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

Phase 2

Completed

Conditions: Lung Cancer

Interventions: Drug: Sorafenib
Drug: Placebo

Registration Number: NCT00064350

Lead Sponsor: Eastern Cooperative Oncology Group

Brief Summary: 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 That is, tumor growth is suspended while the drug is administered but returns to baseline rates when the agent is withdrawn.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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 342

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Induction then Placebo then Sorafenib	Placebo	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.
Induction then Placebo then Sorafenib	Sorafenib	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.
Induction then Sorafenib	Sorafenib	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.
Induction, not randomized	Sorafenib	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.

Primary Outcome Measures

Name	Time	Method
Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization	Two 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

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	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.	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.
Overall Survival	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 is defined as the duration from randomization to death or last known alive. Only randomized patients were included in this analysis.
Best Overall Response	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	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.

Trial Locations

Locations (141): Stanford Comprehensive Cancer Center - Stanford
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Stanford, California, United States
Aurora Presbyterian Hospital
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Aurora, Colorado, United States
Boulder Community Hospital
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Boulder, Colorado, United States
Penrose Cancer Center at Penrose Hospital
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Colorado Springs, Colorado, United States
Porter Adventist Hospital
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Denver, Colorado, United States
Presbyterian - St. Luke's Medical Center
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Denver, Colorado, United States
St. Joseph Hospital
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Denver, Colorado, United States
Rose Medical Center
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Denver, Colorado, United States
CCOP - Colorado Cancer Research Program
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Denver, Colorado, United States
Swedish Medical Center
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Englewood, Colorado, United States
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Stanford Comprehensive Cancer Center - Stanford
🇺🇸Stanford, California, United States