Sorafenib and High-Dose Carboplatin, Paclitaxel, and External-Beam Radiation Therapy in Treating Patients With Stage III Non-Small Cell Lung Cancer

Sponsor

University of Texas Southwestern Medical Center (Other)

Overall Status

Withdrawn

CT.gov ID

NCT00547443

Collaborator

(none)

Enrollment

Locations

Arms

Actual Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. 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. Radiation therapy uses high-energy x-rays to kill tumor cells. Giving sorafenib together with high-dose chemotherapy and external-beam radiation therapy may kill more tumor cells.

PURPOSE: This randomized phase I/II trial is studying the side effects and best dose of sorafenib when given together with high-dose carboplatin, paclitaxel, and external-beam radiation therapy in treating patients with stage III non-small cell lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Lung Cancer	Drug: carboplatin Drug: paclitaxel Drug: sorafenib tosylate Radiation: radiation therapy	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

To determine the median survival from randomization for patients receiving carboplatin and paclitaxel with high-dose radiation therapy (HDRT) or same regimen with sorafenib tosylate.

Secondary

To determine the overall response rate, failure-free survival, and survival for patients receiving carboplatin/paclitaxel with 74 Gy HDRT or same regimen with sorafenib tosylate.
To determine the feasibility of concurrent sorafenib tosylate and chemoradiation as measured by safety (the rate of grade 3 or higher radiation related esophagitis or pulmonary toxicity or chemotherapy related grade 4 hematological or other non-hematological toxicities occurring within 60 days of the start of treatment) and compliance (the completion of the treatment regimen with no more than minor variations).
To correlate outcomes (survival, toxicity, quality of life) with biological parameters.

OUTLINE: This is a multicenter study.

Phase I:
Chemoradiotherapy: Patients receive paclitaxel IV over 60 minutes and carboplatin IV over 30 minutes on day 1. Treatment repeats weekly for 7 weeks. Patients undergo concurrent high-dose external beam radiotherapy (HDRT) 5 days a week for 7.5 weeks. Cohorts of patients also receive escalating doses of oral sorafenib tosylate twice daily for 7 weeks.
Consolidation therapy: Beginning at week 11, patients receive paclitaxel IV over 3 hours and carboplatin IV over 30 minutes on day 1. Treatment repeats every 3 weeks for 6 weeks. Patients also receive oral sorafenib tosylate at the maximum tolerated dose (MTD) twice daily.
Maintenance: Patients receive oral sorafenib tosylate twice daily at the MTD.
Phase II: Patients are randomized to 1 of 2 treatment arms.
Arm I:
Chemoradiotherapy: Patients receive paclitaxel, carboplatin, and HDRT as in phase I.
Consolidation therapy: Patients receive paclitaxel and carboplatin as in phase

Arm II:
Chemoradiotherapy: Patients receive paclitaxel, carboplatin, and HDRT as in phase I. Patients also receive oral sorafenib tosylate as in phase I at the MTD.
Consolidation therapy: Patients receive paclitaxel, carboplatin, and sorafenib tosylate at the MTD as in phase I.
Maintenance: Patients receive sorafenib tosylate at the MTD as in phase I. After completion of study therapy, patients are followed every 3 months for 2 years and then every 6 months for 2 years.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized Phase I/II Study Of Sorafenib In Combination With High Does Chemoradiation In Patients With Stage IIIA/B Non-small Cell Lung Cancer (NSCLC)

Actual Study Start Date :

Jul 1, 2007

Actual Primary Completion Date :

Jul 1, 2009

Actual Study Completion Date :

Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Arm I Patients receive chemoradiotherapy comprising paclitaxel, carboplatin, and high-dose external beam radiotherapy (HDRT) as in phase I. Patients also receive consolidation therapy comprising paclitaxel and carboplatin as in phase I.	Drug: carboplatin Given IV Drug: paclitaxel Given IV Radiation: radiation therapy Given 5 days a week for 7.5 weeks
Experimental: Arm II Patients receive chemoradiotherapy comprising paclitaxel, carboplatin, and HDRT as in phase I. Patients also receive consolidation therapy comprising paclitaxel, carboplatin, and sorafenib tosylate at the MTD as in phase I, as well as maintenance therapy comprising sorafenib tosylate at the MTD as in phase I.	Drug: carboplatin Given IV Drug: paclitaxel Given IV Drug: sorafenib tosylate Given orally Radiation: radiation therapy Given 5 days a week for 7.5 weeks

Arm

Intervention/Treatment

Active Comparator: Arm I

Patients receive chemoradiotherapy comprising paclitaxel, carboplatin, and high-dose external beam radiotherapy (HDRT) as in phase I. Patients also receive consolidation therapy comprising paclitaxel and carboplatin as in phase I.

Drug: carboplatin

Given IV

Drug: paclitaxel

Given IV

Radiation: radiation therapy

Given 5 days a week for 7.5 weeks

Experimental: Arm II

Patients receive chemoradiotherapy comprising paclitaxel, carboplatin, and HDRT as in phase I. Patients also receive consolidation therapy comprising paclitaxel, carboplatin, and sorafenib tosylate at the MTD as in phase I, as well as maintenance therapy comprising sorafenib tosylate at the MTD as in phase I.

Drug: carboplatin

Given IV

Drug: paclitaxel

Given IV

Drug: sorafenib tosylate

Given orally

Radiation: radiation therapy

Given 5 days a week for 7.5 weeks

Outcome Measures

Primary Outcome Measures

Median survival [Mean 24-Months]
To determine the median survival from randomization for patients receiving carboplatin / paclitaxel with high dose radiation therapy or same regimen with Sorafenib.

Secondary Outcome Measures

Progression-free survival [Mean 24-Months]
To determine the overall response rate, failure-free survival and survival for patients receiving carboplatin / paclitaxel with high dose radiation therapy or same regimen with Sorafenib.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Inclusion criteria:

Histologically or cytologically documented non-small cell lung cancer (NSCLC)
Any of the following subtypes allowed:
Adenocarcinoma (including bronchoalveolar cell)
Squamous cell carcinoma
Large cell anaplastic carcinoma (including giant and clear cell carcinomas)
Poorly differentiated (not otherwise specified) NSCLC
No metastasis (patients must be M0)
Stage IIIA (T1 or T2 with N2 or T3N1-2) or stage IIIB (T4 with any N or any T with N2 or N3) disease
Measurable disease
Tumors adjacent to a vertebral body are allowed as long as all gross disease can be encompassed in the radiation boost field
The boost volume must be limited to < 50% of the ipsilateral lung volume
Pleural effusion that is a transudate, cytologically negative, and nonbloody allowed if the radiation oncologists feel the tumor can still be encompassed within a reasonable field of radiotherapy
Pleural effusions seen on the chest CT but too small to tap allowed

Exclusion criteria:

Totally resected tumors
Exudative, bloody, or cytologically malignant effusions
Known brain metastasis
Patients with neurological symptoms must undergo a CT scan/MRI of the brain to exclude brain metastasis

PATIENT CHARACTERISTICS:

Inclusion criteria:

Zubrod performance status 0-1
ANC ≥ 1,500/mm³
Platelet count ≥ 100,000/mm³
Hemoglobin ≥ 9 g/dL (prior to transfusions)
Total bilirubin ≤ 1.5 mg/dL
AST or ALT ≤ 3 times upper limit of normal (ULN)
Alkaline phosphatase ≤ 2.5 times ULN
Glucose ≤ 2 times ULN
Creatinine ≤ 2.0 mg/dL
FEV_1 ≥ 1,200 mL
Weight loss ≤ 10% over the past 3 months
Not pregnant or nursing
Negative pregnancy test
Women of childbearing potential and male participants who are unwilling or unable to use an acceptable method of contraception throughout the study and for 4 weeks after completion of treatment or those who are using a prohibited contraceptive method
INR < 1.5 or a PT/PTT within normal limits

Exclusion criteria:

Known allergy to murine proteins or Cremophor EL
Active pulmonary infection not responsive to conventional antibiotics
History of severe chronic obstructive pulmonary disease requiring ≥ 3 hospitalizations over the past year
Cardiac disease including any of the following:
Congestive heart failure > class II NYHA
Unstable angina (anginal symptoms at rest) or new onset angina (began within the last 3 months)
Myocardial infarction within the past 6 months
Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
Patients with neuropathy > grade 1
Evidence of malignancy in the past 2 years except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other in situ cancer
Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management
Known HIV infection or chronic hepatitis B
Active clinically serious infection > CTCAE grade 2
Thrombolic or embolic events, such as a cerebrovascular accident including transient ischemic attacks, within the past 6 months
Pulmonary hemorrhage or bleeding event ≥ CTCAE grade 2 within the past 4 weeks
Any other hemorrhage or bleeding event ≥ CTCAE Grade 3 within the past 4 weeks
Serious nonhealing wound, ulcer, or bone fracture
Evidence or history of bleeding diathesis or coagulopathy
Known or suspected allergy to sorafenib tosylate or any agent given in the course of this trial
Any condition that impairs patient's ability to swallow whole pills
Any malabsorption problem
Significant traumatic injury within the past 4 weeks

PRIOR CONCURRENT THERAPY:

Inclusion criteria:

Recovered from exploratory thoracotomy
Concurrent anti-coagulation treatment with an agent such as warfarin or heparin allowed provided INR or PT/PTT requirements are met

Exclusion criteria:

Prior systemic chemotherapy for lung cancer and/or thoracic/neck radiotherapy for any reason
Prior surgical resection of present cancer
Prior therapy with any molecular-targeted drugs (for lung cancer)
Currently participating in other phase III therapeutic clinical trials and/or who have participated in other phase III therapeutic clinical trials in the previous 30 days
Major surgery or open biopsy within the past 4 weeks
Concurrent Hypericum perforatum (St. John's wort) or rifampin (rifampicin)
Other concurrent anticancer drugs, including hormonal, immunotherapeutic, or chemotherapeutic agents
Steroids for acute symptom management, adrenal failure, septic shock, or as antiemetics allowed
Hormones administered for nondisease-related conditions (e.g., insulin for diabetes) allowed
Amifostine concurrently with radiotherapy or within 3 months of completion of radiotherapy
Concurrent colony-stimulating factors (i.e., filgrastim [G-CSF] or sargramostim [GM-CSF])

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Arlington Cancer Center - Arlington	Arlington	Texas	United States	76012-2510
2	Simmons Comprehensive Cancer Center at University of Texas Southwestern Medical Center - Dallas	Dallas	Texas	United States	75390