Lung Cancer
Conditions
Keywords
stage IV non-small cell lung cancer, stage IIIB non-small cell lung cancer
Brief summary
RATIONALE: Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Radiation therapy uses high-energy x-rays to kill tumor cells. Nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) may make tumor cells more sensitive to radiation therapy. Giving nab-paclitaxel together with radiation therapy and carboplatin may kill more tumor cells. PURPOSE: This phase I/II trial is studying the side effects and best dose of giving nab-paclitaxel together with carboplatin and radiation therapy and to see how well it works in treating patients with stage III non-small-cell lung cancer that cannot be removed by surgery.
Detailed description
OBJECTIVES: Primary * To determine the maximum tolerated dose of nab-paclitaxel when combined concurrently with carboplatin and radiation followed by two courses of nab-paclitaxel carboplatin as consolidation. (Phase I) * To evaluate the progression-free survival in patients with stage III unresectable non-small cell lung cancer treated with nab-paclitaxel, carboplatin, and radiotherapy followed by two courses of nab-paclitaxel with carboplatin as consolidation. (Phase II) Secondary * To assess safety and tolerability and identify dose-limiting toxicities in patients receiving nab-paclitaxel combined concurrently with carboplatin and radiotherapy. (Phase I) * To assess progression-free survival, response rates, and survival. (Phase I) * To assess overall survival and response rates in all patients treated on this study. (Phase II) * To assess the safety and tolerability of patients receiving nab-paclitaxel combined concurrently with carboplatin and radiotherapy followed by two courses of nab-paclitaxel/carboplatin as consolidation. (Phase II) OUTLINE: This is a multicenter study. * Phase I: * Concurrent chemoradiotherapy: Patients receive escalating doses of nab-paclitaxel IV over 30 minutes and carboplatin IV over 30 minutes on days 1, 8, 15, 22, 29, 36, and 43. They also receive conformal radiotherapy once daily 5 days a week on days 1-5 in weeks 1-7. Patients are evaluated between weeks 8-10. Patients with disease progression are removed from study. Patients with stable disease, partial response, or complete response proceed to consolidation chemotherapy 3 weeks after completion of chemoradiotherapy. * Consolidation chemotherapy: Patients receive nab-paclitaxel IV over 30 minutes on days 1, 8, and 15 and carboplatin IV over 30 minutes on day 1. Treatment repeats ever 21 days for up to 2 courses. * Phase II: Patients receive concurrent chemoradiotherapy at the Maximum Tolerated Dose (MTD) of nab-paclitaxel followed by consolidation chemotherapy as in phase I. After completion of study treatment, patients are followed at 2 months, every 3 months for 2 years, every 4 months for 2 years, and then every 6 months thereafter. PROJECTED ACCRUAL: A total of 98 patients (15 patients for phase I and 83 patients for phase II) will be accrued for this study.
Interventions
DRUGcarboplatin
(AUC 2) through a vein over 30 minutes following nab-paclitaxel, once per week x 7 weeks
DRUGnab-paclitaxel
Phase I: beginning at 40 mg/m2 through a vein over 30 minutes once per week x 7 weeks Phase II: Maximum tolerated dose through a vein over 30 minutes once per week x 7 weeks
RADIATIONRadiation therapy
3D conformal radiotherapy or Intensity-Modulated Radiation Therapy (IMRT), 2.0 Gy per day x 5 days per week for 33 days during Weeks 1-7 ; Total Dose = 66 Gy
Sponsors
National Cancer Institute (NCI)
Vanderbilt-Ingram Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
for Phase I and Phase II Patients: * Patients must voluntarily sign and date an informed consent before the initiation of any study procedures * Patients must have non-metastatic, inoperable, Stage IIIA or IIIB histologically or cytologically documented NSCLC without evidence of malignant pleural effusion * Patients must not have received any prior systemic chemotherapy, thoracic radiotherapy or surgical resection for treatment of NSCLC * Patients must have at least one site of unidirectionally measurable disease as defined by Response Evaluation in Solid Tumors (RECIST) criteria * Patients must be ≥ 3 weeks from a formal exploratory thoracotomy * Patients must have a Radiation Oncology and Medical Oncology consult and approval prior to study entry * Patients must be ≥ 18 years of age * Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Women of childbearing potential must have a negative baseline serum pregnancy or a negative urine pregnancy test within 7 days prior to Week 1, Day 1 and must not be breast feeding. * Women of childbearing potential and men with a sexual partner of child bearing potential must use an effective method of contraception beginning prior to study entry, for the duration of the study participation and for a minimum of 3 months after the last dose of chemotherapy. * Patients must have adequate hepatic, renal, lung and bone marrow function as defined below: * Absolute neutrophil count (ANC) ≥1,500/mm3 * Hemoglobin ≥ 9.0 gm/dL * Serum Creatinine ≤1.5mg/dl * Platelets \> 100,000/mm3 * Total bilirubin ≤ upper limit of normal * AST and ALT \< 2.5 X upper limit of normal * Alkaline phosphatase \< 2.5 X upper limit of normal * Calculated CrCl \> 45 ml/min (via Cockroft-Gault formula) * Forced expiratory volume in 1 second (FEV 1) \> 800 ml
Exclusion criteria
for Phase I and Phase II Patients: * Known hypersensitivity to carboplatin or nab-paclitaxel * Peripheral neuropathy Grade ≥ 2 * Wet stage IIIB (documented malignant pleural effusion) or stage IV NSCLC * Previous chemotherapy or radiation therapy to the chest * Any concomitant malignancy or brain metastasis * Any uncontrolled, clinically significant medical or psychiatric disorder * Pregnant or nursing women * A greater than or equal to 10% weight loss over the past 3 months
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (Phase II) | On-study to lesser of date of progression or date of death from any cause (assessed up to 2 years) | Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: \>= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions |
| Maximum Tolerated Dose of Nab-paclitaxel When Combined Concurrently With Carboplatin and Radiation (Phase I) | 7 weeks | The highest dose in milligrams per meter of body surface squared (mg/m2) of nab-paclitaxel in combination with carboplatin while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of nab-paclitaxel in combination with carboplatin until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs per Common Toxicity Criteria v 3.0: recurring non-hematological (except esophagitis) \> Grade 2, non-hematological or esophagitis \> Grade 3 toxicities that are symptomatically unacceptable to patient and result in treatment delay for \> 2 weeks, persistent toxicity resulting in treatment delay for \> 2 weeks. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (Phase I) | On-study date to date of death from any cause (assessed up to 2 years) | Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details). |
| Response (Phase I) | On-treatment date to date of progressive disease (assessed up to 2 years) | Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) \>=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD. |
| Number of Patients With Each Worst Grade Toxicity (Phase I) | On-study date to 30 days following final dose of study drug | Count of patients according to the worst-grade toxicity (WGT) experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening; Grade 5, death. |
| Number of Patients With Each Worst Grade Toxicity (Phase II) | at 16 weeks | The number of patients with worst-grade toxicity at each of five grades following NCI Common Toxicity Criteria: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, disabling, 5 = death |
| Response (Phase II) | On-treatment date to date of progressive disease (assessed up to 2 years) | Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) \>=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD. |
| Overall Survival (Phase II) | Time Frame: date on study to date of death from any cause or last known date alive | Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details. Too few patients were enrolled in the Phase II arm for an analysis of overall survival |
| Progression-free Survival (Phase I) | On-study to lesser of date of progression or date of death from any cause (assessed up to 2 years) | Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: \>= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions |
Other
| Measure | Time frame | Description |
|---|---|---|
| Secreted Protein Acidic and Rich in Cysteine (SPARC) Gene Expression | On receipt of tumor tissue blocks | Secreted protein acidic and rich in cysteine (SPARC) gene expression in tumor specimens. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited from November 2007 through September 2011
Pre-assignment details
Twenty-two patients signed consent on this study, nine of which were ineligible to receive treatment.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Nab-paclitaxel in mg/m2 of nab-paclitaxel in combination with carboplatin AUC 2 weekly for 7 weeks with concurrent radiotherapy | 11 |
| Phase II MTD of Nab-paclitaxel in mg/m2 in combination with carboplatin AUC 2 with concurrent radiotherapy weekly for 7 weeks. Responding patients will be treated with consolidation chemotherapy of nab-paclitaxel 100 mg/m2 weekly for 3 weeks every 21 days followed by carboplatin on day 1 of each cycle. One cycle is 21 days. Patients receive 2 cycles of this consolidation chemotherapy. | 2 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | progression of disease | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Phase II | Phase I | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 7 Participants | 7 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 4 Participants | 6 Participants |
| Age, Continuous | 56 years STANDARD_DEVIATION 4 | 63 years STANDARD_DEVIATION 9 | 59 years STANDARD_DEVIATION 16 |
| Region of Enrollment United States | 2 participants | 11 participants | 13 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 1 Participants | 9 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 10 | 2 / 2 |
| serious Total, serious adverse events | 5 / 10 | 1 / 2 |
Outcome results
Primary
Maximum Tolerated Dose of Nab-paclitaxel When Combined Concurrently With Carboplatin and Radiation (Phase I)
The highest dose in milligrams per meter of body surface squared (mg/m2) of nab-paclitaxel in combination with carboplatin while maintaining tolerability. Cohorts of 3-6 patients received escalating doses of nab-paclitaxel in combination with carboplatin until the maximum tolerated dose (MTD) was achieved. The MTD is defined as the dose preceding that at which 2 or more of 6 patients experience dose-limiting toxicity (DLT) during the initial cycle of therapy. DLTs per Common Toxicity Criteria v 3.0: recurring non-hematological (except esophagitis) \> Grade 2, non-hematological or esophagitis \> Grade 3 toxicities that are symptomatically unacceptable to patient and result in treatment delay for \> 2 weeks, persistent toxicity resulting in treatment delay for \> 2 weeks.
Time frame: 7 weeks
Population: MTD based on clinical performance of those patients who received the study drug. One patient withdrew before receiving treatment. No formal statistical analysis, such as hypothesis testing, was performed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase I | Maximum Tolerated Dose of Nab-paclitaxel When Combined Concurrently With Carboplatin and Radiation (Phase I) | 40 mg/m2 |
Primary
Progression-free Survival (Phase II)
Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: \>= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions
Time frame: On-study to lesser of date of progression or date of death from any cause (assessed up to 2 years)
Population: All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where either death or progression is an event, with censoring for non-progressed, non-expired patients at greater of off-study date or last known date alive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I | Progression-free Survival (Phase II) | 126 days |
Secondary
Number of Patients With Each Worst Grade Toxicity (Phase I)
Count of patients according to the worst-grade toxicity (WGT) experienced by each, where worst-grade toxicity is per NCI common toxicity criteria: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life-threatening; Grade 5, death.
Time frame: On-study date to 30 days following final dose of study drug
Population: Total number of patients reported with any toxicity. One patient did not experience toxicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase I) | Number of patients with worst Grade 1 toxicity | 0 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase I) | Number of patients with worst grade 2 toxicity | 2 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase I) | Number of patients with worst grade 3 toxicities | 5 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase I) | Number of patients with worst grade 4 toxicity | 3 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase I) | Number of patients with worst grade 5 toxicity | 0 participants |
Secondary
Number of Patients With Each Worst Grade Toxicity (Phase II)
The number of patients with worst-grade toxicity at each of five grades following NCI Common Toxicity Criteria: 1 = mild, 2 = moderate, 3 = severe, 4 = life-threatening, disabling, 5 = death
Time frame: at 16 weeks
Population: Treated patients who experienced a toxicity.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase II) | Number of patients with worst grade 1 toxicity | 0 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase II) | Number of patients with worst grade 2 toxicity | 1 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase II) | Number of patients with worst grade 3 toxicity | 1 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase II) | Number of patients with worst grade 4 toxicity | 0 participants |
| Phase I | Number of Patients With Each Worst Grade Toxicity (Phase II) | Number of patients with worst grade 5 toxicity | 0 participants |
Secondary
Overall Survival (Phase I)
Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details).
Time frame: On-study date to date of death from any cause (assessed up to 2 years)
Population: All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where death is an event, with censoring for non-expired patients at greater of off-study date or last known alive date.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I | Overall Survival (Phase I) | 575 days |
Secondary
Overall Survival (Phase II)
Estimated probable duration of life from on-study date to date of death from any cause, using Kaplan-Meier method with censoring (see Analysis Population Description for additional details. Too few patients were enrolled in the Phase II arm for an analysis of overall survival
Time frame: Time Frame: date on study to date of death from any cause or last known date alive
Population: Too few patients were enrolled in the Phase II arm for an analysis of overall survival
Secondary
Progression-free Survival (Phase I)
Estimated probable duration of life without disease progression, from on-study date to earlier of progression date, or date of death from any cause, using the Kaplan-Meier method with censoring (see Analysis Population Description for additional details). Disease progression is defined by Response Evaluation in Solid Tumors (RECIST) v.1.1: \>= 20% increase in sum of the longest diameter of target lesions, unequivocal progression of non-target lesions, or appearance of new lesions
Time frame: On-study to lesser of date of progression or date of death from any cause (assessed up to 2 years)
Population: All patients are included in the analysis on intention-to-treat basis. Analysis is by Kaplan-Meier method, where either death or progression is an event, with censoring for non-progressed, non-expired patients at greater of off-study date or last known date alive.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase I | Progression-free Survival (Phase I) | 231 days |
Secondary
Response (Phase I)
Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) \>=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD.
Time frame: On-treatment date to date of progressive disease (assessed up to 2 years)
Population: All patients with best overall response data; patients are excluded if best overall response data is missing (0) or if the patient is non-evaluable for best overall response (n = 1)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Response (Phase I) | Complete response | 0 participants |
| Phase I | Response (Phase I) | Partial response | 9 participants |
| Phase I | Response (Phase I) | Stable disease | 1 participants |
| Phase I | Response (Phase I) | Progressive disease | 0 participants |
Secondary
Response (Phase II)
Number of patients in each response category, per Response Evaluation in Solid Tumors (RECIST) v.1.1: complete response (CR), disappearance of target lesions; partial response (PR) \>=30% decrease in sum of longest diameter (LD) of target lesions; progressive disease (PD), \>=20% increase in sum of LD of target lesions or appearance of new lesions; stable disease (SD), insufficient change in target lesions or new lesions to qualify as either PD or PR. Patients are categorized according to the best response achieved prior to occurrence of progressive disease, where best response hierarchy is CR\>PR\>SD\>PD.
Time frame: On-treatment date to date of progressive disease (assessed up to 2 years)
Population: All patients with best overall response data; patients are excluded if best overall response data is missing (n = 0) or if the patient is non-evaluable for best overall response (n = 1)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase I | Response (Phase II) | Complete response | 0 participants |
| Phase I | Response (Phase II) | Partial response | 1 participants |
| Phase I | Response (Phase II) | Stable disease | 0 participants |
| Phase I | Response (Phase II) | Progressive disease | 0 participants |
Other Pre-specified
Secreted Protein Acidic and Rich in Cysteine (SPARC) Gene Expression
Secreted protein acidic and rich in cysteine (SPARC) gene expression in tumor specimens.
Time frame: On receipt of tumor tissue blocks
Population: Investigators elected not to perform this analysis.