Recurrent Non-small Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer
Conditions
Brief summary
This phase I/II trial (phase I closed to accrual as of 09/29/2009) is studying the side effects and best dose of bortezomib, paclitaxel, and carboplatin when given with radiation therapy and to see how well they work in treating patients with stage IIIA or stage IIIB non-small cell lung cancer that cannot be removed by surgery. Bortezomib may stop the growth of tumor cells by blocking the enzymes necessary for their growth. Drugs used in chemotherapy, such as paclitaxel and carboplatin, work in different ways to stop tumor cells from dividing so they stop growing or die. Bortezomib may increase the effectiveness of paclitaxel and carboplatin by making tumor cells more sensitive to the drugs. Radiation therapy uses high-energy x-rays to damage tumor cells. Giving bortezomib, paclitaxel, and carboplatin together with radiation therapy may kill more tumor cells.
Detailed description
PRIMARY OBJECTIVES: I. Determine the maximum tolerated dose of bortezomib, paclitaxel, and carboplatin when administered with fractionated radiotherapy in patients with unresectable stage IIIA or IIIB non-small cell lung cancer. (Phase I) (closed to accrual as of 09/29/2009) II. Determine the 1-year survival of patients treated with this regimen. (Phase II) SECONDARY OBJECTIVES: I. Determine the tolerability of this regimen in these patients. (Phase II) II. Determine the response rate, progression-free survival, and overall survival of patients treated with this regimen. (Phase II) III. Correlate p27 expression in tumor tissue with survival, time to progression, and response in patients treated with this regimen. (Phase II) OUTLINE: This is a multicenter, phase I (closed to accrual as of 09/29/2009), dose-escalation study of bortezomib, paclitaxel, and carboplatin followed by a phase II study. PHASE I: (closed to accrual as of 09/29/2009) Patients receive bortezomib IV on days 1, 4, 8, and 11. Patients also receive paclitaxel IV over 3 hours followed by carboplatin IV over 30 minutes on day 2. Patients undergo radiotherapy once daily on days 1-5, 8-12, 15-19. Treatment repeats every 3 weeks up to 2 courses in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of bortezomib, paclitaxel, and carboplatin until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. PHASE II: Patients receive bortezomib, paclitaxel, and carboplatin as in phase I at the MTD. Patients also undergo radiotherapy as in phase I. Patients are followed up periodically for up to 5 years from the time of registration.
Interventions
RADIATION3-dimensional conformal radiation therapy
DRUGbortezomib
Given IV
DRUGpaclitaxel
Given IV
DRUGcarboplatin
Given IV
Sponsors
National Cancer Institute (NCI)
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
* Histologically or cytologically confirmed non-small cell lung cancer (NSCLC) * Locally advanced stage IIIA or IIIB disease that is considered unresectable * No stage IV disease * Requires radiotherapy * Performance status (PS) - Eastern Cooperative Oncology Group (ECOG) 0-1 * At least 12 weeks * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * aspartate aminotransferase (AST) ≤ 3 times ULN * Creatinine ≤ 1.5 times ULN * No New York Heart Association class III or IV heart disease * Forced expiratory volume (FEV) FEV\_1 ≥ 1 L OR 35% of predicted * Weight loss \< 10% within the past 3 months * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception * No peripheral neuropathy ≥ grade 2 * No other severe underlying disease that would preclude study participation * No uncontrolled infection * No unhealed wound within the past 2 weeks * No other malignancy within the past 5 years except adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas (carcinoma in situ), or localized prostate cancer * No concurrent prophylactic filgrastim (G-CSF) or sargramostim (GM-CSF) * No prior systemic chemotherapy for NSCLC\* * No prior radiotherapy to the chest * More than 2 weeks since prior major surgery Contraindications * Any of the following: * Pregnant wome * Nursing women * Men or women of childbearing potential or their sexual partners who are unwilling to employ adequate contraception (condoms, diaphragm, birth control pills, injections, intrauterine device \[IUD\], or abstinence, etc.) as this regimen may be harmful to a developing fetus or nursing child NOTE: This study involves an investigational agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown. * Any of the following prior therapies: * Prior radiation therapy to the chest * Prior systemic chemotherapy for NSCLC (phase II portion) * New York Heart Association classification III or IV (see Appendix II). * Any other severe underlying diseases which are, in the judgment of the investigator, inappropriate for entry into this study. * uncontrolled infection. * Major surgery or unhealed wound ≤ 2 weeks prior to registration. * Prior history of malignancy ≤ 5 years, except for adequately treated basal cell or squamous cell skin cancer, adequately treated noninvasive carcinomas (carcinoma in situ), or localized prostate cancer. * Peripheral neuropathy ≥grade 2
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Primary Endpoint of This Trial is the Proportion of Patients Alive at 1 Year. Phase II Patients Only. | At 1 year | The primary endpoint of this trial is the proportion of patients alive at 1 year (i.e., 365 days) after study registration. Proportion of successes, defined as the number of patients alive at one year divided by the total number of evaluable patients. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Confirmed Tumor Response | Up to 5 years | Response was assessed using the RECIST v1.1 criteria. Patients were evaluated at 4 weeks post-RT, 3 months post-RT, every 3 months for 1 year post-RT, and every 6 months thereafter for a maximum of 5 years from time of registration. A Complete Response (CR) is defined as the disappearance of all target lesions. A Partial Response (PR) is defined as at least a 20% decrease in the sum of the longest diameter of target lesions from baseline. A confirmed response is defined as a CR or PR as the objective status on 2 consecutive evaluations at least 4 weeks apart. |
| Time to Progression | From study registration to date of disease progression or date of last follow-up, up to 5 years | The distribution of time to progression will be estimated using the method of Kaplan-Meier. |
| Progression-free Survival | From study registration to the first of either death due to any cause or progression, up to 5 years | The distribution of progression-free survival (PFS) is defined as the time from registration to the time of progression or death, whichever comes first. The PFS will be estimated using the method of Kaplan-Meier. |
| Overall Survival | From registration to death due to any cause, up to 5 years | Overall Survival is defined as the time from registration to the time to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. |
| Frequency and Severity of Observed Toxicity, Graded by Common Terminology Criteria for Adverse Events (CTCAE) | Up to 5 years | Toxicity was reported after the first 21 days of treatment and after each 28 day cycle thereafter. Events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. The number of patients reporting grade 3 and higher are tabulated. |
Countries
United States
Participant flow
Pre-assignment details
Fifty two (52) patients were accrued, out of which 4 were cancels. Twenty one (21) patients were accrued for phase I portion of the study. Twenty Seven (27) patients are accrued for phase II portion of the study. Twenty Seven (27) Phase II patients are evaluable for primary outcome measure.
Participants by arm
| Arm | Count |
|---|---|
| PhaseI PHASE I: Cohorts of 3-6 patients receive escalating doses of study medications until the maximum tolerated dose (MTD) is determined. 3-dimensional conformal radiation therapy\> bortezomib: Given IV\> paclitaxel: Given IV\> carboplatin: Given IV | 27 |
| PhaseII PHASE II: Patients receive as in phase I at the MTD. Patients also undergo radiotherapy as in phase I. 3-dimensional conformal radiation therapy\> bortezomib: Given IV\> paclitaxel: Given IV\> carboplatin: Given IV | 21 |
| Total | 48 |
Baseline characteristics
| Characteristic | PhaseI | PhaseII | Total |
|---|---|---|---|
| Age, Continuous | 63 years | 58 years | 58 years |
| Region of Enrollment United States | 21 participants | 27 participants | 48 participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 17 Participants | 13 Participants | 30 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 27 / 27 |
| serious Total, serious adverse events | 9 / 21 | 12 / 27 |
Outcome results
Primary
The Primary Endpoint of This Trial is the Proportion of Patients Alive at 1 Year. Phase II Patients Only.
The primary endpoint of this trial is the proportion of patients alive at 1 year (i.e., 365 days) after study registration. Proportion of successes, defined as the number of patients alive at one year divided by the total number of evaluable patients.
Time frame: At 1 year
Population: This analysis included all 21 patients enrolled in the Phase II portion of the study and 6 patients enrolled in the Phase I who were treated at the Phase II dose level.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| PhaseII | The Primary Endpoint of This Trial is the Proportion of Patients Alive at 1 Year. Phase II Patients Only. | 0.73 proportion of Participants |
Secondary
Confirmed Tumor Response
Response was assessed using the RECIST v1.1 criteria. Patients were evaluated at 4 weeks post-RT, 3 months post-RT, every 3 months for 1 year post-RT, and every 6 months thereafter for a maximum of 5 years from time of registration. A Complete Response (CR) is defined as the disappearance of all target lesions. A Partial Response (PR) is defined as at least a 20% decrease in the sum of the longest diameter of target lesions from baseline. A confirmed response is defined as a CR or PR as the objective status on 2 consecutive evaluations at least 4 weeks apart.
Time frame: Up to 5 years
Population: All 21 patients from Phase II and 6 patients registered to the Phase II dose level of Phase I were included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PhaseII | Confirmed Tumor Response | Complete Response (CR) | 3 Participants |
| PhaseII | Confirmed Tumor Response | Partial Response (PR) | 4 Participants |
Secondary
Frequency and Severity of Observed Toxicity, Graded by Common Terminology Criteria for Adverse Events (CTCAE)
Toxicity was reported after the first 21 days of treatment and after each 28 day cycle thereafter. Events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) v3.0. The number of patients reporting grade 3 and higher are tabulated.
Time frame: Up to 5 years
Population: All 21 patients from Phase II and 6 patients registered to the Phase II dose level of Phase I were included in this analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PhaseII | Frequency and Severity of Observed Toxicity, Graded by Common Terminology Criteria for Adverse Events (CTCAE) | Grade 3 Adverse Event | 22 Participants |
| PhaseII | Frequency and Severity of Observed Toxicity, Graded by Common Terminology Criteria for Adverse Events (CTCAE) | Grade 4 Adverse Event | 15 Participants |
Secondary
Overall Survival
Overall Survival is defined as the time from registration to the time to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier.
Time frame: From registration to death due to any cause, up to 5 years
Population: All 21 patients from Phase II and 6 patients registered to the Phase II dose level of Phase I were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PhaseII | Overall Survival | 25 months |
Secondary
Progression-free Survival
The distribution of progression-free survival (PFS) is defined as the time from registration to the time of progression or death, whichever comes first. The PFS will be estimated using the method of Kaplan-Meier.
Time frame: From study registration to the first of either death due to any cause or progression, up to 5 years
Population: All 21 patients from Phase II and 6 patients registered to the Phase II dose level of Phase I were included in this analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| PhaseII | Progression-free Survival | 8.4 months |
Secondary
Time to Progression
The distribution of time to progression will be estimated using the method of Kaplan-Meier.
Time frame: From study registration to date of disease progression or date of last follow-up, up to 5 years
Population: Study team decision not to run this analysis.