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Selinexor in Combination With Imatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors. (SeliGIST)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04138381
Recruitment Status : Recruiting
First Posted : October 24, 2019
Last Update Posted : October 24, 2019
Sponsor:
Information provided by (Responsible Party):
Grupo Espanol de Investigacion en Sarcomas

Brief Summary:
This is a single-arm, open label phase I/II clinical trial studying the combination of oral imatinib 400 mg, once daily, and oral selinexor given once weekly. The study will consist of an initial escalation phase evaluating increasing doses of selinexor in combination with fixed doses of imatinib administered in repeated 28-day cycles in advanced/metastatic, TKI-refractory GIST patients, followed by an expansion phase testing for safety and preliminary evidence of antitumor activity.

Condition or disease Intervention/treatment Phase
Maximum Tolerated Dose GIST Metastatic Adult Soft Tissue Sarcoma Drug Toxicity Drug Use Drug: Selinexor Drug: Imatinib Phase 1 Phase 2

Detailed Description:

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. Secondary clinical study objectives

  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 with PFS on last prior anti-cancer therapy.

Translational Study Objective:1.- To explore the relationship between GIST genotype and CBR with selinexor and imatinib.

Pharmacokinetics Study Objective: 1.- To measure the plasma concentration of imatinib and selinexor at limited timepoints specificed in schedule of assessment.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: Phase Ib/II, single-arm, non-randomized, open-label, multicenter, national clinical trial, combination products.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicenter, Phase Ib/II Trial of Selinexor in Combination With Imatinib in Patients With Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (GISTs)
Actual Study Start Date : August 16, 2019
Estimated Primary Completion Date : April 16, 2022
Estimated Study Completion Date : December 1, 2022


Arm Intervention/treatment
selinexor in combination with imatinib
This is a single-arm, open label studying the combination of oral imatinib 400 mg, once daily, and oral selinexor given once weekly. The study will consist of an initial escalation phase evaluating increasing doses of selinexor in combination with fixed doses of imatinib administered in repeated 28-day cycles in advanced/metastatic, TKI-refractory GIST patients.
Drug: Selinexor
oral selinexor given once weekly.
Other Name: Drug Combination

Drug: Imatinib
imatinib 400 mg, once daily
Other Name: Drug Combination




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) for the use of Imatinib in combination with Selinexor [ Time Frame: 32 months ]
    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.


Secondary Outcome Measures :
  1. Progression free survival (PFS) [ Time Frame: 32 months ]
    Efficacy measured by PFS assessed by median time. PFS is defined as the time between the date of first experimental treatment dose and the date of disease progression (according to RECIST 1.1 criteria).

  2. Overall survival (OS) [ Time Frame: 32 months ]
    Efficacy measured by OS. OS is defined as the time between the date of first experimental treatment dose and the date of death due to any cause. OS will be censored on the last date a subject was known to be alive, or when the last enrolled patiens are followed up to for 12 months, whichever is early.

  3. Objective response rate (ORR) [ Time Frame: 32 months ]
    Efficacy measured by ORR. ORR is defined as the number of subjects with a best overall response (BOR) of complete response (CR) or partial response (PR) divided by the number of response evaluable subjects (according to RECIST 1.1 and Choi criteria).

  4. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 32 months ]

    Safety profile of the experimental treatment, through assessment of adverse event type, incidence, severity, time of appearance, related causes, as well as physical explorations and laboratory tests. Number of participants with treatment-related adverse events as assessed by CTCAE v4.03.

    Toxicity will be graded and tabulated by using CTCAE 4.03.


  5. GIST genotype and CBR with selinexor and imatinib (Translational) Study Objective [ Time Frame: 32 months ]
    GIST genotype determinations and its correlation with response to the treatment with selinexor and imatinib in terms of clinical benefit (CBR).

  6. Measure the plasma concentration of imatinib and selinexor (Pharmacokinetics)Study Objective [ Time Frame: 32 months ]
    To measure the plasma concentration of imatinib and selinexor at limited timepoints specificed in schedule of assessment.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04138381


Contacts
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Contact: Beatriz Suarez, PhD 658232638 beatriz.suarez.crc@grupogeis.org
Contact: Melissa Fernandez, PM 658232638 melissacrc@grupogeis.org

Locations
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Spain
Hospital Virgen del Rocio Recruiting
Sevilla, Andalucia, Spain, 41013
Contact: Laura Bernal, SC    671 533 319    laura.bernal.exts@juntadeandalucia.es   
Principal Investigator: Javier Martín Broto, MD         
H Vall d'Hebrón Recruiting
Barcelona, Catalonia, Spain, 08035
Contact: Carlos Fernández Sáez, SC       cafernandez@vhio.net   
Principal Investigator: Cesar Serrano García, MD         
Hospital Universitario de Canarias Not yet recruiting
Tenerife, Islas Canarias, Spain, 238320
Contact: Rita Alonso, SC    922 678204    mariaalonsohuc@hotmail.com   
Principal Investigator: Josefina Cruz, MD         
Hospital Miguel Servet Not yet recruiting
Zaragoza, Zaragoza, Aragón, Spain, 50009
Contact: Laura Rodriguez, SC    976765500 ext 143825    lrsastre70@gmail.com   
Principal Investigator: Javier Martínez, MD         
Hospital La Paz Not yet recruiting
Madrid, Spain, 28046
Contact: Susana Feliu, SC    91 727 75 16    susana.ft@hotmail.com   
Principal Investigator: Virgina Martínez, MD         
Hospital Virgen de la Arrixaca Not yet recruiting
Murcia, Spain, 30120
Contact: Paula Ruiz, SC    968 36 93 87    dm.oncoarrixaca2@gmail.com   
Contact: Ana Perez, SC    968 36 93 87    dm.oncoarrixaca@gmail.com   
Principal Investigator: Jerónimo Martínez, MD         
Sponsors and Collaborators
Grupo Espanol de Investigacion en Sarcomas
Investigators
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Principal Investigator: Cesar Serrano, MD Hospital Vall d´Hebron
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Responsible Party: Grupo Espanol de Investigacion en Sarcomas
ClinicalTrials.gov Identifier: NCT04138381    
Other Study ID Numbers: GEIS 41
2017-004761-28 ( EudraCT Number )
First Posted: October 24, 2019    Key Record Dates
Last Update Posted: October 24, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The final publication of the trial results will be written by the international coordinating investigators on the basis of the final analysis performed. The draft manuscript will be reviewed by the coordinating investigators and other co-authors. After revision the manuscript will be sent to a major scientific journal. Results obtained in the different strata may be separately published.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Grupo Espanol de Investigacion en Sarcomas:
GIST
MTD
Imatinib
Selinexor
Phase II
Unresectable
Metastatic
Additional relevant MeSH terms:
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Gastrointestinal Stromal Tumors
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Connective Tissue
Gastrointestinal Neoplasms
Digestive System Neoplasms
Gastrointestinal Diseases
Sarcoma
Drug-Related Side Effects and Adverse Reactions
Digestive System Diseases
Chemically-Induced Disorders
Imatinib Mesylate
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action