Selinexor as Single Agent and With Imatinib in Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (SeliGIST)

NCT04138381 | Unknown Phase 1 DMC

• 2 other identifiers: GEIS 412017-004761-28
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 6

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

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

Outcome Measures

Primary Outcomes (2)

• Maximum tolerated dose (MTD) for the use of Imatinib in combination with Selinexor

  Maximum tolerated dose (MTD) is defined as the highest dose level with ≤1 out of 6 patients experiencing a dose limiting toxicity (DLT) during the first 28 days of treatment. Dose escalation cohort (Phase 1b) seeks to determine the frequency and characteristics of DLTs of the selinexor plus imatinib combination at each dose level during the first cycle of therapy. Phase Ib will be carried out in standard 3+3 format, based on the toxicities found during the first cycle of therapy.

  32 months

• Clinical benefit rate (CBR) for the use of selinexor in monotherapy

  Clinical benefit rate (CBR) is defined as CR+PR+SD ≥ 16 wks

  24 months

Secondary Outcomes (7)

• Progression free survival (PFS)

  32 months

• Overall survival (OS)

  32 months

• Objective response rate (ORR)

  32 months

• Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]

  32 months

• GIST genotype and CBR with selinexor and imatinib (Translational) Study Objective

  32 months

Study Arms (1)

selinexor as a single agent and in combination with imatinib

OTHER

This is a single-arm, two-cohort, open label phase Ib/II 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 en expansion phase (II) testing for safety and preliminary evidence of antitumor activity * Cohort B: single-agent, fixed selinexor dose in the same target population

Drug: Selinexor; Drug: Imatinib

Interventions

Selinexor DRUG

oral selinexor given once weekly (Cohort A), oral selinexor given BIW (Cohort B)

Also known as: Drug Combination, Single agent

selinexor as a single agent and in combination with imatinib

Imatinib DRUG

imatinib 400 mg, once daily (Cohort A)

Also known as: Drug Combination

selinexor as a single agent and in combination with imatinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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)
• ≤2.5 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Grupo Espanol de Investigacion en Sarcomas: lead

Study Sites (6)

Hospital Virgen del Rocio

Seville, Andalusia, 41013, Spain

Location

Hospital Universitario de Canarias

Santa Cruz de Tenerife, Canary Islands, 238320, Spain

Location

H Vall d'Hebrón

Barcelona, Catalonia, 08035, Spain

Location

Hospital Miguel Servet

Zaragoza, Zaragoza, Aragón, 50009, Spain

Location

Hospital La Paz

Madrid, 28046, Spain

Location

Hospital Virgen de la Arrixaca

Murcia, 30120, Spain

Location

MeSH Terms

Conditions

Sarcoma; Drug-Related Side Effects and Adverse Reactions; Neoplasm Metastasis

Interventions

selinexor; Drug Combinations; Pharmaceutical Preparations; Imatinib Mesylate

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Chemically-Induced Disorders; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Cesar Serrano, MD

  Hospital Vall d´Hebron

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Phase Ib/II, single-arm, two-cohort, non-randomized, open-label, multicenter, national clinical trial, single agent, combinations products

Study Record Dates

• First Submitted: September 16, 2019
• First Posted: October 24, 2019
• Study Start: August 16, 2019
• Primary Completion: April 16, 2023
• Study Completion: April 16, 2023
• Last Updated: March 27, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will not share

Locations

ES (6)