Bortezomib, Paclitaxel, Carboplatin and Radiation Therapy for Non-Small Cell Lung Cancer

Study Overview
=================
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.

Official Title
-----------------
Phase I/II Study of PS-341 in Combination With Paclitaxel, Carboplatin, and Concurrent Thoracic Radiation Therapy for Non-small Cell Lung Cancer (NSCLC)

Conditions
-----------------
Recurrent Non-small Cell Lung Cancer, Stage IIIA Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer

Intervention / Treatment
-----------------
* Radiation: 3-dimensional conformal radiation therapy
* Drug: bortezomib
* Drug: paclitaxel
* Drug: carboplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (bortezomib, paclitaxel, carboplatin)<br>PHASE I: Cohorts of 3-6 patients receive escalating doses of study medications until the maximum tolerated dose (MTD) is determined. 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 | Radiation: 3-dimensional conformal radiation therapy<br> <br> Drug: bortezomib<br>* Given IV<br>Drug: paclitaxel<br>* Given IV<br>Drug: carboplatin<br>* Given IV<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | At 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 5 years | 
| Time to Progression | The distribution of time to progression will be estimated using the method of Kaplan-Meier. | From study registration to date of disease progression or date of last follow-up, up to 5 years | 
| 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. | From study registration to the first of either death due to any cause or progression, up to 5 years | 
| 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. | From registration to death due to any cause, up to 5 years | 
| 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. | Up to 5 years |