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

Study Overview
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Brief Summary
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This study is being done to evaluate the safety of the investigational study drug, selinexor when given with docetaxel to patients who have been previously treated for advanced KRAS mutant lung cancer.

Detailed Description
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This is a phase 1/2 single-arm, non-blinded, multi-institutional study. Selinexor will be administered once weekly starting one week before chemotherapy initiation (to permit pharmacodynamic assessment of selinexor alone and in combination with chemotherapy).This study will compare safety and outcomes with historical controls (docetaxel monotherapy).

Official Title
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An Investigator-sponsored, Phase 1/2 Trial of the Oral XPO1 Inhibitor Selinexor (KPT-330) Monotherapy and in Combination With Docetaxel for Previously Treated, Advanced KRAS Mutant Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Selinexor
* Drug: Docetaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must meet all of the following inclusion criteria to be eligible to enroll in this study: Written informed consent in accordance with federal, local, and institutional guidelines. The patient must provide informed consent prior to the first screening procedure. However, the Investigator should not repeat procedures that are performed as part of standard of care (SOC), if they are within the screening window and are done prior to signing the ICF. Age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Histologically or cytologically confirmed advanced (stage 4, according to the American Joint Committee on Cancer [AJCC] version 7.0 Staging manual) NSCLC Molecular identification of a KRAS mutation (codons 12, 13, or 61 mutations detected by sequencing) by a CLIA-certified assay (source documentation required). Tissue available for analysis at time of enrollment for biomarker analysis: 10 unstained slides plus 1 H+E slide. If archival tumor tissue is not available in select cases, subjects may be permitted to enroll on the study with prior approval of the study PI. 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) for advanced NSCLC. Radiographic or clinical disease recurrence or progression during or after the last line of systemic therapy Adequate hematologic function (absolute neutrophil count [ANC] ≥ 1500 cells/µL; hemoglobin ≥ 9 g/dL; platelets ≥ 100,000/µL. Patients may be transfused with PRBCs up to 7 days prior to when enrollment labs are drawn to achieve Hgb ≥9.0 mg/dL. Adequate renal function (calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation) 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. 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 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). Measurable disease according to RECIST v1.1 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. Previous treatment-associated clinically significant toxicities resolved to CTCAE grade ≤2 (except alopecia) or to their baseline. NOTE: Prior immunotherapy-related endocrinopathy controlled with ongoing medical management (eg, hypothyroidism, adrenal insufficiency, diabetes) is permitted 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: Patients who are pregnant or lactating Major surgery (excluding skin biopsies and procedures for insertion of central venous access devices) within 2 weeks of first dose of study drug Any life-threatening illness, medical condition or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety Concurrent active malignancy that would interfere with treatment administration or assessment in the opinion of the treating investigator 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 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 Pre-existing grade 3 or 4 neuropathy Active Hepatitis A, B or C infection Known human immunodeficiency virus (HIV) infection (HIV testing is not required as part of this study) 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 Prior exposure to docetaxel, selinexor, or another selective inhibitor of nuclear transport (SINE) compound (NOTE: prior docetaxel exposure permitted in selinexor monotherapy cohort) Patients unwilling to comply with study protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Docetaxel will be given once every 3 weeks. Treatment will be administered in 21-day cycles. Dose limiting toxicities (DLTs) will be assessed based on the first cycle (7-day lead-in plus 21-day cycle = 28 days) toxicity using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events [NCI CTCAE] version 4.03. A standard 3 + 3 dose escalation paradigm will be used.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Selinexor Monotherapy and in Combination with Docetaxel<br>For the selinexor monotherapy cohort, 6 patients each will be treated in two dosing cohorts (weekly and biweekly). Selinexor once weekly oral (40mg, 60mg, 80mg) OR Selinexor twice weekly oral (60mg, 40mg, 60mg weekly). Selinexor will be administered once weekly starting one week before chemotherapy initiation in combination with docetaxel. Docetaxel will be given once every 3 weeks. Treatment will be administered in 21-day cycles. Selinexor dose escalation: 60, 80, 40 mg once weekly. Docetaxel 75 mg/m2 IV, 60 every 3 weeks. | Drug: Selinexor<br>* Selinexor once weekly oral or twice weekly oral<br>* Other names: KPT-330;Drug: Docetaxel<br>* Docetaxel once every 3 weeks (75 mg/m2 IV)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) | A standard 3 + 3 dose escalation schedule will be used for all escalations. The selinexor will be taken starting 1 week for dose escalation at 60, 80, 100, 40 mg once per week every 3 weeks before the first docetaxel infusion. The docetaxel will be given the first day of each 21 day cycle at the dose of either 60 or 75 mg/m2 every 3 weeks. | Each 21 day cycle for 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor size will be assessed using the RECIST v1.1 | To evaluate the efficacy of selinexor monotherapy and in combination with docetaxel in patients with advanced KRAS mutant NSCLC. Tumor size will be assessed at baseline and every 2 cycles (ie, after 7 weeks for first 2 cycles, and then every 6 weeks) during the treatment period using the Response Evaluation Criteria in Solid Tumors RECIST v1.1 criterion. | Each 21 day cycle for 2 years |