Selinexor as a Single Agent and in Combination With Imatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors.

STATUS

Recruiting
End date

Dec 1, 2022
participants needed

30
sponsor

Grupo Espanol de Investigacion en Sarcomas

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Updated on 26 January 2021

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renal function

medication treatment

imatinib

metastatic disease

measurable disease

growth factor

serum bilirubin

metastasis

neutrophil count

liver metastasis

blood transfusion

liver metastases

imatinib 400 mg

gastrointestinal stromal tumor

Summary

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

Description

Clinical Study Objectives:

Primary clinical study objective

Cohort A:

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.

Cohort B:

To evaluate the clinical benefit rate (CBR: CR+PR+SD 16 wks)

Secondary clinical study objectives (both cohorts A and B)

To evaluate the clinical benefit rate (CBR: CR+PR+ SD 16 wks)
To evaluate progression free survival (PFS)
To evaluate overall survival (OS)
To evaluate the objective response rate (ORR)
To evaluate the safety profile according to CTCAE 4.03
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.

Details

Condition	Maximum Tolerated Dose, Drug abuse, Substance Abuse, Drug use, overdose of drug with toxic effect, gastrointestinal stromal tumor, Diet and Nutrition, Chronic Diarrhea, Skin Wounds, Chronic Shoulder Pain, Vaginal Atrophy, Adverse Effects, Drugs, Injection Port, Breast Cancer - HER2 Positive, Anal Dysplasia, Primary Immunodeficiency, Pediatric Health, Near-Sighted Corrective Surgery, Peripheral Arterial Occlusive Disease, Brain Function, Recurrent Respiratory Papillomatosis, Razor Bumps (Pseudofolliculitis Barbae), Metastatic Adult Soft Tissue Sarcoma, Metastatic Triple-Negative Breast Cancer, Substance Abuse, Drug use, drug toxicity, gastrointestinal stromal tumors, gist
Treatment	Imatinib, Selinexor
Clinical Study Identifier	NCT04138381
Sponsor	Grupo Espanol de Investigacion en Sarcomas
Last Modified on	26 January 2021

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Eligibility		Yes	No	Not Sure
Inclusion Criteria
	Age 18 years at the time of study entry
	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
	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
	Measurable disease per modified RECIST 1.1
	ECOG performance status 0 to 2
	Adequate hematopoietic function (within 7 days prior to enrollment)
	Hemoglobin 9.0 g/dL (90 g/L)
	Absolute neutrophil count 1000/mm3
	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
	Adequate organ function (within 7 days prior to enrollment)
	Alanine aminotransferanse (ALT) and aspartate aminotransferanse (AST)
	5 x upper limit of normal (ULN), or 5.0 x ULN if liver metastases are
	present
	\. Alkaline phosphatase (ALP) limit < 2.5 x ULN or 5.0 x ULN if liver
	metastases are present
	\. Total serum bilirubin 2 x ULN. Patients with Gilbert's syndrome must have
	a total bilirubin of < 3 ULN
	\. Adequate renal function: estimated creatinine clearance of 30 mL/min
	calculated using the formula of Cockroft and Gault
	\. Patients must be able to swallow oral medication and no malabsorption
	condition
	\. 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
	\. Women of childbearing potential must have a negative pregnancy test
	performed within 7 days of the start of study drug administration
	\. Ability to understand and the willingness to sign a written informed
	consent document
Exclusion Criteria
	Cohort A: Intolerance to first-line treatment imatinib 400mg daily
	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
	Participants who have had radiotherapy within 4 weeks prior to study entry
	Major surgery or significant traumatic injury within 4 weeks prior to study entry
	Presence of symptomatic or uncontrolled brain or central nervous system metastases
	Known or suspected allergy or hypersensitivity to the selinexor, imatinib or any of its components
	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.)
	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
	Ongoing infection > Grade 2
	Patients with any seizure disorder requiring medication
	HIV-positive individuals on combination antiretroviral
	Patients with active hepatitis B or C, or chronic hepatitis B or C requiring treatment with antiviral therapy
	Serious psychiatric or medical conditions that could interfere with treatment
	Pregnant or lactating females
	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

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Selinexor as a Single Agent and in Combination With Imatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors.