Stage IIIA Lung Non-Small Cell Cancer AJCC v7, Stage IIIB Lung Non-Small Cell Cancer AJCC v7, Stage IV Lung Non-Small Cell Cancer AJCC v7
Conditions
Brief summary
Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Vorinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving carboplatin and paclitaxel together is more effective with or without vorinostat in treating non-small cell lung cancer.
Detailed description
PRIMARY OBJECTIVES: I. To compare progression-free survival associated with the combination of carboplatin, paclitaxel and vorinostat versus carboplatin, paclitaxel and placebo for patients with previously untreated, advanced NSCLC. SECONDARY OBJECTIVES: I. To determine the response rate, time to treatment failure, and overall survival for the two regimens. II. To assess the safety profile of the regimen of vorinostat, carboplatin and paclitaxel for patients with advanced NSCLC. III. To understand the mechanistic aspects of drug effect by conducting correlative science studies on peripheral blood and archived tumor tissue. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive paclitaxel IV over 3 hours, and carboplatin IV over 30 minutes on day 0. Patients also receive vorinostat orally (PO) once daily on days -2 to 2. ARM II: Patients receive paclitaxel and carboplatin as in arm I. Patients also receive placebo PO once daily on days -2 to 2. In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 30 days, quarterly for 1 year, and then twice a year thereafter.
Interventions
DRUGCarboplatin
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPaclitaxel
Given IV
OTHERPlacebo Administration
Given PO
DRUGVorinostat
Given PO
Sponsors
National Cancer Institute (NCI)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically confirmed non-small cell lung cancer * No prior chemotherapy for advanced or metastatic disease * ECOG performance status 0 or 1 * Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as \>= 20 mm with conventional techniques or as \>= 10 mm with spiral CT scan * Life expectancy of greater than 12 weeks * Leukocytes \>= 3,000/mcL * Absolute neutrophil count \>= 1,500/mcL * Platelets \>= 100,000/mcL * Total bilirubin within normal institutional limits * AST(SGOT)/ALT(SGPT) =\< 2.5 x institutional upper limit of normal * Creatinine within normal institutional limits OR creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with creatinine levels above institutional normal * Ability to understand and the willingness to sign a written informed consent document
Exclusion criteria
* Patients who have had chemotherapy or radiotherapy in a metastatic setting * Patients may not be receiving any other investigational agents * Patients with untreated brain metastases should be excluded from this clinical trial; however, patients who have stable brain disease (should be off corticosteroids) at least 3 weeks after completion of appropriate therapy are eligible * Patients who have received any prior HDAC inhibitor (except valproic acid for seizure control provided that the valproic acid has been stopped at least 30 days before beginning therapy on this protocol) are excluded from this study * Peripheral neuropathy of severity greater than grade 1 * Known history of allergic reactions to paclitaxel * Prior therapy with paclitaxel * Inability to take oral medications on a continuous basis; patients unable to swallow the vorinostat capsules whole are ineligible (the capsules cannot be crushed or broken) * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements * Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with vorinostat; women of childbearing potential must use an appropriate double barrier method of birth control (such as female use of a diaphragm, intrauterine device \[IUD\], sponge and spermicide, in addition to the male use of a condom) or a prescribed birth control implant or practice abstinence; both double barrier contraception and implants must be used for at least one week prior to the start of the research study and continue for at least two weeks following the last study visit; please note that birth control pills should not be used while on this study as they may have a negative interaction with the experimental drug in this study * HIV-positive patients receiving combination antiretroviral therapy are ineligible
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From first day of treatment to the first observation of disease progression or death due to any cause, assessed up to 1 year | Estimated using the product-limit method of Kaplan and Meier. PFS defined as time from randomization to progression or death due to any cause. Progression defined as Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) (Phase I) | 4 weeks from start of treatment, up to 1 year | DLT is defined as any grade III or higher non-hematological toxicity except nausea, vomiting or alopecia. Nausea or vomiting (\> grade 2) that last longer than 48 hours despite maximal medical therapy. Absolute neutrophil count \< 1000/uL lasting longer than 7 days. Grade 4 thrombocytopenia (platelet \< 25,000/uL). Grade 3 or 4 neutropenia associated with sepsis or fever \> 38 C. Delay in starting cycle 2 by more than 2 weeks due to toxicity.Abnormal non-hematological laboratory criteria (Grade 3 or higher) will be considered a DLT, if clinically significant and drug-related. If baseline value is elevated prior to drug therapy, an increase will not be considered a DLT unless there is an elevation by more than 2 grades, and it is of clinical significance. Dose escalation schedule for vorinostat: 600 mg QD; 800 mg QD. |
| Maximum Tolerated Dose (MTD) (Phase I) | 4 weeks from start of treatment, up to 1 year | The highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. The MTD is one dose level below the lowest dose in which 33% or more of the patients experience a DLT. The MTD is based on the first cycle of therapy. The recommended Phase II dose is generally the MTD, although secondary considerations of toxicity and dose reductions on subsequent cycles and other secondary considerations may result in the recommended Phase II dose being below the MTD. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Dose Level 1 Patients receive A fixed dose of Carboplatin at AUC 6 mg/ml.min iv on day 0 of each cycle and Paclitaxel 200 mg/m2, iv on day 0 of each cycle. Patients also receive 600 mg QD of Vorinostat on days -2 to 2. Each cycle is 21 days.
Paclitaxel: Given IV
Carboplatin: Given IV
Vorinostat: Given PO
Laboratory Biomarker Analysis: Correlative studies | 6 |
| Phase I: Dose Level 2 Patients receive A fixed dose of Carboplatin at AUC 6 mg/ml.min iv on day 0 of each cycle and Paclitaxel 200 mg/m2, iv on day 0 of each cycle. Patients also receive 800 mg QD of Vorinostat on days -2 to 2. Each cycle is 21 days.
Paclitaxel: Given IV
Carboplatin: Given IV
Vorinostat: Given PO
Laboratory Biomarker Analysis: Correlative studies | 6 |
| Phase II (Vorinostat) Patients receive A fixed dose of Carboplatin at AUC 6 mg/ml.min iv on day 0 of each cycle and Paclitaxel 200 mg/m2, iv on day 0 of each cycle. Patients randomized to 800 mg QD of Vorinostat on days -2 to 2. Each cycle is 21 days.
Paclitaxel: Given IV
Carboplatin: Given IV
Vorinostat: Given PO
Laboratory Biomarker Analysis: Correlative studies | 4 |
| Phase II (Placebo) Patients receive A fixed dose of Carboplatin at AUC 6 mg/ml.min iv on day 0 of each cycle and Paclitaxel 200 mg/m2, iv on day 0 of each cycle. Patients randomized to 800 mg QD of Vorinostat on days -2 to 2. Each cycle is 21 days.
Paclitaxel: Given IV
Carboplatin: Given IV
Placebo: Given PO
Laboratory Biomarker Analysis: Correlative studies | 7 |
| Total | 23 |
Baseline characteristics
| Characteristic | Phase I: Dose Level 1 | Phase I: Dose Level 2 | Phase II (Vorinostat) | Phase II (Placebo) | Total |
|---|---|---|---|---|---|
| Age, Continuous | 61 years | 59 years | 72 years | 65 years | 63 years |
| Region of Enrollment United States | 6 participants | 6 participants | 4 participants | 7 participants | 23 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 1 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 5 Participants | 16 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 | 6 / 6 | 4 / 4 | 7 / 7 |
| serious Total, serious adverse events | 3 / 6 | 3 / 6 | 3 / 4 | 5 / 7 |
Outcome results
Primary
Progression-free Survival (PFS)
Estimated using the product-limit method of Kaplan and Meier. PFS defined as time from randomization to progression or death due to any cause. Progression defined as Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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: From first day of treatment to the first observation of disease progression or death due to any cause, assessed up to 1 year
Population: Due to early termination phase II portion of the study did not reach planned accrual.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase II: Vorinostat | Progression-free Survival (PFS) | 4.1 months |
| Phase II: Placebo | Progression-free Survival (PFS) | 7.3 months |
Secondary
Dose Limiting Toxicity (DLT) (Phase I)
DLT is defined as any grade III or higher non-hematological toxicity except nausea, vomiting or alopecia. Nausea or vomiting (\> grade 2) that last longer than 48 hours despite maximal medical therapy. Absolute neutrophil count \< 1000/uL lasting longer than 7 days. Grade 4 thrombocytopenia (platelet \< 25,000/uL). Grade 3 or 4 neutropenia associated with sepsis or fever \> 38 C. Delay in starting cycle 2 by more than 2 weeks due to toxicity.Abnormal non-hematological laboratory criteria (Grade 3 or higher) will be considered a DLT, if clinically significant and drug-related. If baseline value is elevated prior to drug therapy, an increase will not be considered a DLT unless there is an elevation by more than 2 grades, and it is of clinical significance. Dose escalation schedule for vorinostat: 600 mg QD; 800 mg QD.
Time frame: 4 weeks from start of treatment, up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: Vorinostat | Dose Limiting Toxicity (DLT) (Phase I) | 1 participants with DLTs |
| Phase II: Placebo | Dose Limiting Toxicity (DLT) (Phase I) | 0 participants with DLTs |
Secondary
Maximum Tolerated Dose (MTD) (Phase I)
The highest dose tested in which fewer than 33% of patients experience an attributable DLT to the study drug, when at least 6 patients are treated at that dose and are evaluable for toxicity. The MTD is one dose level below the lowest dose in which 33% or more of the patients experience a DLT. The MTD is based on the first cycle of therapy. The recommended Phase II dose is generally the MTD, although secondary considerations of toxicity and dose reductions on subsequent cycles and other secondary considerations may result in the recommended Phase II dose being below the MTD.
Time frame: 4 weeks from start of treatment, up to 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase II: Vorinostat | Maximum Tolerated Dose (MTD) (Phase I) | 800 mg |