A Phase 2 Trial of Bortezomib in KRAS-Mutant Non-Small Cell Lung Cancer in Never Smokers or Those With KRAS G12D

Inclusion Criteria:

- Pathologic or cytologic evidence of non-small cell lung cancer (NSCLC)

- Documented KRAS mutation

- History of smoking < 100 cigarettes (never-smoker) OR patient with a KRAS G12D
mutation regardless of smoking history

- Clinical stage IIIB/IV or recurrent/medically inoperable NSCLC

- Age ≥ 18 years

- Three (3) weeks since last chemotherapy, and three (3) weeks since prior radiation
therapy and recovered from treatment

- Karnofsky performance status ≥ 70%

- Adequate hematologic, and/or hepatic function WBC ≥ 3,000/ul or absolute neutrophil
count ≥ 1,000/ul Hemoglobin ≥ 9.0 g/dl Platelet count ≥ 100,000/ul AST ≤ 2.0 X ULN
(upper limit of normal)

- Total bilirubin ≤1.5 x ULN Measurable indicator lesions by RECIST v1.1 criteria.

- Voluntary written informed consent before performance of any study-related procedure
not part of normal medical care, with the understanding that consent may be withdrawn
by the subject at any time without prejudice to future medical care.

- Female subject is either postmenopausal for at least 1 year before the screening
visit, is surgically sterilized or if they are of childbearing potential, agree to
practice 2 effective methods of contraception from the time of signing the informed
consent form through 30 days after the last dose of bortezomib, or agree to
completely abstain from heterosexual intercourse.

- Male subjects must agree to 1 of the following: practice effective barrier
contraception during the entire study treatment period and through a minimum of 30
days after the last dose of study drug, or completely abstain from heterosexual
intercourse.

Exclusion Criteria:

- Uncontrolled central nervous system metastases defined as any lesion which is either
a. symptomatic, or requiring escalating doses of corticosteroids

- Significant medical history or unstable medical condition such as uncontrolled
diabetes myocardial infarction within 6 months prior to enrollment New York Heart
Association Class III or IV heart failure severe uncontrolled ventricular arrythmias
uncontrolled angina ECG evidence of acute ischemia or active conduction system
abnormalities

- Baseline ≥ grade 2 peripheral neuropathy by CTCAE v 4.0 (Appendix B)

- Known hypersensitivity to boron or mannitol

- Female patients who are pregnant/lactating or have a positive serum or urine β-hCG
pregnancy test

- Serious medical or psychiatric illness likely to interfere with participation in this
clinical study.

- No active concurrent malignancy, with the exception of in-situ malignancy completely
resected basal cell carcinoma or squamous cell carcinomas of the skin low-risk
prostate cancer after curative therapy

- Participation in clinical trials with other investigational agents not included in
this trial, within 14 days of the start of this trial and throughout the duration of
this trial