
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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT + Cisplatin + Placebo | Percentage of Participants Alive Without Progression (Progression-free Survival) | 34.6 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Alive Without Progression (Progression-free Survival) | 43.1 percentage of participants |
Comparison: 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%.p-value: 0.343695% CI: [0.56, 1.46]Log Rank
Secondary
Functional Assessment of Cancer Therapy - Head & Neck.
Time frame: 3 months, 1 year, and 2 years.
Secondary
HER2, EGFR, EMT as Biomarkers of Response.
Time frame: End of Study
Population: No assays were performed, and no data were collected for this outcome measure. Specimen use will require funding separate from this trial.
Secondary
Percentage of Participants Alive (Overall Survival)
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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT + Cisplatin + Placebo | Percentage of Participants Alive (Overall Survival) | 55.1 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Alive (Overall Survival) | 49.9 percentage of participants |
p-value: 0.583695% CI: [0.61, 1.86]Log Rank
Secondary
Percentage of Participants Who Complied With Protocol Treatment
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).
Population: All randomized participants
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMRT + Cisplatin + Placebo | Percentage of Participants Who Complied With Protocol Treatment | Cisplatin | 90.6 percentage of participants |
| IMRT + Cisplatin + Placebo | Percentage of Participants Who Complied With Protocol Treatment | Concurrent lapatinib/placebo | 79.7 percentage of participants |
| IMRT + Cisplatin + Placebo | Percentage of Participants Who Complied With Protocol Treatment | Pre-IMRT lapatinib/placebo | 84.4 percentage of participants |
| IMRT + Cisplatin + Placebo | Percentage of Participants Who Complied With Protocol Treatment | Maintenance lapatinib/placebo | 56.3 percentage of participants |
| IMRT + Cisplatin + Placebo | Percentage of Participants Who Complied With Protocol Treatment | IMRT | 76.6 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Who Complied With Protocol Treatment | Maintenance lapatinib/placebo | 49.2 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Who Complied With Protocol Treatment | IMRT | 84.1 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Who Complied With Protocol Treatment | Cisplatin | 88.9 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Who Complied With Protocol Treatment | Pre-IMRT lapatinib/placebo | 87.3 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants Who Complied With Protocol Treatment | Concurrent lapatinib/placebo | 84.1 percentage of participants |
p-value: 0.3728Fisher Exact
p-value: 0.7781Fisher Exact
p-value: 0.8Fisher Exact
p-value: 0.6459Fisher Exact
p-value: 0.4792Fisher Exact
Secondary
Percentage of Participants With Distant Metastases
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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT + Cisplatin + Placebo | Percentage of Participants With Distant Metastases | 19.9 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants With Distant Metastases | 12.4 percentage of participants |
p-value: 0.174395% CI: [0.25, 1.65]Log Rank
Secondary
Percentage of Participants With Local-regional Progression
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.
Population: All randomized participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT + Cisplatin + Placebo | Percentage of Participants With Local-regional Progression | 33.7 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants With Local-regional Progression | 37.7 percentage of participants |
p-value: 0.673595% CI: [0.62, 2.17]Log Rank
Secondary
Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events
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.
Population: Participants Who Started Protocol Treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| IMRT + Cisplatin + Placebo | Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events | 84.7 percentage of participants |
| IMRT + Cisplatin + Lapatinib | Percentage of Participants With Treatment-related Grade 3 or Higher Adverse Events | 86.7 percentage of participants |
p-value: 0.7989Fisher Exact
Secondary
Performance Status Scale for Head & Neck Cancer.
Time frame: 3 months, 1 year, and 2 years
Secondary
University of Michigan Xerostomia-Related Quality of Life Scale.
Time frame: 3 months, 1 year, and 2 years.