Lung Cancer
Conditions
Keywords
recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer, squamous cell lung cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as gemcitabine and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. AZD2171 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. Giving gemcitabine and carboplatin together with AZD2171 may kill more tumor cells. PURPOSE: This randomized phase II trial is studying how well giving gemcitabine and carboplatin together with AZD2171 works compared to giving gemcitabine and carboplatin without AZD2171 as first-line therapy in treating patients with stage IIIB or stage IV non-small cell lung cancer.
Detailed description
OBJECTIVES: Primary * Assess the objective tumor response rate in patients with stage IIIB or IV non-small cell lung cancer treated with gemcitabine hydrochloride, carboplatin, and AZD2171 as first-line therapy. Secondary * Compare the proportion of patients who are progression-free at 6 months after treatment with gemcitabine hydrochloride and carboplatin with vs without AZD2171. * Compare the duration of response for responding patients treated with these regimens. * Compare the time-to-progression and time-to-treatment failure. * Compare the 1-year overall survival. * Compare the clinical toxicities. * Assess the safety and tolerability of these regimens in these patients. Tertiary * Collect blood and tumor specimens for future evaluation of pharmacogenetic and proteomic markers of tumor response and toxicity to therapy with these agents. * Bank paraffin-embedded tissue blocks/slides and blood samples for future histochemistry evaluation and DNA extraction. OUTLINE: This is a randomized, multicenter study. Patients are stratified according to prior adjuvant therapy (yes vs no) and ECOG performance status (0 vs 1). Patients are randomized to 1 of 2 treatment arms. * Arm I: Patients receive gemcitabine hydrochloride IV over 30 minutes on days 1 and 8, carboplatin IV over 30 minutes on day 1, and oral AZD2171 once daily on days 1-21. Treatment repeats every 21 days for up to 6 courses. Patients achieving stable disease, partial response, or complete response after 6 courses of therapy receive AZD2171 alone as above. Treatment with AZD2171 repeats every 21 days in the absence of disease progression or unacceptable toxicity. * Arm II: Patients receive gemcitabine and carboplatin as in arm I. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo blood collection periodically during study for pharmacologic correlative studies. After completion of study treatment, patients are followed periodically for 5 years. PROJECTED ACCRUAL: A total of 102 patients will be accrued for this study.
Interventions
DRUGcarboplatin
Given IV
DRUGcediranib maleate
Given orally
DRUGgemcitabine hydrochloride
Given IV
Sponsors
National Cancer Institute (NCI)
Alliance for Clinical Trials in Oncology
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) * Squamous cell histology allowed * No mixed histology with small cell component * Stage IIIB (with pleural effusion) or stage IV disease * Presence of peritoneal or pericardial effusion alone in the absence of cytologic evidence is not allowed * Measurable disease, defined as ≥ 1 lesion with longest diameter ≥ 2.0 cm by conventional techniques OR ≥ 1.0 cm by spiral CT scan * If the only site of measurable disease was previously irradiated, progressive disease must be evident * Ineligible for bevacizumab therapy * No symptomatic, untreated, or uncontrolled CNS metastases * CNS metastases treated with whole-brain radiation (WBRT) allowed 4 weeks after completion of WBRT PATIENT CHARACTERISTICS: * ECOG performance status 0-1 * Life expectancy ≥ 12 weeks * Absolute neutrophil count ≥ 1,500/mm\^3 * Hemoglobin ≥ 9 g/dL * Platelet count ≥ 100,000/mm\^3 * Bilirubin ≤ 3 times upper limit of normal (ULN) * ALT and AST ≤ 3 times ULN (5 times ULN if liver involvement) * Alkaline phosphatase ≤ 5 times ULN * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective nonhormonal contraception * No proteinuria ≥ 1+ * No uncontrolled blood pressure (BP), defined as systolic BP \> 150 mm Hg and/or diastolic BP \> 100 mm Hg in spite of adequate antihypertensive therapy * No impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of AZD2171 (e.g., ulcerative disease, uncontrolled nausea, vomiting, or diarrhea, malabsorption syndrome, or small bowel resection) * No seizure disorder * No significant traumatic injury within 4 weeks prior to study entry * No second primary malignancy except any of the following: * Carcinoma in situ of the cervix * Nonmelanoma skin cancer * Prior malignancy diagnosed and definitively treated ≥ 5 years ago with no subsequent evidence of recurrence * History of low-grade (Gleason score ≤ 6) localized prostate cancer even if diagnosed \< 5 years prior to registration * Treated stage I breast cancer ≤ 5 years prior to registration * No uncontrolled intercurrent illness, including, but not limited to, any of the following: * Ongoing or active infection * Significant pulmonary symptoms at baseline due to disease * Symptomatic congestive heart failure * Unstable angina pectoris * Cardiac arrhythmia * Psychiatric illness or social situation that would limit compliance with study requirements * Baseline hemoptysis * Cavitating lesions * No QTc prolongation \> 500 msec or other significant ECG abnormality within the past 14 days * No New York Heart Association class III or IV disease PRIOR CONCURRENT THERAPY: * See Disease Characteristics * No prior chemotherapy for advanced lung cancer * Neoadjuvant or adjuvant therapy for lung cancer within the past 12 months allowed * More than 12 months since prior immunotherapy and biologic therapy * More than 4 weeks since prior radiotherapy (2 weeks for palliative radiotherapy to skeletal metastases) * At least 2 weeks since prior WBRT * No radiotherapy to ≥ 25% of bone marrow * No major surgery (i.e., laparotomy) or open biopsy within 4 weeks prior to study entry (2 weeks for minor surgery) * Insertion of a vascular access device not considered major or minor surgery * No concurrent combination antiretroviral therapy for HIV-positive patients * No concurrent grapefruit or grapefruit juice during AZD2171 treatment * No concurrent drugs or biologics with proarrhythmic potential * Concurrent palliative radiotherapy to nontarget sites (i.e., painful pre-existing bony metastasis) allowed with AZD2171 (chemotherapy is held until completion of radiotherapy)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II Patients Only) | Up to 5 years | A confirmed tumor response was defined as a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: * Complete Response (CR): disappearance of all target lesions; * Partial Response (PR) 30% decrease in sum of longest diameter of target lesions |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (Phase II Patients Only) | Up to 5 years | Progression-free survival was defined as the time from study enrollment to the first date of disease progression or death as a result of any cause, whichever occurs first. Progression-free survival will be censored at the date of the last contact for patients who are still alive and who have not had disease progression. |
| Time to Treatment Failure (Phase II Patients Only) | Up to 15 months | Time to treatment failure was defined to be the time from date of registration to the date at which the patient was removed from the treatment due to progression, toxicity, refusal or death from any cause. |
| Progression-free Survival Rate at 6 Months After Randomization (Phase II Patients Only) | 6 months | Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), 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. |
| Overall Survival (Phase II Patients Only) | Up to 5 years | Overall survival was defined as the time from study enrollment to the time of death from any cause. Overall survival will be censored at the date of the last follow-up visit for patients who are still alive or lost to follow-up. |
| Dose Limiting Toxicity (DLT) (Lead-in Phase Arm I Patients Only) | Cycle 1 (up to 3 weeks) | DLT was defined as an adverse event occurring in cycle 1 only, at least possibly attributed to the study treatment and meeting the following criteria: 1) Grade 4 absolute neutrophil count (ANC) \>5 days or of any duration with fever \>38.5 degree Celsius; 2) Grade 4 platelet count; 3) Grade 3 or higher non-hematologic toxicities (for nausea, vomiting or diarrhea, grade 3 toxicities will be DLT if they occur despite maximal use of anti-emetic support or anti-diarrhea agents, respectively); 4) Cediranib dose interruption of \>14 days for drug-related toxicities. |
| Overall Survival at 1 Year After Randomization (Phase II Patients Only) | 1 year | Overall survival was defined as the time from study enrollment to the time of death from any cause. A patient is classified as a success if alive at 1 year. |
Countries
United States
Participant flow
Recruitment details
One hundred-and one (101) participants were enrolled between June 15, 2007 and December 5, 2008. Data for this report were frozen on September 13, 2011.
Pre-assignment details
Five participants were excluded from all analyses due to withdrew consent or never received study treatment: 1 lead-in arm I; 2 phase II arm I; and 2 phase II arm II. The starting cediranib dose of 45 mg was not tolerable and was reduced to 30 mg once daily on a continuous schedule for the phase II portion of the study.
Participants by arm
| Arm | Count |
|---|---|
| Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin) Patients receive oral cediranib 45mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles. | 6 |
| Lead-in Phase: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles. | 3 |
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) Patients receive oral cediranib 30mg once daily in combination with chemotherapy, gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles. | 58 |
| Phase II: Arm II (Gemcitabine + Carboplatin) Patients receive gemcitabine 1000 mg/m2 on days 1 and 8 and carboplatin dosed to an area under the serum concentration time curve of 5 on day 1 via intravenous infusion every 3 weeks for a maximum of six cycles. | 29 |
| Total | 96 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 32 | 3 |
| Overall Study | Alternate Treatment | 1 | 0 | 0 | 0 |
| Overall Study | Death | 0 | 0 | 1 | 2 |
| Overall Study | Disease Progression | 3 | 1 | 13 | 11 |
| Overall Study | Other Unspecified Reason | 0 | 0 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 5 | 2 |
Baseline characteristics
| Characteristic | Lead-in Phase: Arm II (Gemcitabine + Carboplatin) | Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Lead-in Phase: Arm I (Cediranib + Gemcitabine + Carboplatin) | Phase II: Arm II (Gemcitabine + Carboplatin) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 74 years | 65 years | 65.5 years | 64 years | 64 years |
| Before adjuvant treatment No | 3 Participants | 56 Participants | 5 Participants | 28 Participants | 92 Participants |
| Before adjuvant treatment Yes | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Cell type Adenocarcinoma | 1 Participants | 22 Participants | 4 Participants | 16 Participants | 43 Participants |
| Cell type All other | 1 Participants | 27 Participants | 2 Participants | 5 Participants | 35 Participants |
| Cell type Squamous | 1 Participants | 9 Participants | 0 Participants | 8 Participants | 18 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0=Asymptomatic and fully active | 1 Participants | 33 Participants | 3 Participants | 17 Participants | 54 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1=Symptomatic and fully ambulatory | 2 Participants | 25 Participants | 3 Participants | 12 Participants | 42 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 3 Participants | 55 Participants | 6 Participants | 26 Participants | 90 Participants |
| Region of Enrollment United States | 3 participants | 58 participants | 6 participants | 29 participants | 96 participants |
| Sex: Female, Male Female | 3 Participants | 26 Participants | 4 Participants | 12 Participants | 45 Participants |
| Sex: Female, Male Male | 0 Participants | 32 Participants | 2 Participants | 17 Participants | 51 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 58 / 58 | 29 / 29 |
| serious Total, serious adverse events | 2 / 6 | 2 / 3 | 39 / 58 | 8 / 29 |
Outcome results
Primary
Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II Patients Only)
A confirmed tumor response was defined as a complete response (CR) or partial response (PR) noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. Response was defined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria: * Complete Response (CR): disappearance of all target lesions; * Partial Response (PR) 30% decrease in sum of longest diameter of target lesions
Time frame: Up to 5 years
Population: All phase II participants who met eligibility criteria and have received at least one cycle of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II Patients Only) | 19 percentage of participants |
| Phase II: Arm II (Gemcitabine + Carboplatin) | Confirmed Response Rate (Complete Response and Partial Response) as Assessed by Response Evaluation Criteria in Solid Tumors (RECIST) (Phase II Patients Only) | 20 percentage of participants |
Secondary
Dose Limiting Toxicity (DLT) (Lead-in Phase Arm I Patients Only)
DLT was defined as an adverse event occurring in cycle 1 only, at least possibly attributed to the study treatment and meeting the following criteria: 1) Grade 4 absolute neutrophil count (ANC) \>5 days or of any duration with fever \>38.5 degree Celsius; 2) Grade 4 platelet count; 3) Grade 3 or higher non-hematologic toxicities (for nausea, vomiting or diarrhea, grade 3 toxicities will be DLT if they occur despite maximal use of anti-emetic support or anti-diarrhea agents, respectively); 4) Cediranib dose interruption of \>14 days for drug-related toxicities.
Time frame: Cycle 1 (up to 3 weeks)
Population: The first 6 participants treated on Arm I (lead-in phase).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Dose Limiting Toxicity (DLT) (Lead-in Phase Arm I Patients Only) | 1 participants |
Secondary
Overall Survival at 1 Year After Randomization (Phase II Patients Only)
Overall survival was defined as the time from study enrollment to the time of death from any cause. A patient is classified as a success if alive at 1 year.
Time frame: 1 year
Population: All phase II participants who met eligibility criteria and started the treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Overall Survival at 1 Year After Randomization (Phase II Patients Only) | 48 percentage of participants |
| Phase II: Arm II (Gemcitabine + Carboplatin) | Overall Survival at 1 Year After Randomization (Phase II Patients Only) | 41 percentage of participants |
Secondary
Overall Survival (Phase II Patients Only)
Overall survival was defined as the time from study enrollment to the time of death from any cause. Overall survival will be censored at the date of the last follow-up visit for patients who are still alive or lost to follow-up.
Time frame: Up to 5 years
Population: All phase II participants who met eligibility criteria and started the treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Overall Survival (Phase II Patients Only) | 12.0 months |
| Phase II: Arm II (Gemcitabine + Carboplatin) | Overall Survival (Phase II Patients Only) | 9.9 months |
Secondary
Progression-free Survival (Phase II Patients Only)
Progression-free survival was defined as the time from study enrollment to the first date of disease progression or death as a result of any cause, whichever occurs first. Progression-free survival will be censored at the date of the last contact for patients who are still alive and who have not had disease progression.
Time frame: Up to 5 years
Population: All phase II participants who met eligibility criteria and have received at least one cycle of treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Progression-free Survival (Phase II Patients Only) | 6.3 months |
| Phase II: Arm II (Gemcitabine + Carboplatin) | Progression-free Survival (Phase II Patients Only) | 4.5 months |
Secondary
Progression-free Survival Rate at 6 Months After Randomization (Phase II Patients Only)
Estimated using the Binomial point estimator (number of successes divided by the total number of evaluable patients). A patient is classified as a success if alive and progression-free at 6 months. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), 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: 6 months
Population: All phase II participants who met eligibility criteria and have received at least one cycle of treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Progression-free Survival Rate at 6 Months After Randomization (Phase II Patients Only) | 48 percentage of participants |
| Phase II: Arm II (Gemcitabine + Carboplatin) | Progression-free Survival Rate at 6 Months After Randomization (Phase II Patients Only) | 38 percentage of participants |
Secondary
Time to Treatment Failure (Phase II Patients Only)
Time to treatment failure was defined to be the time from date of registration to the date at which the patient was removed from the treatment due to progression, toxicity, refusal or death from any cause.
Time frame: Up to 15 months
Population: All phase II participants who met the eligibility criteria and have ended the study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Arm I (Cediranib + Gemcitabine + Carboplatin) | Time to Treatment Failure (Phase II Patients Only) | 2.48 months |
| Phase II: Arm II (Gemcitabine + Carboplatin) | Time to Treatment Failure (Phase II Patients Only) | 2.89 months |