Clinical trial NCT04138381: Selinexor as Single Agent and With Imatinib in Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (SeliGIST)
Official title: A Multicenter, Phase Ib/II Trial of Selinexor as a Single Agent and in Combination With Imatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GISTs)
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Maximum Tolerated Dose
GIST
Metastatic Adult Soft Tissue Sarcoma
Drug Toxicity
Drug Use
Keywords: GIST
MTD
Imatinib
Selinexor
Phase Ib
Phase II
Unresectable
Metastatic
Lead sponsor: Grupo Espanol de Investigacion en Sarcomas
Sponsor class: OTHER
First posted: 2019-10-24
Enrollment: 30
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Phase Ib/II, single-arm, two-cohort, non-randomized, open-label, multicenter, national clinical trial, single agent, combinations products
Primary purpose: TREATMENT

Brief 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

Detailed 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:

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.

Eligibility criteria: Inclusion Criteria:

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 present.
   2. Alkaline phosphatase (ALP) limit \< 2.5 x ULN or ≤ 5.0 x ULN if liver metastases are present.
   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.

Exclusion Criteria:

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 its components.
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.

Primary outcomes:
measure: Maximum tolerated dose (MTD) for the use of Imatinib in combination with Selinexor
timeFrame: 32 months
measure: Clinical benefit rate (CBR) for the use of selinexor in monotherapy
timeFrame: 24 months
Secondary outcomes:
measure: Progression free survival (PFS)
timeFrame: 32 months
measure: Overall survival (OS)
timeFrame: 32 months
measure: Objective response rate (ORR)
timeFrame: 32 months
measure: Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
timeFrame: 32 months
measure: GIST genotype and CBR with selinexor and imatinib (Translational) Study Objective
timeFrame: 32 months
measure: Measure the plasma concentration of imatinib and selinexor (Pharmacokinetics)Study Objective
timeFrame: 32 months
measure: Clinical benefit rate (CBR)
timeFrame: 24 months
Other outcomes:
Locations:
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio
state: Andalucia
city: Barcelona
country: Spain
facility: H Vall d'Hebrón
state: Catalonia
city: Tenerife
country: Spain
facility: Hospital Universitario de Canarias
state: Islas Canarias
city: Zaragoza
country: Spain
facility: Hospital Miguel Servet
state: Zaragoza, Aragón
city: Madrid
country: Spain
facility: Hospital La Paz
city: Murcia
country: Spain
facility: Hospital Virgen de la Arrixaca
Study officials:
affiliation: Hospital Vall d´Hebron
name: Cesar Serrano, MD
role: PRINCIPAL_INVESTIGATOR
References: