Sorafenib in Treating Patients With Refractory Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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RATIONALE: Preclinical studies indicate that sorafenib is a potent inhibitor of Raf kinase in vitro and in vivo, with significant dose-dependent, anti-tumor activity in four different human tumor types including colon, pancreatic, lung, and ovarian. This activity was cytostatic in nature and was maintained if dosing was continued. That is, tumor growth is suspended while the drug is administered but returns to baseline rates when the agent is withdrawn. Therefore, the optimal schedule will be an uninterrupted one. To assess the activity of sorafenib in a timely manner and with a meaningful interpretation, a randomized discontinuation design was adopted in the present trial, conducted in a population who were potentially sensitive to sorafenib. PURPOSE: This randomized phase II trial is studying sorafenib to see how well it works compared to placebo in treating patients with refractory non-small cell lung cancer.

Detailed Description
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OBJECTIVES: To determine the percent of patients maintaining stable disease or objective response two months after randomization with continued sorafenib treatment, compared to patients switched to placebo. To determine progression-free survival, overall survival, and response rate. OUTLINE: This is a randomized, double-blind, multicenter study. Patients are stratified according to number of prior chemotherapy regimens (2 vs more than 2) and prior epidermal growth factor receptor inhibitor treatment (yes vs no). Induction: All patients receive oral sorafenib twice daily on days 1-28. Treatment continues for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease proceed to randomization. Patients with responding disease continue to receive sorafenib for up to 1 year in the absence of disease progression. Randomization: Patients are randomized to 1 of 2 treatment arms. Arm I: Patients receive oral sorafenib twice daily for up to 1 year in the absence of disease progression or unacceptable toxicity. Arm II: Patients receive oral placebo twice daily for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients who develop disease progression within 1 year after randomization cross over to arm I. Patients are followed every 3 months for 2 years and then every 6 months for 3 years. PROJECTED ACCRUAL: A total of 311 patients will be accrued for this study within approximately 3 years.

Official Title
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A Double Blind Phase II Study of BAY 43-9006 in Patients With Non-Small Cell Lung Cancer Who Have Failed at Least Two Prior Chemotherapy Regimens

Conditions
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Lung Cancer

Intervention / Treatment
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* Drug: Sorafenib
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically confirmed advanced non-small cell lung cancer (NSCLC) Disease must have progressed after at least 2 prior chemotherapy regimens for NSCLC Patients must have measurable or nonmeasurable disease Absolute neutrophil count at least 1,500/mm^3 Platelet count at least 100,000/mm^3 Bilirubin no greater than 1.5 times upper limit of normal (ULN) AST and ALT no greater than 3 times ULN (5 times ULN in patients with liver disease) Creatinine less than 1.5 times ULN or calculated creatinine clearance greater than 50 mL/min More than 3 weeks since prior chemotherapy, radiotherapy, immunotherapy or other investigational drug use Recovered from all prior therapy Fertile patients must use effective contraception Age >= 18 ECOG performance status of 0-1 Exclusion Criteria: Prior primary or metastatic brain or meningeal tumors unless clinically and radiographically stable and off therapy for at least 2 months Active second malignancy Clinically evident congestive heart failure, serious cardiac arrhythmias, or symptoms of coronary heart disease Prior radiotherapy to the only site of measurable or evaluable disease unless there is evidence of disease progression in that site Prior exposure to a ras pathway inhibitor (e.g., farnesyl transferase inhibitor) Concurrent medications known to be metabolized by the liver with a narrow therapeutic index, including the following: Ketoconazole Itraconazole Quinidine Digoxin Cyclosporine Ritonavir Grapefruit products Carbamazepine Phenytoin Phenobarbital Pregnant or nursing Clinically serious active infection Medical conditions, substance abuse or psychological/social situation that would preclude study participation

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Induction then Sorafenib<br>Induction: All patients receive oral sorafenib twice daily on days 1-28. Treatment continues for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with stable disease proceed to randomization. Patients with responding disease continue to receive sorafenib for up to 1 year in the absence of disease progression. Randomization: Patients with stable disease after the induction treatment were randomized to either the sorafenib arm or the placebo arm. Patients on the sorafenib arm receive sorafenib twice daily for up to 1 year in the absence of disease progression or unacceptable disease. | Drug: Sorafenib<br>* Step 1 (induction): Sorafenib was giventwice daily for two cycles to all patients. Patients with progression (PD) discontinued treatment. Those who responded after two cycles continued treatment up to 1 year or until PD. With response after 1 year, patients were given the option to continue treatment until PD. Patients who were stable after the end of induction were then randomized onto Step 2 to either continue sorafenib or receive placebo. Step 2 (randomization): Patients with stable disease after induction will be randomized in a double-blinded manner to placebo or sorafenib. If a patient has progressed, the arm will be unblinded. Patients on placebo with PD can then crossover to receive sorafenib; patients with PD on the sorafenib arm will be removed from the study. Step 3 (crossover): If patients on placebo progressed within 1 year from randomization, they crossed over to the treatment arm and receive sorafenib for up to 1 year or until PD, unacceptable toxicity, or death.<br>* Other names: BAY 43-9006;|
| Placebo Comparator: Induction then Placebo then Sorafenib<br>Induction: All patients receive oral sorafenib twice daily on days 1-28. Treatment continues for 2 cycles in the absence of disease progression or unacceptable toxicity. Patients with stable disease proceed to randomization. Patients with responding disease continue to receive sorafenib for up to 1 year in the absence of disease progression. Randomization: Patients with stable disease after the induction treatment were randomized to either the sorafenib arm or the placebo arm. Patients on the placebo arm receive oral placebo twice daily for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients on the placebo arm who develop disease progression within 1 year after randomization may cross over to sorafenib arm. | Drug: Sorafenib<br>* Step 1 (induction): Sorafenib was giventwice daily for two cycles to all patients. Patients with progression (PD) discontinued treatment. Those who responded after two cycles continued treatment up to 1 year or until PD. With response after 1 year, patients were given the option to continue treatment until PD. Patients who were stable after the end of induction were then randomized onto Step 2 to either continue sorafenib or receive placebo. Step 2 (randomization): Patients with stable disease after induction will be randomized in a double-blinded manner to placebo or sorafenib. If a patient has progressed, the arm will be unblinded. Patients on placebo with PD can then crossover to receive sorafenib; patients with PD on the sorafenib arm will be removed from the study. Step 3 (crossover): If patients on placebo progressed within 1 year from randomization, they crossed over to the treatment arm and receive sorafenib for up to 1 year or until PD, unacceptable toxicity, or death.<br>* Other names: BAY 43-9006;Drug: Placebo<br>* Patients randomized to the placebo arm in step 2 continued receiving placebo until disease progression or one year from randomization. Placebo was given orally twice a day (BID).<br>|
| Other: Induction, not randomized<br>Induction: All patients receive oral sorafenib twice daily on days 1-28. Treatment continues for 2 cycles in the absence of disease progression or unacceptable toxicity. Post-induction: Patients with responding disease or disease progression were not randomized in Step 2. Patients with responding disease continue to receive sorafenib for up to 1 year in the absence of disease progression, while patients with disease progression were removed from the study. | Drug: Sorafenib<br>* Step 1 (induction): Sorafenib was giventwice daily for two cycles to all patients. Patients with progression (PD) discontinued treatment. Those who responded after two cycles continued treatment up to 1 year or until PD. With response after 1 year, patients were given the option to continue treatment until PD. Patients who were stable after the end of induction were then randomized onto Step 2 to either continue sorafenib or receive placebo. Step 2 (randomization): Patients with stable disease after induction will be randomized in a double-blinded manner to placebo or sorafenib. If a patient has progressed, the arm will be unblinded. Patients on placebo with PD can then crossover to receive sorafenib; patients with PD on the sorafenib arm will be removed from the study. Step 3 (crossover): If patients on placebo progressed within 1 year from randomization, they crossed over to the treatment arm and receive sorafenib for up to 1 year or until PD, unacceptable toxicity, or death.<br>* Other names: BAY 43-9006;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Per RECIST Criteria (V1.0): Complete Response (CR): disappearance of all target lesions Partial Response (PR): >=30% decrease in the sum of the longest diameter of target lesions Progressive Disease (PD): >=20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum of longest diameter recorded since randomization, or the appearance of new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD | Two months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival | Progression-free survival is defined as the duration from randomization to disease progression or death, whichever occurs first. Only randomized patients were included in this analysis. | Assessed every 8 weeks while on treatment. After the end of treatment, assessed every 3 months for 2 years, then every 6 months for 3 years. | 
| Overall Survival | Overall survival is defined as the duration from randomization to death or last known alive. Only randomized patients were included in this analysis. | Assessed every 8 weeks while on treatment. After the end of treatment, assessed every 3 months for 2 years, then every 6 months for 3 years | 
| Best Overall Response | The best overall response is the best response (per RECIST 1.0) recorded from randomization until disease progression/recurrence, taking as reference for progressive disease the smallest measurements recorded since randomization. | Assessed every 8 weeks while on treatment. After the end of treatment, assessed every 3 months for 2 years, then every 6 months for 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sorafenib, recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer