Lung Cancer
Conditions
Keywords
recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, sorafenib
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 That is, tumor growth is suspended while the drug is administered but returns to baseline rates when the agent is withdrawn.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.
Interventions
DRUGSorafenib
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.
DRUGPlacebo
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).
Sponsors
National Cancer Institute (NCI)
Eastern Cooperative Oncology Group
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
The first patient was accrued on May 28, 2004.
Participants by arm
| Arm | Count |
|---|---|
| Induction Then 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.
Randomization: Patients with stable disease after the induction treatment were randomized to receive either sorafenib or placebo. Patients on the sorafenib arm receive sorafenib twice daily for up to 1 year in the absence of disease progression or unacceptable disease.
In the study design, only patients on the placebo arm with progressive disease may cross over to receive sorafenib. Due to drug dispensing error, even though some patients actually received straight sorafenib during Step 2 (randomization) treatment, they were thought to be randomized onto the placebo arm upon progression and unblinding (before finding out the fact of the dispensing error). Consequently, these patients were crossed over to Step 3, and there were 10 of them. | 50 |
| Induction Then Placebo Then 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. 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. | 31 |
| Induction, Not Randomized 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 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.
To show baseline characteristics for eligible and treated patients in both the randomization phase (the most important part of this study) and the induction phase, this group contains the following patients:
* eligible and treated patients who were not randomized (n=194)
* randomized patients who were not eligible or did not start treatment in the randomization phase (n=24)
There were 218 patients in this group so the total number of patients is 299 and the entire cohort represents all eligible and treated patients in the induction phase. | 218 |
| Total | 299 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Cross-Over | Adverse Event | 0 | 1 | 0 |
| Cross-Over | Death | 1 | 3 | 0 |
| Cross-Over | Ineligible or never started treatment | 3 | 6 | 0 |
| Cross-Over | Other | 0 | 2 | 0 |
| Cross-Over | Withdrawal by Subject | 2 | 2 | 0 |
| Induction Treatment | Adverse Event | 0 | 2 | 49 |
| Induction Treatment | Death | 0 | 0 | 9 |
| Induction Treatment | Disease Progression | 5 | 1 | 110 |
| Induction Treatment | Ineligible or never started treatment | 3 | 6 | 34 |
| Induction Treatment | Other | 0 | 0 | 13 |
| Induction Treatment | Withdrawal by Subject | 0 | 0 | 21 |
| Randomization | Adverse Event | 8 | 3 | 0 |
| Randomization | Death | 3 | 0 | 0 |
| Randomization | Ineligible or never started treatment | 9 | 15 | 0 |
| Randomization | Other | 5 | 0 | 0 |
| Randomization | Withdrawal by Subject | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Induction Then Sorafenib | Induction Then Placebo Then Sorafenib | Induction, Not Randomized | Total |
|---|---|---|---|---|
| Age, Continuous | 64.5 years | 69 years | 63 years | 64 years |
| Sex/Gender, Customized Female | 27 participants | 13 participants | 90 participants | 130 participants |
| Sex/Gender, Customized Male | 23 participants | 18 participants | 127 participants | 168 participants |
| Sex/Gender, Customized Unknown | 0 participants | 0 participants | 1 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 307 / 333 | 42 / 45 | 34 / 38 | 11 / 12 | 35 / 35 |
| serious Total, serious adverse events | 133 / 333 | 16 / 45 | 7 / 38 | 2 / 12 | 15 / 35 |
Outcome results
Primary
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
Time frame: Two months after randomization
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Response | 0 participants |
| Sorafenib | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Stable Disease | 27 participants |
| Sorafenib | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Progression | 19 participants |
| Sorafenib | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Unevaluable | 4 participants |
| Placebo | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Unevaluable | 1 participants |
| Placebo | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Response | 0 participants |
| Placebo | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Progression | 23 participants |
| Placebo | Number of Patients Maintaining Stable Disease or Objective Response 2 Months After Randomization | Stable Disease | 7 participants |
Comparison: Compare the proportion of patients maintaining stable disease or objective response at 2 months after randomization between the two arms.p-value: 0.005Fisher Exact
Secondary
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.
Time frame: 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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sorafenib | Best Overall Response | Unevaluable | 1 Participants |
| Sorafenib | Best Overall Response | Complete Response | 0 Participants |
| Sorafenib | Best Overall Response | Partial Response | 1 Participants |
| Sorafenib | Best Overall Response | Stable Disease | 28 Participants |
| Sorafenib | Best Overall Response | Progression | 20 Participants |
| Placebo | Best Overall Response | Progression | 24 Participants |
| Placebo | Best Overall Response | Stable Disease | 6 Participants |
| Placebo | Best Overall Response | Complete Response | 0 Participants |
| Placebo | Best Overall Response | Unevaluable | 0 Participants |
| Placebo | Best Overall Response | Partial Response | 1 Participants |
Secondary
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.
Time frame: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib | Overall Survival | 13.7 Months |
| Placebo | Overall Survival | 9.0 Months |
Comparison: Compare OS between the Sorafenib arm and the placebo armp-value: 0.12Log Rank
Secondary
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.
Time frame: 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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sorafenib | Progression-free Survival | 3.3 Months |
| Placebo | Progression-free Survival | 2.0 Months |
Comparison: Compare PFS between the Sorafenib arm and the placebo armp-value: 0.014Log Rank