Phase 1/2 Trial of Selinexor (KPT-330) With Docetaxel for Non-small Cell Lung Cancer (NSCLC)

This is a phase 1/2 clinical trial of the oral XPO1 inhibitor selinexor (KPT-330) in
combination with docetaxel for previously treated, advanced KRAS mutant non-small cell lung
cancer (NSCLC). It is a single-arm, non-blinded study, which will compare safety and outcomes
with historical controls (docetaxel monotherapy). The multi-center study will be conducted
within the Academic Thoracic Oncology Medical Investigator Consortium (ATOMIC).

Inclusion Criteria:

- Patients must meet all of the following inclusion criteria to be eligible to enroll in
this study:

1. Written informed consent in accordance with federal, local, and institutional
guidelines. The patient must provide informed consent prior to the first
screening procedure.

2. Age ≥ 18 years

3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

4. Histologically or cytologically confirmed advanced (stage 4, according to the
American Joint Committee on Cancer [AJCC] version 7.0 Staging manual) NSCLC

5. Molecular identification of a KRAS mutation (codons 12, 13, or 61)

6. Tissue available for analysis at time of enrollment for biomarker analysis (may
be obtained via biopsy prior to initiation of treatment, or submission of
available archival tissue): 10-15 slides, or 5 slides with 3 sections per slide

7. At least one and up to two previous lines of systemic cytotoxic therapy for
advanced NSCLC, of which one must have been a platinum-based doublet therapy. Up
to four total previous lines of systemic therapy (including immunotherapy and
molecularly targeted therapy)

8. Radiographic or clinical disease recurrence or progression during or after the
last line of systemic therapy

9. Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1500 cells/μL;
hemoglobin ≥ 9 g/dL; platelets ≥ 100,000/μL. Use of PRBC transfusion to achieve
Hgb ≥9.0 mg/dL is allowed.

10. Adequate renal function (calculated creatinine clearance ≥ 30 mL/min using the
Cockcroft-Gault equation)

11. Adequate hepatic function (total bilirubin ≤ upper limit of normal [ULN], alanine
aminotransferase [ALT] ≤ 2 × ULN and aspartate aminotransferase [AST] ≤ 2 × ULN).
ALT and/or AST may be ≤ 5 × ULN if due to liver metastases. If ALT or AST is > 2
and ≤ 5 × ULN in patients with liver metastases, alkaline phosphatase must be ≤
2.5 × ULN (unless elevated alkaline phosphatase clearly due to skeletal—rather
than hepatic—process; eg, normal GGT, presence of multiple bone metastases,
absence of bulky and/or central liver metastases). Patients with Gilbert's
syndrome are allowed if total bilirubin ≤ 2 × ULN and direct bilirubin is ≤ ULN.

12. Prothrombin time (PT) and/or international normalized ratio (INR) ≤ 1.5 × ULN and
activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN if patient is not on
anticoagulant therapy (a therapeutic PT and/or INR and aPTT is acceptable if the
patient is on anticoagulants)

13. Female patients of childbearing potential must agree to use 2 methods of
contraception (including 1 highly effective and 1 effective method of
contraception) and have a negative serum pregnancy test at Screening. Male
patients must use an effective barrier method of contraception if sexually active
with a female of childbearing potential. For both male and female patients,
effective methods of contraception must be used throughout the study and for 3
months following the last dose of study treatment. Female patients of
child-bearing potential must have a negative serum pregnancy test at screening
and agree to use 2 reliable methods of contraception throughout the study and for
3 months after their last dose of medication. Female patients are considered NOT
of childbearing potential if they have a history of surgical sterility (including
hysterectomy and/or bilateral oophorectomy, but not tubal ligation alone) or
evidence of post-menopausal status defined as any of the following:

- Natural menopause with last menses >1 year ago and confirmed by FSH blood
level

- Radiation-induced oophorectomy with last menses >1 year ago

- Chemotherapy-induced menopause with last menses >1 year ago. Male patients
and their partners must use 2 reliable methods of contraception, at least
one of them a barrier method (if sexually active with a female of
child-bearing potential).

14. Measurable disease according to RECIST v1.1

15. Previously treated (surgery and/or radiation therapy) or untreated brain
metastases are eligible, provided that patients are asymptomatic and not
requiring escalating doses of corticosteroids

16. Previous treatment-associated clinically significant toxicities resolved to CTCAE
grade ≤1 (except alopecia) or to their baseline

17. At least 3 weeks or 5 half-lives, whichever is shorter, since receiving systemic
anticancer therapy, including investigational agents, prior to starting study
therapy. At least 2 weeks since receiving radiation therapy prior to starting
study therapy

Exclusion Criteria:

- Patients meeting any of the following exclusion criteria are not eligible to enroll in
this study:

1. Patients who are pregnant or lactating

2. Major surgery (excluding skin biopsies and procedures for insertion of central
venous access devices) within 2 weeks of first dose of study drug

3. Any life-threatening illness, medical condition or organ system dysfunction
which, in the investigator's opinion, could compromise the patient's safety

4. Presence of symptomatic brain metastases or brain metastases requiring the
escalating doses of corticosteroids to control neurological symptoms

5. Other concurrent cancer (with the exception of non-melanoma skin cancer and
low-risk localized prostate cancer on active surveillance)

6. Unstable cardiovascular function:

- Symptomatic ischemia, or

- Uncontrolled clinically significant conduction abnormalities (i.e.,
ventricular tachycardia on anti-arrhythmics is excluded; 1st degree AV block
or asymptomatic LAFB/RBBB are not excluded; asymptomatic rate controlled
atrial fibrillation is not excluded), or

- Congestive heart failure (CHF) of NYHA Class ≥3, or

- Myocardial infarction (MI) within 3 months

7. Uncontrolled (i.e., clinically unstable) infection requiring parenteral
antibiotics, antivirals, or antifungals within one week prior to first dose;
however, prophylactic use of these agents is acceptable even if parenteral

8. Pre-existing grade 3 or 4 neuropathy

9. Active Hepatitis A, B or C infection

10. Known human immunodeficiency virus (HIV) infection (HIV testing is not required
as part of this study)

11. Patients unable to swallow tablets, patients with malabsorption syndrome, or any
other GI disease or GI dysfunction that could interfere with absorption of study
treatment

12. Prior exposure to docetaxel, selinexor, or another selective inhibitor of nuclear
transport (SINE) compound

13. Patients unwilling to comply with study protocol.