This is a single-arm, two cohort, open label phase I/II clinical trial studying the
combination of oral imatinib 400 mg, once daily, and oral selinexor given once weekly (Cohort
A); and single-agent oral selinexor 60 mg BIW (Cohort B). The study will consist of:
- Cohort A: an initial escalation phase (Ib) evaluating increasing doses of selinexor in
combination with fixed doses of imatinib administered in repeated 28-day cycles in
advanced/metastatic, imatinib-resistant GIST patients, followed by an expansion phase
(II) testing for safety and preliminary evidence of antitumor activity
- Cohort B: single-agent, fixed selinexor dose in the same target population
Clinical Study Objectives:
Primary clinical study objective
1.- To determine the maximum tolerated dose (MTD) and recommended phase II doses (RP2D) of
selinexor in combination with imatinib among unresectable and/or metastatic GIST patients
with prior failure to at least imatinib for advanced/metastatic disease.
1. To evaluate the clinical benefit rate (CBR: CR+PR+SD ≥ 16 wks)
Secondary clinical study objectives (both cohorts A and B)
1. To evaluate the clinical benefit rate (CBR: CR+PR+ SD ≥ 16 wks)
2. To evaluate progression free survival (PFS)
3. To evaluate overall survival (OS)
4. To evaluate the objective response rate (ORR)
5. To evaluate the safety profile according to CTCAE 4.03
6. To compare PFS on selinexor and imatinib and on selinexor in monotherapy with PFS on
last prior anti-cancer therapy.
Translational Study Objective - To explore the relationship between GIST genotype and CBR
with selinexor and imatinib, and selinexor as single-agent
Pharmacokinetics Study Objective
- To measure the plasma concentration of imatinib and selinexor at limited timepoints
specificed in schedule of assessment.
1. Age ≥18 years at the time of study entry.
2. Histologically confirmed metastatic and/or unresectable GIST. Patients must
demonstrate prior failure to at least imatinib. Any number of previous therapies for
GIST is allowed.
3. Failure of imatinib is defined as disease progression after ≥ 6 months of treatment
with imatinib for advanced/metastatic disease. Exception to this rule is GIST patients
with documented KIT or PDGFRA mutations.
4. Measurable disease per modified RECIST 1.1.
5. ECOG performance status 0 to 2.
6. Adequate hematopoietic function (within 7 days prior to enrollment):
1. Hemoglobin ≥ 9.0 g/dL (90 g/L).
2. Absolute neutrophil count ≥ 1000/mm3.
3. Platelets ≥ 100,000 /mm3. Patients must have at least a 2-week interval from the
last red blood cell (RBC) transfusion and/or growth factor support prior to the
Screening hemoglobin and neutrophil assessment. However, patients may receive
RBC, growth factor support, and/or platelet transfusions as clinically indicated
per institutional guidelines during the study.
7. Adequate organ function (within 7 days prior to enrollment):
1. Alanine aminotransferanse (ALT) and aspartate aminotransferanse (AST)
≤2.5 x upper limit of normal (ULN), or ≤ 5.0 x ULN if liver metastases are
2. Alkaline phosphatase (ALP) limit < 2.5 x ULN or ≤ 5.0 x ULN if liver metastases
3. Total serum bilirubin ≤ 2 x ULN. Patients with Gilbert's syndrome must have a
total bilirubin of < 3 × ULN.
4. Adequate renal function: estimated creatinine clearance of ≥ 30 mL/min,
calculated using the formula of Cockroft and Gault
8. Patients must be able to swallow oral medication and no malabsorption condition.
9. Willingness to use effective means of birth control throughout the duration of
clinical study and for at least 3 months after completion of study drug.
10. Women of childbearing potential must have a negative pregnancy test performed within 7
days of the start of study drug administration.
11. Ability to understand and the willingness to sign a written informed consent document.
1. Cohort A: Intolerance to first-line treatment imatinib 400mg daily.
2. Use of any approved tyrosine kinase inhibitors or investigational agents within 1 week
or 5 half-lives of the agent, whichever is shorter, prior to receiving study drugs.
3. Participants who have had radiotherapy within 4 weeks prior to study entry.
4. Major surgery or significant traumatic injury within 4 weeks prior to study entry.
5. Presence of symptomatic or uncontrolled brain or central nervous system metastases.
6. Known or suspected allergy or hypersensitivity to the selinexor, imatinib or any of
7. Patient has a history of another primary malignancy that has been diagnosed or
required therapy within 1 year prior to the first dose of study drug (The following
are exempt from the 1-year limit: completely resected basal cell and squamous cell
skin cancer, curatively treated localized prostate cancer, and completely resected
carcinoma in situ of any site.)
8. Unstable cardiovascular function: • Symptomatic ischemia, or • Uncontrolled clinically
significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic
agents are excluded; 1st degree atrioventricular (AV) block or asymptomatic left
anterior fascicular block/right bundle branch block (LAFB/RBBB) will not be excluded),
or • Congestive heart failure (CHF) NYHA Class ≥ 3, or • Myocardial infarction (MI)
within 3 months. • Left ventricular ejection fraction < 40 %. • Hypertension > 140 mm
Hg systolic or > 90 mm Hg diastolic with or without antihypertensive therapy.
9. Ongoing infection > Grade 2.
10. Patients with any seizure disorder requiring medication.
11. HIV-positive individuals on combination antiretroviral.
12. Patients with active hepatitis B or C, or chronic hepatitis B or C requiring treatment
with antiviral therapy.
13. Serious psychiatric or medical conditions that could interfere with treatment.
14. Pregnant or lactating females.
15. Strong CYP3A4 inhibitors (e.g. clarithromycin, indinavir, itraconazole, ketoconazole ,
nefazodone , nelfinavir , posaconazole, ritonavir, saquinavir, telithromycin,
voriconazole) or strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin,
rifampin, St. John's Wort) within 28 days or 5 drug half-lives (if drug half-life in
patients is known), whichever is longer, before start of study treatment.