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

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.

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