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

Primary Purpose

Maximum Tolerated Dose, GIST, Metastatic Adult Soft Tissue Sarcoma

Status
Active
Phase
Phase 1
Locations
Spain
Study Type
Interventional
Intervention
Selinexor
Imatinib
Sponsored by
Grupo Espanol de Investigacion en Sarcomas
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Maximum Tolerated Dose focused on measuring GIST, MTD, Imatinib, Selinexor, Phase Ib, Phase II, Unresectable, Metastatic

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hospital Virgen del Rocio
  • H Vall d'Hebrón
  • Hospital Universitario de Canarias
  • Hospital Miguel Servet
  • Hospital La Paz
  • Hospital Virgen de la Arrixaca

Arms of the Study

Arm 1

Arm Type

Other

Arm Label

selinexor as a single agent and in combination with imatinib

Arm Description

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

Outcomes

Primary Outcome Measures

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.
Clinical benefit rate (CBR) for the use of selinexor in monotherapy
Clinical benefit rate (CBR) is defined as CR+PR+SD ≥ 16 wks

Secondary Outcome Measures

Progression free survival (PFS)
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).
Overall survival (OS)
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.
Objective response rate (ORR)
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).
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
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.
GIST genotype and CBR with selinexor and imatinib (Translational) Study Objective
GIST genotype determinations and its correlation with response to the treatment with selinexor and imatinib in terms of clinical benefit (CBR).
Measure the plasma concentration of imatinib and selinexor (Pharmacokinetics)Study Objective
To measure the plasma concentration of imatinib and selinexor at limited timepoints specificed in schedule of assessment.
Clinical benefit rate (CBR)
Number of patient with CBR ≥ 30% lasting ≥ 16 weeks

Full Information

First Posted
September 16, 2019
Last Updated
March 24, 2023
Sponsor
Grupo Espanol de Investigacion en Sarcomas
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1. Study Identification

Unique Protocol Identification Number
NCT04138381
Brief Title
Selinexor as Single Agent and With Imatinib in Metastatic and/or Unresectable Gastrointestinal Stromal Tumors (SeliGIST)
Acronym
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

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 16, 2019 (Actual)
Primary Completion Date
April 16, 2023 (Anticipated)
Study Completion Date
April 16, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Grupo Espanol de Investigacion en Sarcomas

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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) 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Maximum Tolerated Dose, GIST, Metastatic Adult Soft Tissue Sarcoma, Drug Toxicity, Drug Use
Keywords
GIST, MTD, Imatinib, Selinexor, Phase Ib, Phase II, Unresectable, Metastatic

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
Phase Ib/II, single-arm, two-cohort, non-randomized, open-label, multicenter, national clinical trial, single agent, combinations products
Masking
None (Open Label)
Allocation
N/A
Enrollment
30 (Actual)

8. Arms, Groups, and Interventions

Arm Title
selinexor as a single agent and in combination with imatinib
Arm Type
Other
Arm Description
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
Intervention Type
Drug
Intervention Name(s)
Selinexor
Other Intervention Name(s)
Drug Combination, Single agent
Intervention Description
oral selinexor given once weekly (Cohort A), oral selinexor given BIW (Cohort B)
Intervention Type
Drug
Intervention Name(s)
Imatinib
Other Intervention Name(s)
Drug Combination
Intervention Description
imatinib 400 mg, once daily (Cohort A)
Primary Outcome Measure Information:
Title
Maximum tolerated dose (MTD) for the use of Imatinib in combination with Selinexor
Description
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.
Time Frame
32 months
Title
Clinical benefit rate (CBR) for the use of selinexor in monotherapy
Description
Clinical benefit rate (CBR) is defined as CR+PR+SD ≥ 16 wks
Time Frame
24 months
Secondary Outcome Measure Information:
Title
Progression free survival (PFS)
Description
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).
Time Frame
32 months
Title
Overall survival (OS)
Description
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.
Time Frame
32 months
Title
Objective response rate (ORR)
Description
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).
Time Frame
32 months
Title
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
Description
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.
Time Frame
32 months
Title
GIST genotype and CBR with selinexor and imatinib (Translational) Study Objective
Description
GIST genotype determinations and its correlation with response to the treatment with selinexor and imatinib in terms of clinical benefit (CBR).
Time Frame
32 months
Title
Measure the plasma concentration of imatinib and selinexor (Pharmacokinetics)Study Objective
Description
To measure the plasma concentration of imatinib and selinexor at limited timepoints specificed in schedule of assessment.
Time Frame
32 months
Title
Clinical benefit rate (CBR)
Description
Number of patient with CBR ≥ 30% lasting ≥ 16 weeks
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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) ≤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 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Cesar Serrano, MD
Organizational Affiliation
Hospital Vall d´Hebron
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Virgen del Rocio
City
Sevilla
State/Province
Andalucia
ZIP/Postal Code
41013
Country
Spain
Facility Name
H Vall d'Hebrón
City
Barcelona
State/Province
Catalonia
ZIP/Postal Code
08035
Country
Spain
Facility Name
Hospital Universitario de Canarias
City
Tenerife
State/Province
Islas Canarias
ZIP/Postal Code
238320
Country
Spain
Facility Name
Hospital Miguel Servet
City
Zaragoza
State/Province
Zaragoza, Aragón
ZIP/Postal Code
50009
Country
Spain
Facility Name
Hospital La Paz
City
Madrid
ZIP/Postal Code
28046
Country
Spain
Facility Name
Hospital Virgen de la Arrixaca
City
Murcia
ZIP/Postal Code
30120
Country
Spain

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing 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.

Learn more about this trial

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

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