Lung Cancer
Conditions
Keywords
adenocarcinoma of the lung, large cell lung cancer, recurrent non-small cell lung cancer, stage IIIB non-small cell lung cancer, stage IV non-small cell lung cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as hydroxychloroquine, carboplatin, and paclitaxel and work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Bevacizumab may also stop the growth of tumor cells by blocking blood flow to the tumor. Giving hydroxychloroquine together with carboplatin, paclitaxel and bevacizumab may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of hydroxychloroquine when given together with carboplatin, paclitaxel, and bevacizumab and to see how well they work in treating patients with recurrent advanced non-small cell lung cancer.
Detailed description
OBJECTIVES: Primary * To determine the recommended phase II dose of hydroxychloroquine and carboplatin in combination with paclitaxel and bevacizumab in patients with advanced recurrent non-small cell lung cancer. (Phase I) * To assess the antitumor activity, as measured by tumor response rate, of this regimen in these patients. (Phase II) Secondary * To measure time to progression, progression-free survival, and overall survival of these patients. * To assess the incidence of toxicity of this regimen in these patients. OUTLINE: This is a multicenter study. This is a phase I, dose-escalation study of carboplatin and hydroxychloroquine followed by a phase II study. Patients receive paclitaxel IV over 3 hours, carboplatin IV over 15-30 minutes, and bevacizumab IV over 90 minutes on day 1 and oral hydroxychloroquine on days 1-21. Treatment repeats every 21 days for a total of 4 courses. Patients then receive bevacizumab IV over 30-90 minutes every 21 days and oral hydroxychloroquine daily for up to 1 year in the absence of disease progression or unacceptable toxicity. After completion of study therapy, patients are followed every 6 months.
Interventions
BIOLOGICALbevacizumab
Only patients eligible for bevacizumab will receive bevacizumab. Dose is at 15 mg/kg on day 1 of each cycle.
DRUGcarboplatin
Carboplatin will be given at AUC = 6 by IV over 15-30 minutes on Day 1 immediately following paclitaxel
DRUGhydroxychloroquine
200 mg orally BID (total daily dose of 400 mg)
DRUGpaclitaxel
Dose of 200 mg/m2 IV on day 1 of each cycle
Sponsors
National Cancer Institute (NCI)
University of Medicine and Dentistry of New Jersey
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically or cytologically confirmed advanced non-small cell lung cancer, meeting the following criteria: * Recurrent disease * No component of squamous cell carcinoma * Mixed tumors will be categorized by predominant cell type * No mixed histology with small cell component * Diagnosis established on metastatic tumor aspirate or biopsy (not sputum cytology alone) and meets 1 of the following staging criteria: * Stage IIIB disease with malignant pleural effusion * Stage IV disease * Measurable disease * More than 1 year since post-operative adjuvant therapy for previously resected non-small cell lung cancer with evidence of disease progression * No known CNS metastases by CT scan or brain MRI within the past 28 days PATIENT CHARACTERISTICS: * ECOG performance status 0-1 * ANC ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * Hemoglobin ≥ 9 g/dL * Total bilirubin ≤ 1.5 times upper limit of normal (ULN) (≤ 2 times ULN and no other liver function test abnormality in patients with Gilbert disease) * AST/ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases) * Alkaline phosphatase ≤ 2.5 times ULN * Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min * INR ≤ 1.5 and aPTT normal * Urine protein:creatinine ratio \< 1.0 OR urine protein ratio \< 1,000 mg by 24-hour urine collection * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No ongoing or active infection * No psoriasis or porphyria * No HIV positivity * No significant traumatic injury within the past 28 days * No serious non-healing wound, ulcer, or bone fracture * No peripheral or sensory neuropathy \> grade 1 * No hypertension that cannot be controlled by antihypertensive medication (i.e., blood pressure \> 150/100 mm Hg despite optimal medical therapy) * No cardiovascular disease, including any of the following: * Unstable angina * New York Heart Association class II-IV congestive heart failure * History of significant vascular disease (e.g., aortic aneurysm) * Symptomatic peripheral vascular disease within the past 6 months * Myocardial infarction within the past 6 months * Stroke within the past 6 months * No other active malignancy within the past 3 years, except curatively treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or ductal or lobular carcinoma in situ of the breast, or other curatively treated malignancy with no evidence of disease \> 3 years * No retinal or visual field changes from prior 4-aminoquinoline compound therapy * No known hypersensitivity to 4-aminoquinoline compound * No known glucose-6-phosphate (G-6P) deficiency * No known bleeding diathesis or coagulopathy * No known gastrointestinal pathology that would interfere with drug bioavailability * No known prior hypersensitivity to carboplatin, paclitaxel, bevacizumab, hydroxychloroquine, or any of their components * No history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months * No history of gross hemoptysis (i.e., bright red blood of a ½ teaspoon or more) within the past 3 months * No history of any social or medical condition that, in the investigator's opinion, might interfere with the patient's ability to comply with the protocol or pose additional or unacceptable risk to the patient PRIOR CONCURRENT THERAPY: * See Disease Characteristics * At least 2 weeks since prior radiation to sites other than the brain, and recovered to ≤ grade 1 * At least 28 days since prior and no concurrent full-dose anticoagulants or thrombolytic agents * At least 28 days since prior major surgical procedure or open biopsy and no anticipated need for such during study therapy * Vascular access device placement with wound recovery allowed before study * No prior cytotoxic chemotherapy or targeted therapy in the advanced or metastatic setting * No concurrent treatment for rheumatoid arthritis or systemic lupus erythematosus * No concurrent combination antiretroviral therapy * No concurrent hydroxychloroquine for treatment or prophylaxis of malaria * No concurrent aurothioglucose * No other concurrent investigational or commercial agent or therapy for this malignancy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Recommended Phase II Dose of Hydroxychloroquine and Carboplatin When Administered With Paclitaxel and Bevacizumab (Phase I) | Followed for the duration of the phase 1 treatment, an average of 18 weeks |
| Overall Response (Phase II) | Treatment start date to date of best response |
Secondary
| Measure | Time frame |
|---|---|
| Time to Progression (Phase II) | Treatment start date and date of progression |
| Progression-free Survival at 1 Year (Phase II) | Treatment start date to 1 year |
| Overall Survival (Phase II) | Treatment start date to date of death |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Cancer Institute of New Jersey (a comprehensive cancer center) and the Robert Wood Johnson University Hospital-Hamilton in New Jersey from June 2008 through December 2010.
Participants by arm
| Arm | Count |
|---|---|
| Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab Cohort 1: Bevacizumab Eligible Patients All on Day 1 Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min Bevacizumab 15 mg/kg IV over 90 min for PLUS Hydroxychloroquine 200 mg PO BID Cycles every 3 weeks for 4-6 Cycles | 8 |
| Hydroxychloroquine, Carboplatin, Paclitaxel Cohort 2: Bevacizumab Ineligible Patients All on Day 1 Paclitaxel 200mg/m2 IV over 3 hours Carboplatin AUC= 6 IV over 15-30 min PLUS Hydroxychloroquine 200 mg PO BID Cycles every 3 weeks for 4-6 Cycles | 0 |
| Total | 8 |
Baseline characteristics
| Characteristic | Total | Hydroxychloroquine, Carboplatin, Paclitaxel, Bevacizumab |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 4 Participants | 4 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants |
| Age, Continuous | 63.3 years STANDARD_DEVIATION 8.4 | 63.3 years STANDARD_DEVIATION 8.4 |
| Region of Enrollment United States | 8 participants | 8 participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 8 / 8 | 0 / 0 |
| serious Total, serious adverse events | 2 / 8 | 0 / 0 |
Outcome results
Primary
Overall Response (Phase II)
Time frame: Treatment start date to date of best response
Population: Study was terminated early and insufficient data were collected to assess this outcome measure.
Primary
Recommended Phase II Dose of Hydroxychloroquine and Carboplatin When Administered With Paclitaxel and Bevacizumab (Phase I)
Time frame: Followed for the duration of the phase 1 treatment, an average of 18 weeks
Population: Study was terminated early and insufficient data were collected to assess this outcome measure.
Secondary
Overall Survival (Phase II)
Time frame: Treatment start date to date of death
Population: Study was terminated early and insufficient data were collected to assess this outcome measure.
Secondary
Progression-free Survival at 1 Year (Phase II)
Time frame: Treatment start date to 1 year
Population: Study was terminated early and insufficient data were collected to assess this outcome measure.
Secondary
Time to Progression (Phase II)
Time frame: Treatment start date and date of progression
Population: Study was terminated early and insufficient data were collected to assess this outcome measure.