Chemotherapy and Radiation Therapy With or Without Panitumumab in Treating Patients With Stage IIIA Non-Small Cell Lung Cancer

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00979212
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 71
• Locations: 31
• Arms: 2
• Duration (Months): 135.6
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy (CT), such as paclitaxel and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy (RT) uses high-energy x-rays to kill tumor cells. Monoclonal antibodies, such as panitumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving these treatments before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. It is not yet known whether chemotherapy and radiation therapy are more effective when given with or without panitumumab in treating patients with non-small cell lung cancer.

PURPOSE: This randomized phase II trial is studying chemotherapy and radiation therapy to see how well they work when given with or without panitumumab in treating patients with stage IIIA non-small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Drug: panitumumab; Drug: carboplatin; Drug: paclitaxel; Procedure: surgery	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the mediastinal nodal clearance after completion of induction chemoradiotherapy with or without panitumumab in patients with stage IIIA non-small cell lung cancer.

Secondary

• Assess overall survival of these patients.

• Evaluate patterns of first failure in these patients.

• Determine the acute and late adverse events associated with these regimens.

• Assess surgical morbidities in patients with resectable disease at reassessment.

• Determine the correlation between pre- and post-treatment biomarkers (including epidermal growth factor receptor (EGFR) and ras mutation status) and outcomes (mediastinal nodal clearance and overall survival).

• Evaluate the prognostic value of plasma osteopontin and microRNA for overall survival.

• Assess the ability of FDG-PET/CT scan re-staging to predict outcome.

OUTLINE: This is a multicenter study. Patients are randomized to 1 of 2 treatment arms.

• Arm I: Patients receive induction therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, and 36. Patients also undergo intensity-modulated radiotherapy (IMRT) or 3-dimensional conformal radiotherapy (3D-CRT) once daily on days 1-5, 8-12, 15-19, 22-26, 29-33, and 36-40. Beginning approximately 6-12 weeks later, patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21.

• Arm II: Patients receive induction therapy comprising panitumumab IV over 1 hour on days 1, 8, 15, 22, 29, and 36 and paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 8, 15, 22, 29, and 36. Patients also undergo IMRT or 3D-CRT once daily on days 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. Beginning approximately 6-12 weeks later, patients receive consolidation therapy comprising paclitaxel IV over 1 hour and carboplatin IV over 30 minutes on days 1 and 21.

• In both arms, patients with resectable disease and no disease progression may proceed to surgery (thoracotomy, lobectomy, or pneumonectomy) approximately 4-6 weeks after completion of induction therapy. After surgery, patients proceed to consolidation therapy.

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

Study Design

• Study Type: Interventional
• Actual Enrollment: 71 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Study of Pre-operative Chemoradiotherapy +/- Panitumumab (IND #110152) Followed by Consolidation Chemotherapy in Potentially Operable Locally Advanced (Stage IIIA, N2+) Non-Small Cell Lung Cancer
• Study Start Date: Feb 1, 2011
• Actual Primary Completion Date: Dec 1, 2015
• Actual Study Completion Date: May 20, 2022

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Induction CT+RT Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Drug: carboplatin; Induction: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, AUC=6, IV, days 1 and 22.; Other Names: Paraplatin ; Drug: paclitaxel; Induction: 50 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, 200 mg/m2, IV, days 1 and 22.; Other Names: Taxol Abraxane ; Procedure: surgery; A lobectomy or pneumonectomy performed 4-6 weeks after completion of induction chemoradiation; Other Names: lobectomy pneumonectomy
Experimental: Induction CT+RT+Panitumumab Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Drug: panitumumab; Induction: 2.5 mg/kg, IV, days 1, 8, 15, 22, 29, 36 of radiation therapy before administration of chemotherapy and radiation therapy.; Other Names: Vectibix ; Drug: carboplatin; Induction: AUC=2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, AUC=6, IV, days 1 and 22.; Other Names: Paraplatin ; Drug: paclitaxel; Induction: 50 mg/m2, IV, days 1, 8, 14, 22, 29, and 36 of radiation therapy. Consolidation, 6-12 weeks following surgery, 200 mg/m2, IV, days 1 and 22.; Other Names: Taxol Abraxane ; Procedure: surgery; A lobectomy or pneumonectomy performed 4-6 weeks after completion of induction chemoradiation; Other Names: lobectomy pneumonectomy

Outcome Measures

Primary Outcome Measures

1. Mediastinal Nodal Clearance After Completion of Induction Chemoradiotherapy With or Without Panitumumab. [From date of randomization to time of protocol surgery, approximately 12 weeks.]

   The assessment of whether mediastinal nodes which were involved at the time of study registration were clear of disease following induction chemoradiotherapy with or without panitumumab; the assessment is made at the time of surgery 4-6 weeks after chemoradiation. If surgery could not be performed, the patient was considered as not having had mediastinal nodal clearance.

Secondary Outcome Measures

1. Overall Survival [Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study]

   Survival time was calculated from the date of randomization to the date of death from any cause or the date of last follow-up. The Kaplan-Meier method was used to estimate the overall survival rates. One-year survival rates were estimated, not compared.

2. Patterns of First Failure [Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study.]

   The first failure site will be tabulated, not compared.

3. Percentage of Patients With Grade 3 or Higher Acute and Late Adverse Events [Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study.]

   Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Does not include surgical morbidities. An acute adverse event is defined as any grade 3 or worse toxicity occurring during protocol treatment and within 30 days from the end of protocol treatment that is possibly, probably, or definitely related to treatment. Acute adverse events are any adverse events occurring within 30 days of the end of all protocol treatment. Late adverse events are any adverse events occurring after 30 days after the end of all protocol treatment.

4. Surgical Morbidities in Patients With Resectable Disease at Reassessment [From date of surgery to 30 days following surgery.]

   A surgical morbidity is any toxicity occurring within 30 days of protocol surgery, as evaluated using CTCAE v4.0. Rates of grade 3 and higher surgical morbidity were calculated; the rates across arms were not compared.

5. Ability of FDG-PET/CT Scan Data to Predict Outcome [Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study.]

6. Response Rate [From date of randomization to time of protocol surgery, approximately 12 weeks.]

   Patients are assessed for best response to protocol treatment using the RECIST criteria. The response rate was calculated as the number of patients who have a complete response (CR) or partial response (PR) divided by the total number of analyzable patients at completion of induction chemoradiation +/- panitumumab and prior to anticipated surgery in each arm. Patients without a documented assessment are considered as not having a CR or PR. Rates are not compared across arms.

Eligibility Criteria

Criteria

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

DISEASE CHARACTERISTICS:

• Histologically confirmed* non-small cell lung cancer (NSCLC), including any of the following histologies:

• Adenocarcinoma

• Adenosquamous

• Large cell carcinoma

• Squamous cell carcinoma

• Non-lobar and non-diffuse bronchoalveolar cell carcinoma

• NSCLC not otherwise specified NOTE: *Documentation of NSCLC may originate from the mediastinal node biopsy or aspiration

• Stage IIIA (T1-T3) disease with a single primary lung parenchymal lesion AND positive ipsilateral mediastinal node or nodes (N2) with or without positive ipsilateral hilar nodes (N1)

• N2 nodes must be separate from primary tumor by either CT scan or surgical exploration

• Maximum nodal diameter of involved N2 nodes cannot exceed 3.0 cm

• N2 status must be pathologically confirmed to be positive by one of the following methods*:

• Mediastinoscopy

• Mediastinotomy (Chamberlain procedure)

• Transesophageal needle biopsy using endoscopic ultrasound (EUS-TBNA)

• Endobronchial ultrasound biopsy using endoscopic ultrasound guidance (EBUS-TBNA)

• Thoracotomy

• Video-assisted thoracoscopy

• Transbronchial needle biopsy by Wang technique (TBNA)

• Fine-needle aspiration under CT guidance NOTE: *PET positivity in the ipsilateral mediastinal lymph nodes is not sufficient to establish N2 nodal status

• Ipsilateral mediastinal nodes associated with right-sided tumor must be biopsied unless all of the following are true:

• Tumor is left sided

• Paralyzed left true vocal cord documented by bronchoscopy or indirect laryngoscopy

• Nodes visible in the anterior/posterior (level 5) region on CT scan

• Distinct primary tumor separate from nodes visible on CT scan

• Histologic (biopsy) or cytologic (needle aspiration or sputum) proof of non-small cell histology from the primary tumor

• If lymph nodes in the contralateral mediastinum and neck are visible on contrast CT scan of the chest and are > 1.0 cm in short axis or if contralateral involvement is suggested by PET scan, then the nodes must be confirmed to be negative

• Measurable disease as determined by contrast-enhanced CT scan

• Primary lung tumor distinct from mediastinal lymph nodes

• If a pleural effusion is present, the following criteria must be met to exclude malignant involvement (incurable M1a disease):

• When pleural fluid is visible on both the CT scan and on a chest x-ray, a pleuracentesis is required to confirm that the pleural fluid is cytologically negative.

• Exudative pleural effusions are excluded, regardless of cytology;

• Effusions that are minimal (i.e. not visible under ultrasound guidance) that are too small to safely tap are eligible.

• No palpable lymph nodes in the supraclavicular areas or higher in the neck, unless proven to be benign by fine-needle aspiration or biopsy

• No distant metastases

PATIENT CHARACTERISTICS:

• Zubrod performance status 0-1

• Absolute neutrophil count (ANC) ≥ 1,500/mm³

• Platelet count ≥ 100,000/mm³

• Hemoglobin ≥ 10.0 g/dL (transfusion allowed)

• Creatinine clearance ≥ 60 mL/min

• Total bilirubin ≤ 1.5 times upper limit of normal (ULN)

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times ULN

• Alkaline phosphatase ≤ 2.5 times ULN

• Serum albumin > 3.0 g/dL

• Serum magnesium normal (supplementation allowed)

• Not pregnant

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 6 months after completion of treatment

• Forced expiratory volume at one second (FEV1) ≥ 2.0 L OR predicted post-resection FEV1 ≥ 0.8 L

• Diffusion capacity ≥ 50% predicted

• No other invasive malignancy within the past 3 years, except nonmelanoma skin cancer or carcinoma in situ of the breast, oral cavity, or cervix

• No severe, active co-morbidity, including any of the following:

• Current uncontrolled cardiac disease (e.g., uncontrolled hypertension, unstable angina, myocardial infarction within the past 6 months, uncontrolled congestive heart failure, or cardiomyopathy with decreased ejection fraction (<50%)

• Acute bacterial or fungal infection requiring IV antibiotics

• Chronic obstructive pulmonary disease exacerbation or other respiratory illness requiring hospitalization or that would preclude study therapy within the past 4 weeks

• Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects

• AIDS or known HIV positivity

• No unintentional weight loss ≥ 5% of body weight within the past 6 months

• No prior severe infusion reaction to a monoclonal antibody

• No pre-existing peripheral neuropathy ≥ grade 2

PRIOR CONCURRENT THERAPY:

• No prior systemic chemotherapy or biological therapy (including erlotinib hydrochloride or similar agents) for the study cancer

• Prior chemotherapy for a different cancer allowed

• No prior radiotherapy to the region of the study cancer that would result in overlap of radiotherapy fields

• No prior therapy that specifically and directly targets the EGFR pathway

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mercy Cancer Center at Mercy San Juan Medical Center	Carmichael	California	United States	95608
2	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California	United States	95815
3	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
4	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
5	CCOP - Ochsner	New Orleans	Louisiana	United States	70121
6	Greenebaum Cancer Center at University of Maryland Medical Center	Baltimore	Maryland	United States	21201
7	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
8	Cancer Institute at St. Joseph Medical Center	Towson	Maryland	United States	21204
9	Boston University Cancer Research Center	Boston	Massachusetts	United States	02118
10	Fairview Southdale Hospital	Edina	Minnesota	United States	55435
11	Virginia Piper Cancer Institute at Abbott - Northwestern Hospital	Minneapolis	Minnesota	United States	55407
12	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
13	Methodist Estabrook Cancer Center	Omaha	Nebraska	United States	68114
14	NYU Cancer Institute at New York University Medical Center	New York	New York	United States	10016
15	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
16	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
17	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
18	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
19	Natalie Warren Bryant Cancer Center at St. Francis Hospital	Tulsa	Oklahoma	United States	74136
20	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
21	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
22	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
23	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301-1792
24	Kimmel Cancer Center at Thomas Jefferson University - Philadelphia	Philadelphia	Pennsylvania	United States	19107-5541
25	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
26	Albert Einstein Cancer Center	Philadelphia	Pennsylvania	United States	19141
27	McGlinn Family Regional Cancer Center at Reading Hospital and Medical Center	Reading	Pennsylvania	United States	19612-6052
28	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
29	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania	United States	17405
30	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
31	Veterans Affairs Medical Center - Milwaukee	Milwaukee	Wisconsin	United States	53295

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Martin J. Edelman, MD, University of New Maryland

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00979212
• Other Study ID Numbers: RTOG-0839; CDR0000654690; NCI-2011-01970
• First Posted: Sep 17, 2009
• Last Update Posted: Jun 15, 2022
• Last Verified: May 1, 2022

• Keywords provided by Radiation Therapy Oncology Group: stage IIIA non-small cell lung cancer; adenocarcinoma of the lung; adenosquamous cell lung cancer; bronchoalveolar cell lung cancer; large cell lung cancer; squamous cell lung cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Paclitaxel; Carboplatin; Panitumumab

Study Results

Participant Flow

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Period Title: Overall Study
STARTED	24	47
COMPLETED	22	39
NOT COMPLETED	2	8

Baseline Characteristics

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab	Total
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Total of all reporting groups
Overall Participants	22	39	61
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61	61	61
Sex: Female, Male (Count of Participants)
Female	13 59.1%	18 46.2%	31 50.8%
Male	9 40.9%	21 53.8%	30 49.2%

Outcome Measures

1. Primary Outcome

Title	Mediastinal Nodal Clearance After Completion of Induction Chemoradiotherapy With or Without Panitumumab.
Description	The assessment of whether mediastinal nodes which were involved at the time of study registration were clear of disease following induction chemoradiotherapy with or without panitumumab; the assessment is made at the time of surgery 4-6 weeks after chemoradiation. If surgery could not be performed, the patient was considered as not having had mediastinal nodal clearance.
Time Frame	From date of randomization to time of protocol surgery, approximately 12 weeks.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	22	39
Number (95% Confidence Interval) [percentage of participants]	68.2 310%	48.7 124.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Induction CT+RT, Induction CT+RT+Panitumumab
	Comments	Null hypothesis (H0) was that the experimental treatment was not effective vs the alternative hypothesis (HA) that it was. H0: OR ≤ 1 vs. HA: OR > 1, where odds ratio (OR)= [p2*(1- p1)]/ [p1*(1- p2)], p1 denotes the mediastinal clearance rate (MCR) on Induction chemoradiation; p2 denotes the MCR on Induction chemoradiation + panitumumab. Fisher's exact test was used to compare the MCRs; the 95% confidence interval was calculated using Clopper-Pearson method. 97 patients were required.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.96
	Comments	One-sided test at significance level of 0.05
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Overall Survival
Description	Survival time was calculated from the date of randomization to the date of death from any cause or the date of last follow-up. The Kaplan-Meier method was used to estimate the overall survival rates. One-year survival rates were estimated, not compared.
Time Frame	Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	22	39
Number (95% Confidence Interval) [percentage of participants]	94.4 429.1%	89.1 228.5%

3. Secondary Outcome

Title	Patterns of First Failure
Description	The first failure site will be tabulated, not compared.
Time Frame	Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	22	39
Alive, no failure	15 68.2%	20 51.3%
Dead, no failure	1 4.5%	3 7.7%
Distant failure only	4 18.2%	9 23.1%
Local and distant failure	1 4.5%	2 5.1%
Local and regional failure	0 0%	1 2.6%
Local, regional, and distant failure	0 0%	2 5.1%
Regional failure only	1 4.5%	2 5.1%

4. Secondary Outcome

Title	Percentage of Patients With Grade 3 or Higher Acute and Late Adverse Events
Description	Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. Does not include surgical morbidities. An acute adverse event is defined as any grade 3 or worse toxicity occurring during protocol treatment and within 30 days from the end of protocol treatment that is possibly, probably, or definitely related to treatment. Acute adverse events are any adverse events occurring within 30 days of the end of all protocol treatment. Late adverse events are any adverse events occurring after 30 days after the end of all protocol treatment.
Time Frame	Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	22	39
Acute	81.8 371.8%	69.2 177.4%
Late	30.3 137.7%	15.2 39%

5. Secondary Outcome

Title	Surgical Morbidities in Patients With Resectable Disease at Reassessment
Description	A surgical morbidity is any toxicity occurring within 30 days of protocol surgery, as evaluated using CTCAE v4.0. Rates of grade 3 and higher surgical morbidity were calculated; the rates across arms were not compared.
Time Frame	From date of surgery to 30 days following surgery.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment and received protocol surgery

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	19	30
Number (95% Confidence Interval) [percentage of patients]	42.1	20

6. Secondary Outcome

Title	Ability of FDG-PET/CT Scan Data to Predict Outcome
Time Frame	Patients are followed until death. Analysis occurs at time of primary analysis, approximately five years from start of study.

Outcome Measure Data

Analysis Population Description

FDG-PET/CT scan data was not obtained and therefore this outcome measure cannot be reported.

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	0	0

7. Secondary Outcome

Title	Response Rate
Description	Patients are assessed for best response to protocol treatment using the RECIST criteria. The response rate was calculated as the number of patients who have a complete response (CR) or partial response (PR) divided by the total number of analyzable patients at completion of induction chemoradiation +/- panitumumab and prior to anticipated surgery in each arm. Patients without a documented assessment are considered as not having a CR or PR. Rates are not compared across arms.
Time Frame	From date of randomization to time of protocol surgery, approximately 12 weeks.

Outcome Measure Data

Analysis Population Description

All eligible patients who started study treatment

Arm/Group Title	Induction CT+RT	Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)	Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
Measure Participants	22	39
Number (95% Confidence Interval) [percentage of participants]	77.3 351.4%	61.5 157.7%

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given adverse event are counted only once for that adverse event. Note, with yearly update of adverse events, eligibility determination of one patient changed and as a result the number at risk shown for adverse events now differs from the Participant Flow table which was entered previously.
Arm/Group Title	Induction CT+RT		Induction CT+RT+Panitumumab
Arm/Group Description	Chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)		Panitumumab plus chemotherapy (paclitaxel and carboplatin) plus radiation therapy followed by surgery (if operable) followed by consolidation chemotherapy (paclitaxel and carboplatin)
All Cause Mortality
	Induction CT+RT		Induction CT+RT+Panitumumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Induction CT+RT		Induction CT+RT+Panitumumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/22 (36.4%)		20/38 (52.6%)
Blood and lymphatic system disorders
Anemia	1/22 (4.5%)		0/38 (0%)
Cardiac disorders
Atrial fibrillation	0/22 (0%)		2/38 (5.3%)
Cardiac arrest	0/22 (0%)		1/38 (2.6%)
Gastrointestinal disorders
Diarrhea	2/22 (9.1%)		2/38 (5.3%)
Dysphagia	0/22 (0%)		1/38 (2.6%)
Esophagitis	1/22 (4.5%)		2/38 (5.3%)
Gastritis	0/22 (0%)		1/38 (2.6%)
Hemorrhoidal hemorrhage	0/22 (0%)		1/38 (2.6%)
Ileus	1/22 (4.5%)		0/38 (0%)
Nausea	1/22 (4.5%)		2/38 (5.3%)
Rectal hemorrhage	0/22 (0%)		1/38 (2.6%)
Vomiting	1/22 (4.5%)		2/38 (5.3%)
General disorders
Fatigue	0/22 (0%)		1/38 (2.6%)
Infusion related reaction	0/22 (0%)		1/38 (2.6%)
Immune system disorders
Anaphylaxis	0/22 (0%)		1/38 (2.6%)
Infections and infestations
Lung infection	2/22 (9.1%)		5/38 (13.2%)
Pleural infection	0/22 (0%)		1/38 (2.6%)
Sepsis	0/22 (0%)		3/38 (7.9%)
Skin infection	0/22 (0%)		1/38 (2.6%)
Upper respiratory infection	0/22 (0%)		1/38 (2.6%)
Urinary tract infection	0/22 (0%)		1/38 (2.6%)
Wound infection	0/22 (0%)		1/38 (2.6%)
Injury, poisoning and procedural complications
Postoperative thoracic procedure complication	0/22 (0%)		1/38 (2.6%)
Investigations
Electrocardiogram QT corrected interval prolonged	0/22 (0%)		1/38 (2.6%)
Lymphocyte count decreased	1/22 (4.5%)		2/38 (5.3%)
Neutrophil count decreased	1/22 (4.5%)		2/38 (5.3%)
White blood cell decreased	0/22 (0%)		1/38 (2.6%)
Metabolism and nutrition disorders
Dehydration	0/22 (0%)		1/38 (2.6%)
Musculoskeletal and connective tissue disorders
Myalgia	0/22 (0%)		1/38 (2.6%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Treatment related secondary malignancy	0/22 (0%)		1/38 (2.6%)
Nervous system disorders
Nervous system disorders - Other	0/22 (0%)		1/38 (2.6%)
Peripheral sensory neuropathy	1/22 (4.5%)		0/38 (0%)
Recurrent laryngeal nerve palsy	1/22 (4.5%)		0/38 (0%)
Stroke	1/22 (4.5%)		0/38 (0%)
Renal and urinary disorders
Acute kidney injury	0/22 (0%)		1/38 (2.6%)
Urinary retention	0/22 (0%)		1/38 (2.6%)
Respiratory, thoracic and mediastinal disorders
Aspiration	0/22 (0%)		1/38 (2.6%)
Bronchial stricture	0/22 (0%)		1/38 (2.6%)
Bronchopleural fistula	0/22 (0%)		2/38 (5.3%)
Bronchopulmonary hemorrhage	0/22 (0%)		1/38 (2.6%)
Dyspnea	1/22 (4.5%)		2/38 (5.3%)
Hypoxia	0/22 (0%)		1/38 (2.6%)
Pleural hemorrhage	1/22 (4.5%)		0/38 (0%)
Pleuritic pain	1/22 (4.5%)		1/38 (2.6%)
Pneumonitis	0/22 (0%)		3/38 (7.9%)
Pulmonary edema	0/22 (0%)		1/38 (2.6%)
Respiratory failure	0/22 (0%)		2/38 (5.3%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	0/22 (0%)		1/38 (2.6%)
Vascular disorders
Thromboembolic event	2/22 (9.1%)		0/38 (0%)
Other (Not Including Serious) Adverse Events
	Induction CT+RT		Induction CT+RT+Panitumumab
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/22 (100%)		37/38 (97.4%)
Blood and lymphatic system disorders
Anemia	13/22 (59.1%)		20/38 (52.6%)
Cardiac disorders
Atrial fibrillation	7/22 (31.8%)		4/38 (10.5%)
Atrial flutter	2/22 (9.1%)		0/38 (0%)
Chest pain - cardiac	2/22 (9.1%)		0/38 (0%)
Sinus tachycardia	5/22 (22.7%)		2/38 (5.3%)
Ventricular arrhythmia	3/22 (13.6%)		0/38 (0%)
Gastrointestinal disorders
Constipation	6/22 (27.3%)		17/38 (44.7%)
Diarrhea	7/22 (31.8%)		7/38 (18.4%)
Dyspepsia	7/22 (31.8%)		11/38 (28.9%)
Dysphagia	9/22 (40.9%)		17/38 (44.7%)
Esophagitis	8/22 (36.4%)		15/38 (39.5%)
Gastroesophageal reflux disease	2/22 (9.1%)		4/38 (10.5%)
Nausea	13/22 (59.1%)		19/38 (50%)
Vomiting	6/22 (27.3%)		7/38 (18.4%)
General disorders
Chills	3/22 (13.6%)		4/38 (10.5%)
Fatigue	20/22 (90.9%)		30/38 (78.9%)
Fever	5/22 (22.7%)		6/38 (15.8%)
Flu like symptoms	2/22 (9.1%)		0/38 (0%)
Non-cardiac chest pain	3/22 (13.6%)		3/38 (7.9%)
Pain	8/22 (36.4%)		11/38 (28.9%)
Infections and infestations
Infections and infestations - Other	2/22 (9.1%)		0/38 (0%)
Lung infection	4/22 (18.2%)		4/38 (10.5%)
Urinary tract infection	3/22 (13.6%)		2/38 (5.3%)
Injury, poisoning and procedural complications
Dermatitis radiation	6/22 (27.3%)		3/38 (7.9%)
Investigations
Alkaline phosphatase increased	4/22 (18.2%)		4/38 (10.5%)
Creatinine increased	2/22 (9.1%)		2/38 (5.3%)
Lymphocyte count decreased	9/22 (40.9%)		10/38 (26.3%)
Lymphocyte count increased	2/22 (9.1%)		0/38 (0%)
Neutrophil count decreased	7/22 (31.8%)		9/38 (23.7%)
Platelet count decreased	10/22 (45.5%)		8/38 (21.1%)
Weight loss	6/22 (27.3%)		11/38 (28.9%)
White blood cell decreased	12/22 (54.5%)		12/38 (31.6%)
Metabolism and nutrition disorders
Anorexia	13/22 (59.1%)		11/38 (28.9%)
Glucose intolerance	2/22 (9.1%)		1/38 (2.6%)
Hyperglycemia	8/22 (36.4%)		12/38 (31.6%)
Hypoalbuminemia	3/22 (13.6%)		7/38 (18.4%)
Hypocalcemia	4/22 (18.2%)		8/38 (21.1%)
Hypomagnesemia	4/22 (18.2%)		9/38 (23.7%)
Hyponatremia	4/22 (18.2%)		4/38 (10.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/22 (13.6%)		4/38 (10.5%)
Back pain	6/22 (27.3%)		3/38 (7.9%)
Chest wall pain	6/22 (27.3%)		2/38 (5.3%)
Generalized muscle weakness	3/22 (13.6%)		2/38 (5.3%)
Musculoskeletal and connective tissue disorder - Other	2/22 (9.1%)		3/38 (7.9%)
Myalgia	2/22 (9.1%)		3/38 (7.9%)
Pain in extremity	3/22 (13.6%)		3/38 (7.9%)
Nervous system disorders
Dizziness	6/22 (27.3%)		5/38 (13.2%)
Dysgeusia	4/22 (18.2%)		6/38 (15.8%)
Headache	4/22 (18.2%)		5/38 (13.2%)
Paresthesia	4/22 (18.2%)		3/38 (7.9%)
Peripheral sensory neuropathy	6/22 (27.3%)		11/38 (28.9%)
Psychiatric disorders
Anxiety	3/22 (13.6%)		5/38 (13.2%)
Depression	4/22 (18.2%)		3/38 (7.9%)
Insomnia	5/22 (22.7%)		6/38 (15.8%)
Renal and urinary disorders
Urinary retention	2/22 (9.1%)		1/38 (2.6%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	9/22 (40.9%)		3/38 (7.9%)
Chylothorax	3/22 (13.6%)		0/38 (0%)
Cough	9/22 (40.9%)		14/38 (36.8%)
Dyspnea	16/22 (72.7%)		17/38 (44.7%)
Hoarseness	2/22 (9.1%)		1/38 (2.6%)
Pleural effusion	10/22 (45.5%)		5/38 (13.2%)
Pleuritic pain	3/22 (13.6%)		0/38 (0%)
Pneumothorax	7/22 (31.8%)		3/38 (7.9%)
Productive cough	4/22 (18.2%)		2/38 (5.3%)
Sore throat	3/22 (13.6%)		3/38 (7.9%)
Skin and subcutaneous tissue disorders
Alopecia	6/22 (27.3%)		12/38 (31.6%)
Hyperhidrosis	2/22 (9.1%)		0/38 (0%)
Rash maculo-papular	3/22 (13.6%)		13/38 (34.2%)
Vascular disorders
Hypertension	2/22 (9.1%)		1/38 (2.6%)
Hypotension	4/22 (18.2%)		3/38 (7.9%)
Thromboembolic event	2/22 (9.1%)		0/38 (0%)

Limitations/Caveats

Following a recommendation on July 13, 2015 by the NRG Data Monitoring Committee accrual was halted early after accruing only 71 of 97 patients due to unexpectedly high rates of grade 5 toxicity on the panitumumab arm.

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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.