Combination Chemotherapy, Bev, RT, and Erlotinib in Treating Patients With Stage III Non-Small Cell Lung Cancer

• Sponsor: UNC Lineberger Comprehensive Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00280150
• Collaborator: Genentech, Inc. (Industry), Eli Lilly and Company (Industry)
• Enrollment: 46
• Locations: 3
• Arms: 4
• Duration (Months): 84
• Patients Per Site: 15.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, 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. Bevacizumab may also stop the growth of non-small cell lung cancer by blocking blood flow to the tumor. Radiation therapy uses high energy x-rays to kill tumor cells. Erlotinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving combination chemotherapy together with bevacizumab, radiation therapy, and erlotinib may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of bevacizumab and erlotinib when given together with combination chemotherapy and radiation therapy and to see how well they work in treating patients with stage III non-small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Biological: bevacizumab; Drug: carboplatin; Drug: erlotinib hydrochloride; Drug: paclitaxel; Radiation: 3-dimensional conformal radiation therapy	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the maximum tolerated dose of bevacizumab and erlotinib hydrochloride when given together with carboplatin, paclitaxel, and thoracic conformal radiotherapy in patients with stage IIIA or IIIB non-small cell lung cancer. (Phase I [closed to accrual as of 1/3/2008])

• Determine the safety and toxicity profile of this regimen in these patients. (Phase I [closed to accrual as of 1/3/2008])

• Determine the progression-free survival of patients treated with induction therapy comprising carboplatin, paclitaxel, and bevacizumab followed by chemoradiotherapy comprising thoracic conformal radiotherapy, carboplatin, paclitaxel, bevacizumab, and erlotinib hydrochloride and consolidation therapy comprising bevacizumab and erlotinib hydrochloride. (Phase II)

• Determine the overall toxicity profile of this regimen in these patients. (Phase II)

Secondary

• Determine the response rate in patients treated with induction therapy comprising carboplatin, paclitaxel, and bevacizumab. (Phase I[closed to accrual as of 1/3/2008] and II)

• Determine the toxicity profile of induction therapy in these patients. (Phase I [closed to accrual as of 1/3/2008] and II)

• Determine the overall response rate and survival profile in patients treated with this regimen. (Phase I [closed to accrual as of 1/3/2008] and II)

• Determine the feasibility and tolerability of administering consolidation therapy comprising erlotinib hydrochloride and bevacizumab after treatment with combined modality therapy (induction therapy and chemoradiotherapy) in these patients. (Phase I [closed to accrual as of 1/3/2008] and II)

• Collect tumor and blood samples from these patients for future analysis of correlation between molecular markers and clinical benefit. (Phase I [closed to accrual as of 1/3/2008] and II)

OUTLINE: This is a nonrandomized, open-label, controlled, phase I (closed to accrual as of 1/3/2008), dose-escalation study of bevacizumab and erlotinib hydrochloride, followed by a phase II study.

• Phase I (closed to accrual as of 1/3/2008):

• Induction therapy: Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 2 courses. Patients with stable or responding disease proceed to chemoradiotherapy.

• Chemoradiotherapy: Patients receive chemoradiotherapy according to their assigned dose cohort:

• Cohort 1: Patients undergo thoracic conformal radiotherapy (TCRT) on days 1-5, 8-12, 15-19, 22-26, 29-33, 36-40, and 43-47. Patients also receive carboplatin IV and paclitaxel IV on days 1, 8, 15, 22, 29, 36, and 43 and bevacizumab IV over 30-90 minutes on days 1, 15, 29, and 43.

• Cohort 2: Patients undergo TCRT and receive carboplatin, paclitaxel, and bevacizumab as in cohort 1. Patients also receive oral erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47.

• Cohort 3: Patients undergo TCRT and receive carboplatin, paclitaxel, and bevacizumab as in cohort 1. Patients also receive higher doses of oral erlotinib hydrochloride on days 2-5, 9-12, 16-19, 23-26, 30-33, 37-40, and 44-47.

Cohorts of 5 patients receive chemoradiotherapy as described above until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 (with grade 4 toxicity) or 3 (with grade 3 toxicity) of 5 patients experience dose-limiting toxicity.

Three to 6 weeks after completion of chemoradiotherapy, patients proceed to consolidation therapy.

• Consolidation therapy: Patients receive bevacizumab IV on day 1 and oral erlotinib hydrochloride on days 1-21. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

• Phase II:

• Induction therapy: Patients receive induction therapy as in phase I (closed to accrual as of 1/3/2008).

• Chemoradiotherapy: Patients undergo TCRT and receive carboplatin and paclitaxel as in phase I (closed to accrual as of 1/3/2008). Patients also receive bevacizumab and erlotinib hydrochloride as in phase I (closed to accrual as of 1/3/2008) at the MTD/drug combination determined in phase I (closed to accrual as of 1/3/2008).

• Consolidation therapy: Patients receive consolidation therapy as in phase I (closed to accrual as of 1/3/2008).

Tumor tissue and peripheral blood is collected at baseline for future correlative and biomarker studies.

After completion of study therapy, patients are followed every 2 months for 2 years, every 4 months for 2 years, every 6 months for 2 years, and then annually thereafter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 46 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Induction Carboplatin/Paclitaxel With Bevacizumab Followed by Concurrent Thoracic Conformal Radiation Therapy With Carboplatin/Paclitaxel, Bevacizumab and Erlotinib in Stage IIIA/B Non-Small Cell Lung Cancer
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Bevacizumab 10 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Biological: bevacizumab; Given IV; Drug: carboplatin; Given IV; Drug: paclitaxel; Given IV; Radiation: 3-dimensional conformal radiation therapy; Given 5 days a week for 7 weeks
Experimental: Cohort 2 Bevacizumab 10 mg + Erlotinib 100 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Biological: bevacizumab; Given IV; Drug: carboplatin; Given IV; Drug: erlotinib hydrochloride; Given orally; Drug: paclitaxel; Given IV; Radiation: 3-dimensional conformal radiation therapy; Given 5 days a week for 7 weeks
Experimental: Cohort 3 Bevacizumab + Erlotinib 150 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Biological: bevacizumab; Given IV; Drug: carboplatin; Given IV; Drug: erlotinib hydrochloride; Given orally; Drug: paclitaxel; Given IV; Radiation: 3-dimensional conformal radiation therapy; Given 5 days a week for 7 weeks
Experimental: Phase II Bevacizumab + Erlotinib 100 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Biological: bevacizumab; Given IV; Drug: carboplatin; Given IV; Drug: erlotinib hydrochloride; Given orally; Drug: paclitaxel; Given IV; Radiation: 3-dimensional conformal radiation therapy; Given 5 days a week for 7 weeks

Outcome Measures

Primary Outcome Measures

1. Maximum Dose of Erlotinib When Given Together With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy (Phase I [Closed to Accrual as of 1/3/2008]) [6 weeks after completion of therapy]

   Dose-limiting toxicities (DLTs) were used to establish which cohort would be used for the phase II portion of the trial. DLTs were defined as any grade 3 or 4 nonhematologic toxicity with the exception of esophagitis, which had to be grade 4; grade 4 neutropenia lasting greater than or equal to 7 days and thrombocytopenia to less than 20,000/microliter.

2. Safety and Toxicity Profile of Combining Both Bevacizumab and Erlotinib Hydrochloride With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy [6 weeks after completion of therapy]

   A list of Hematologic and nonhematologic toxicities associated with induction and concurrent therapy. This includes the percentage of patients who experienced grades 2-4 based on the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).

Secondary Outcome Measures

1. Progression-free Survival (PFS) [5 years]

   The length of time during and after the treatment of a stage IIIA/B NSCLC that a patient lives with the disease but it does not get worse. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Response Rate to Induction Therapy (Phase I [Closed to Accrual as of 1/3/2008] and II) [5 years]

   Measurable lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10mm with spiral CT scan or nonmeasurable, but evaluable. Evaluable is nonmeasurable disease that includes ascites, malignant pleural/pericardial effusion, bone lesions, or marrow involvement. The same method of assessment and the same techniques should be used to characterize each identified and reported lesion at baseline and during follow-up. Complete Response (CR)- Disappearance of all target lesions

3. Overall Response Rate and Survival Profile [5 years]

   The overall response rate (ORR) to the two cycles of induction therapy plus bevacizumab in stage IIIA/B NSCLC. ORR is the portion of patients with a tumor size reduction for a minimum time period. Response duration is measured from the time of initial response until documented tumor progression.

4. Feasibility and Tolerability of Administering Consolidation Therapy [6 cycles]

   The proportion of patients who were able to complete consolidation therapy after induction therapy and chemoradiotherapy

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Diagnosis of non-small cell lung cancer

• Stage IIIA or IIIB disease

• No malignant pleural or pericardial effusions

• No palpable supraclavicular adenopathy

• Squamous cell histology allowed provided there is no hemoptysis and no central invasive lesions that abut or invade major blood vessels in the chest (with or without cavitation)

• Considered suitable and appropriate for combined modality therapy and thoracic conformal radiotherapy, as determined by the treating medical and radiation oncologist

PATIENT CHARACTERISTICS:

• Eastern Cooperative Oncology Group (ECOG) performance status 0-1

• Hemoglobin ≥ 9.0 mg/dL

• Platelet count ≥ 100,000/mm³

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

• Forced expiratory volume 1 (FEV_1) ≥ 1 L

• Creatinine ≤ 1.5 times upper limit of normal (ULN)

• Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≤ 2.5 times ULN

• Bilirubin normal

• Partial thromboplastin time (PTT) and international normalized ratio (INR) normal

• Urine protein:creatinine ratio < 1.0

• Blood pressure ≤ 150/100 mm Hg on 3 separate occasions

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No significant recent hemoptysis (> ½ teaspoon of bright red blood)

• No unstable angina

• No New York Heart Association (NYHA) congestive heart failure ≥ class II

• No myocardial infarction or stroke within the past 6 months

• No clinically significant peripheral vascular disease

• No evidence of bleeding diathesis or coagulopathy

• No abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months

• No serious, non-healing wound, ulcer, or bone fracture

• No thrombosis requiring therapeutic anticoagulation

• No significant traumatic injury within the last 28 days

PRIOR CONCURRENT THERAPY:

• Recovered from prior surgery

• At least 4 weeks since prior and no concurrent participation in another experimental drug study

• At least 4 weeks since prior and no concurrent major surgical procedure or open biopsy

• At least 2 weeks since prior mediastinoscopy or mediastinotomy

• At least 1 week since prior fine needle aspirations or core biopsies

• No other concurrent antineoplastic or antitumor agents, including chemotherapy, radiotherapy, immunotherapy, or hormonal anticancer therapy

• No other concurrent investigational agents

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lineberger Comprehensive Cancer Center at University of North Carolina - Chapel Hill	Chapel Hill	North Carolina	United States	27599-7295
2	Batte Cancer Center at Northeast Medical Center	Concord	North Carolina	United States	28025
3	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096

Sponsors and Collaborators

• UNC Lineberger Comprehensive Cancer Center
• Genentech, Inc.
• Eli Lilly and Company

Investigators

• Principal Investigator: Thomas Stinchcombe, MD, UNC Lineberger Comprehensive Cancer Center
• Principal Investigator: Thomas A. Stinchcombe, MD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• UNC Lineberger Comprehensive Cancer Center

Publications

None provided.

• Responsible Party: UNC Lineberger Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00280150
• Other Study ID Numbers: LCCC 0511; UNC IRB 05-2091
• First Posted: Jan 20, 2006
• Last Update Posted: Jun 19, 2017
• Last Verified: May 1, 2017

• Keywords provided by UNC Lineberger Comprehensive Cancer Center: stage IIIA non-small cell lung cancer; stage IIIB non-small cell lung cancer; recurrent non-small cell lung cancer; squamous cell lung cancer
• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Paclitaxel; Bevacizumab; Carboplatin; Erlotinib Hydrochloride

Study Results

Participant Flow

Recruitment Details	Participants were recruited from four institutions between February 2006 and April 2010.
Pre-assignment Detail	Of the 48 participants screened for eligibility, 46 were deemed eligible and went on to treatment, 1 was ineligible, and 1 was initially ruled eligible but the liver functioning tests (LFTs) continued to increase so the PI felt the participant should not be treated.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Phase II
Arm/Group Description	Bevacizumab 10 mg + Chemoradiotherapy	Bevacizumab 10 mg + Erlotinib 100 mg + Chemoradiotherapy	Bevacizumab 10 mg + Erlotinib 150 mg + Chemoradiotherapy	Bevacizumab + Erlotinib 100 mg + Chemoradiotherapy
Period Title: Overall Study
STARTED	5	5	6	30
Cohort Induction	5	5	6	30
Consolidation Therapy	2	5	3	0
COMPLETED	2	4	1	20
NOT COMPLETED	3	1	5	10

Baseline Characteristics

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Phase II	Total
Arm/Group Description	Bevacizumab 10 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Bevacizumab 10 mg + Erlotinib 100 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Bevacizumab + Erlotinib 150 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Bevacizumab + Erlotinib100 mg + Chemoradiotherapy (carboplatin, paclitaxel, and 3-dimensional conformal radiation therapy)	Total of all reporting groups
Overall Participants	5	5	6	30	46
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	4 80%	3 60%	3 50%	18 60%	28 60.9%
>=65 years	1 20%	2 40%	3 50%	12 40%	18 39.1%
Sex: Female, Male (Count of Participants)
Female	1 20%	2 40%	3 50%	16 53.3%	22 47.8%
Male	4 80%	3 60%	3 50%	14 46.7%	24 52.2%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	1 3.3%	1 2.2%
Not Hispanic or Latino	5 100%	5 100%	6 100%	29 96.7%	45 97.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	1 20%	0 0%	0 0%	1 3.3%	2 4.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 20%	2 33.3%	7 23.3%	10 21.7%
White	4 80%	4 80%	4 66.7%	22 73.3%	34 73.9%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	5 100%	5 100%	6 100%	30 100%	46 100%

Outcome Measures

1. Primary Outcome

Title	Maximum Dose of Erlotinib When Given Together With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy (Phase I [Closed to Accrual as of 1/3/2008])
Description	Dose-limiting toxicities (DLTs) were used to establish which cohort would be used for the phase II portion of the trial. DLTs were defined as any grade 3 or 4 nonhematologic toxicity with the exception of esophagitis, which had to be grade 4; grade 4 neutropenia lasting greater than or equal to 7 days and thrombocytopenia to less than 20,000/microliter.
Time Frame	6 weeks after completion of therapy

Outcome Measure Data

Analysis Population Description

This was a phase I objective only, so the phase II participants are not included.

Arm/Group Title	Cohort 1	Cohort 2	Cohort 3	Phase II
Arm/Group Description	Bevacizumab 10 mg + Chemoradiotherapy	Bevacizumab 10 mg + Erlotinib 100 mg + Chemoradiotherapy	Bevacizumab 10 mg + Erlotinib 150 mg + Chemoradiotherapy	Bevacizumab + Erlotinib 100 mg + Chemoradiotherapy
Measure Participants	5	5	6	0
Number [DLTs]	0	0	2

2. Primary Outcome

Title	Safety and Toxicity Profile of Combining Both Bevacizumab and Erlotinib Hydrochloride With Carboplatin, Paclitaxel, and Thoracic Conformal Radiotherapy
Description	A list of Hematologic and nonhematologic toxicities associated with induction and concurrent therapy. This includes the percentage of patients who experienced grades 2-4 based on the National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0).
Time Frame	6 weeks after completion of therapy

Outcome Measure Data

Analysis Population Description

Of the 46 patients, one was retrospectively diagnosed as having stage IV NSCLC after induction therapy was withdrawn from the protocol therapy leaving 45 evaluable for toxicity. 42 patients were eligible for concurrent therapy.

Arm/Group Title	Induction Therapy	Concurrent Therapy
Arm/Group Description	Percentage of all patients receiving induction therapy	Percentage of all patients receiving concurrent therapy
Measure Participants	45	42
Anemia	4 80%	17 340%
Neutrophenia	52 1040%	35 700%
Thrombocytopenia	0 0%	16 320%
Febrile neutropenia	0 0%	2 40%
Nausea/vomiting	7 140%	6 120%
Fatigue	20 400%	22 440%
Alopecia	42 840%	9 180%
Hypertension	9 180%	4 80%
Myalgias/arthralgias	27 540%	0 0%
Diarrhea	6 120%	2 40%
Neuropathy	2 40%	2 40%
Rash	2 40%	11 220%
Anorexia	0 0%	6 120%
Esophagitis	0 0%	40 800%
Dehydration	0 0%	11 220%
Hemorrhage	0 0%	6 120%
Hypomagnesemia	0 0%	4 80%
Proteinuria	0 0%	2 40%
Weight loss	0 0%	9 180%
Pneumonitis	0 0%	2 40%
Hypersensitivity reaction	4 80%	2 40%

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	The length of time during and after the treatment of a stage IIIA/B NSCLC that a patient lives with the disease but it does not get worse. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Of the 46 patients, one was retrospectively diagnosed as having stage IV NSCLC after induction therapy was withdrawn from the protocol therapy leaving 45 evaluable patients.

Arm/Group Title	Overall Study
Arm/Group Description	This includes patients from all cohorts.
Measure Participants	45
Median (95% Confidence Interval) [Months]	10.2

4. Secondary Outcome

Title	Response Rate to Induction Therapy (Phase I [Closed to Accrual as of 1/3/2008] and II)
Description	Measurable lesions must be accurately measured in at least one dimension (longest diameter to be recorded) as > 20 mm with conventional techniques or as > 10mm with spiral CT scan or nonmeasurable, but evaluable. Evaluable is nonmeasurable disease that includes ascites, malignant pleural/pericardial effusion, bone lesions, or marrow involvement. The same method of assessment and the same techniques should be used to characterize each identified and reported lesion at baseline and during follow-up. Complete Response (CR)- Disappearance of all target lesions
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

43 of 45 patients received both cycles of induction C/P therapy plus bevacizumab.

Arm/Group Title	Overall Study
Arm/Group Description	This includes patients from all cohorts.
Measure Participants	43
Count of Participants [Participants]	0 0%

5. Secondary Outcome

Title	Overall Response Rate and Survival Profile
Description	The overall response rate (ORR) to the two cycles of induction therapy plus bevacizumab in stage IIIA/B NSCLC. ORR is the portion of patients with a tumor size reduction for a minimum time period. Response duration is measured from the time of initial response until documented tumor progression.
Time Frame	5 years

Outcome Measure Data

Analysis Population Description

Of the 46 patients, one was retrospectively diagnosed as having stage IV NSCLC after induction therapy was withdrawn from the protocol therapy leaving 45 evaluable patients.

Arm/Group Title	Overall Study
Arm/Group Description	All 45 patients were included in the summary of efficacy outcomes.
Measure Participants	45
Number (95% Confidence Interval) [percentage of participants]	39 780%

6. Secondary Outcome

Title	Feasibility and Tolerability of Administering Consolidation Therapy
Description	The proportion of patients who were able to complete consolidation therapy after induction therapy and chemoradiotherapy
Time Frame	6 cycles

Outcome Measure Data

Analysis Population Description

Of the initial 14 patients, only 9 (64%) patients were able to start consolidation therapy and only 5 (36%) patients were able to complete 6 cycles.

Arm/Group Title	Overall Study
Arm/Group Description	This includes patients from all cohorts.
Measure Participants	14
Count of Participants [Participants]	5 100%

Adverse Events

Time Frame	5 years
Arm/Group Title	Overall Study
Arm/Group Description	Of the 46 patients, one was retrospectively diagnosed as having stage IV NSCLC after induction therapy was withdrawn from the protocol therapy leaving 45 evaluable patients. This includes patients from all cohorts.
All Cause Mortality
	Overall Study
	Affected / at Risk (%)	# Events
Total	30/45 (66.7%)
Serious Adverse Events
	Overall Study
	Affected / at Risk (%)	# Events
Total	19/45 (42.2%)
Blood and lymphatic system disorders
Febrile neutropenia (fever of unknown origin without clinically or microbiologically documented infe	2/45 (4.4%)
Gastrointestinal disorders
Esophagitis	1/45 (2.2%)
Diarrhea	1/45 (2.2%)
Esophagitis	5/45 (11.1%)
Pain - Abdomen NOS	1/45 (2.2%)
Vomiting	1/45 (2.2%)
General disorders
Pain - Chest/thorax NOS	1/45 (2.2%)
Fever (in the absence of neutropenia, where neutropenia is defined as ANC <1.0 x 10e9/L)	1/45 (2.2%)
Rigors/chills	1/45 (2.2%)
Infections and infestations
Infection with unknown ANC - Esophagus	2/45 (4.4%)
Infection with unknown ANC - Lung (pneumonia)	1/45 (2.2%)
Opportunistic infection associated with >=Grade 2 Lymphopenia	1/45 (2.2%)
Investigations
Neutrophils/granulocytes (ANC/AGC)	1/45 (2.2%)
Metabolism and nutrition disorders
Dehydration	2/45 (4.4%)
Sodium, serum-low (hyponatremia)	1/45 (2.2%)
Nervous system disorders
Dizziness	1/45 (2.2%)
Neurology - Other (Specify, __)	1/45 (2.2%)
Renal and urinary disorders
Renal failure	1/45 (2.2%)
Respiratory, thoracic and mediastinal disorders
Hemorrhage, pulmonary/upper respiratory - Bronchus	1/45 (2.2%)
Pneumonitis/pulmonary infiltrates	1/45 (2.2%)
Vascular disorders
Hemorrhage/Bleeding - Other (Specify, __)	1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	Overall Study
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
Febrile neutropenia	1/45 (2.2%)
Hemoglobin	22/45 (48.9%)
Hemolysis (e.g., immune hemolytic anemia, drug-related hemolysis)	5/45 (11.1%)
Cardiac disorders
Cardiac Arrhythmia - Other (Specify, __)	1/45 (2.2%)
Eye disorders
Vision-blurred vision	2/45 (4.4%)
Gastrointestinal disorders
Constipation	9/45 (20%)
Diarrhea	18/45 (40%)
Dry mouth/salivary gland (xerostomia)	3/45 (6.7%)
Dysphagia (difficulty swallowing)	7/45 (15.6%)
Esophagitis	27/45 (60%)
Gastritis (including bile reflux gastritis)	1/45 (2.2%)
Gastrointestinal - Other (Specify, __)	1/45 (2.2%)
Heartburn/dyspepsia	6/45 (13.3%)
Hemorrhoids	1/45 (2.2%)
Mucositis/stomatitis (clinical exam) - Esophagus	1/45 (2.2%)
Mucositis/stomatitis (clinical exam) - Oral cavity	5/45 (11.1%)
Mucositis/stomatitis (functional/symptomatic) - Esophagus	1/45 (2.2%)
Nausea	18/45 (40%)
Pain - Abdomen NOS	2/45 (4.4%)
Pain - Esophagus	1/45 (2.2%)
Pain - Oral-gums	2/45 (4.4%)
Pain - Rectum	1/45 (2.2%)
Stricture/stenosis (including anastomotic), GI - Esophagus	9/45 (20%)
Taste alteration (dysgeusia)	5/45 (11.1%)
Ulcer, GI - Esophagus	7/45 (15.6%)
Vomiting	9/45 (20%)
Gastrointestinal - Other (Specify,___)	1/45 (2.2%)
General disorders
Edema: head and neck	1/45 (2.2%)
Edema: limb	2/45 (4.4%)
Extremity-lower (gait/walking)	1/45 (2.2%)
Fatigue (asthenia, lethargy, malaise)	34/45 (75.6%)
Injection site reaction/extravasation changes	1/45 (2.2%)
Pain - Chest/thorax NOS	2/45 (4.4%)
Pain - Other (Specify, __)	2/45 (4.4%)
Pain - Pain NOS	2/45 (4.4%)
Immune system disorders
Allergic reaction/hypersensitivity (including drug fever)	6/45 (13.3%)
Cytokine release syndrome/acute infusion reaction	1/45 (2.2%)
Infections and infestations
Infection - Other (Specify, __)	2/45 (4.4%)
Infection	2/45 (4.4%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Foreign body	1/45 (2.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Lung (pneumonia)	1/45 (2.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Sinus	1/45 (2.2%)
Infection with normal ANC or Grade 1 or 2 neutrophils - Urinary tract NOS	1/45 (2.2%)
Infection with unknown ANC - Esophagus	1/45 (2.2%)
Infection with unknown ANC - Lung (pneumonia)	1/45 (2.2%)
Infection with unknown ANC - Sinus	2/45 (4.4%)
Injury, poisoning and procedural complications
Bruising (in absence of Grade 3 or 4 thrombocytopenia)	3/45 (6.7%)
Burn	1/45 (2.2%)
Rash: dermatitis associated with radiation - Chemoradiation	4/45 (8.9%)
Rash: dermatitis associated with radiation - Radiation	3/45 (6.7%)
Investigations
Alkaline phosphatase	2/45 (4.4%)
Neutrophils/granulocytes (ANC/AGC)	1/45 (2.2%)
ALT, SGPT (serum glutamic pyruvic transaminase)	2/45 (4.4%)
AST, SGOT(serum glutamic oxaloacetic transaminase)	1/45 (2.2%)
Bilirubin (hyperbilirubinemia)	1/45 (2.2%)
Creatinine	4/45 (8.9%)
Leukocytes (total WBC)	7/45 (15.6%)
Metabolic/Laboratory - Other (Specify, __)	3/45 (6.7%)
Neutrophils/granulocytes (ANC/AGC)	34/45 (75.6%)
Platelets	20/45 (44.4%)
Weight loss	7/45 (15.6%)
Metabolism and nutrition disorders
Anorexia	12/45 (26.7%)
Dehydration	6/45 (13.3%)
Glucose, serum-high (hyperglycemia)	2/45 (4.4%)
Glucose, serum-low (hypoglycemia)	1/45 (2.2%)
Joint-function	1/45 (2.2%)
Magnesium, serum-low (hypomagnesemia)	7/45 (15.6%)
Potassium, serum-high (hyperkalemia)	2/45 (4.4%)
Sodium, serum-low (hyponatremia)	1/45 (2.2%)
Uric acid, serum-high (hyperuricemia)	1/45 (2.2%)
Musculoskeletal and connective tissue disorders
Muscle weakness, generalized or specific area (not due to neuropathy) - Extraocular	7/45 (15.6%)
Musculoskeletal/Soft Tissue - Other (Specify, __)	1/45 (2.2%)
Pain - Back	6/45 (13.3%)
Pain - Bone	2/45 (4.4%)
Pain - Chest wall	1/45 (2.2%)
Pain - Extremity-limb	1/45 (2.2%)
Pain - Joint	24/45 (53.3%)
Pain - Muscle	15/45 (33.3%)
Pain - Neck	1/45 (2.2%)
Nervous system disorders
Cognitive disturbance	1/45 (2.2%)
Dizziness	8/45 (17.8%)
Neurology - Other (Specify, __)	2/45 (4.4%)
Neuropathy: motor	1/45 (2.2%)
Neuropathy: sensory	21/45 (46.7%)
Mental Status	1/45 (2.2%)
Psychiatric disorders
Insomnia	4/45 (8.9%)
Mood alteration - Anxiety	1/45 (2.2%)
Mood alteration - Depression	1/45 (2.2%)
Renal and urinary disorders
Glomerular filtration rate	2/45 (4.4%)
Hemorrhage, GU - Bladder	1/45 (2.2%)
Proteinuria	3/45 (6.7%)
Renal failure	1/45 (2.2%)
Renal/Genitourinary - Other (Specify, __)	1/45 (2.2%)
Reproductive system and breast disorders
Vaginitis (not due to infection)	1/45 (2.2%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis (including sneezing, nasal stuffiness, postnasal drip)	2/45 (4.4%)
Cough	8/45 (17.8%)
Dyspnea (shortness of breath)	6/45 (13.3%)
Hemorrhage, pulmonary/upper respiratory - Lung	1/45 (2.2%)
Hemorrhage, pulmonary/upper respiratory - Nose	13/45 (28.9%)
Hiccoughs (hiccups, singultus)	1/45 (2.2%)
Pain - Throat/pharynx/larynx	3/45 (6.7%)
Voice changes/dysarthria (e.g., hoarseness, loss or alteration in voice, laryngitis)	3/45 (6.7%)
Skin and subcutaneous tissue disorders
Dry skin	1/45 (2.2%)
Hair loss/alopecia (scalp or body)	35/45 (77.8%)
Hypopigmentation	1/45 (2.2%)
Nail changes	3/45 (6.7%)
Pruritus/itching	5/45 (11.1%)
Rash/desquamation	4/45 (8.9%)
Rash: acne/acneiform	12/45 (26.7%)
Sweating (diaphoresis)	2/45 (4.4%)
Ulceration	1/45 (2.2%)
Vascular disorders
Flushing	1/45 (2.2%)
Hematoma	1/45 (2.2%)
Hemorrhage/Bleeding - Other (Specify, __)	6/45 (13.3%)
Hot flashes/flushes	2/45 (4.4%)
Hypertension	10/45 (22.2%)
Hypotension	3/45 (6.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.