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A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients

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ClinicalTrials.gov Identifier: NCT04811196
Recruitment Status : Recruiting
First Posted : March 23, 2021
Last Update Posted : March 30, 2021
Sponsor:
Information provided by (Responsible Party):
University Health Network, Toronto

Brief Summary:

This is a phase 1, open-label, single centre study of investigational drug selinexor in participants with soft tissue sarcomas that cannot be treated with standard therapies. Selinexor has been given to 3111 participants with cancer to date including 142 sarcoma patients. Early findings have shown that selinexor is effective in multiple cancer types. The current study is being done to test low doses and different dosing schedules of selinexor to find out if it reduces the side effects without compromising the benefits.

This study has 2 groups or Arms: Arm A and Arm B.

Arm A (Dose escalation Arm): Participants will receive selinexor by mouth 4 days a week to find out the safety, tolerability and anti-tumor effect of low doses of Selinexor in participants with advanced or metastatic malignant peripheral nerve sheath tumors (MPNST), endometrial stromal sarcomas (ESS) and leiomyosarcoma (LMS). Participants will continue on study until disease progression or unacceptable side effects. Up to 36 participants will be enrolled in this Arm.

Arm B: Participants with any soft tissue sarcoma subtypes will be enrolled in this Arm. They will receive flat doses of Selinexor by mouth once weekly, 3 times a day. Safety and tolerability will be assessed in this Arm. Up to 20 participants will be enrolled and they will continue to receive selinexor until disease progression or unacceptable side effects.

Cancer is the uncontrolled growth of human cells. One of the ways cancers cells continue to grow is by getting rid of proteins called "tumor suppressor proteins" that would normally cause cancer cells to die. The study drug works by trapping "tumor suppressor proteins" within the cell, causing the cancer cells to die or stop growing.

The study comprises 3 periods: Screening (up to 28 days), Study Drug (until disease progression), and Survival Follow-Up (once every 3 months). Procedures for research purposes only will include blood collection and study questionnaire.


Condition or disease Intervention/treatment Phase
Soft Tissue Sarcoma Malignant Peripheral Nerve Sheath Tumor (MPNST) Leiomyosarcoma Endometrial Stromal Sarcoma Drug: Selinexor Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 56 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

This is a phase 1/1b single centre study with two arms. Arm A is a dose escalation study assessing the safety, tolerability and preliminary antitumor activity of low dose metronomic Selinexor in adult patients with locally advanced/unresectable or metastatic MPNST, endometrial stromal cell sarcomas or angiogenic tumors. This is a dose escalation study and will consist of ascending doses of Selinexor administered metronomically as a single agent.

Up to 36 patients will be enrolled in Arm A.

Arm B of this study will enroll all soft tissue sarcoma histologies to receive flat dosing Selinexor 40mg in the morning, 20mg in the afternoon and 20mg at night orally on days 1, 8, 15, 22 of a 28-day cycle. Twenty patients will be enrolled to this arm. This pattern will continue until disease progression or unacceptable toxicity. Quality of life assessments will occur at pre-dosing, cycle 2 day 1, cycle 6 day 1 and cycle 12 day 1 for those who remain on study.

Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of Metronomic Selinexor in Select Soft Tissue Sarcomas and Split Dosing of Selinexor in All Soft Tissue Sarcomas
Actual Study Start Date : March 29, 2021
Estimated Primary Completion Date : February 2025
Estimated Study Completion Date : February 2025


Arm Intervention/treatment
Experimental: Metronomic dosing

This Arm is an open-label, non-randomized, phase 1 study of metronomic dosing of selinexor in patients with locally advanced or metastatic MPNST, ESS, LMS. Up to seven dose levels of Selinexor will be investigated.

Patients will undergo 3+3 based dose escalation to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of Selinexor.

Escalating doses of selinexor will be given starting with 2.5 mg (taken orally 4 days in a row followed by 3 days break from treatment, repeating this weekly as part of a 28-day cycle). The first dose for the first 2 patients at each dose level will be staggered by 7 days. Minimum number of patients treated in this trial arm is 18 patients, and maximum 36 patients.

Schedule:

Selinexor flat dosing with dose levels (DLs) of 2.5mg (DL1), 5mg (DL2), 7.5mg (DL3), 10mg (DL4), 12.5mg (DL5), 15mg (DL6), 17.5mg (DL7). A DL-1 (1.25 mg) is also incorporated.

Drug: Selinexor
Selinexor
Other Name: KPT-330, XPOVIO

Experimental: Split dosing
The second arm of the study is an open-label, non randomized, phase 1b study of selinexor in patients with any histological subtype of STS administered orally one day per week, 40mg in the morning, 20mg in the afternoon and 20mg at night as part of a 28 day cycle. Twenty patients will be accrued to this arm.
Drug: Selinexor
Selinexor
Other Name: KPT-330, XPOVIO




Primary Outcome Measures :
  1. Incidence of toxicity and safety of Selinexor given on either a metronomic (Arm A) or split dosing (Arm B) schedule: Adverse Events [ Time Frame: Up to 14 days after completion of study treatment ]
    Graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Analyses will be performed using descriptive statistics.

  2. Recommended phase 2 dose of Selinexor given metronomically [ Time Frame: Up to 28 days ]
    Toxicity will be assessed using the NCI CTCAE, version 5.0. Adverse events will be tabulated and summarized by major organ category, grade, anticipation, and drug attribution.


Secondary Outcome Measures :
  1. Progression-Free Survival (PFS) of metronomic Selinexor [ Time Frame: From date of first dose of selinexor until the date of first documented progression, assessed up to 12 months. ]
    The Kaplan-Meier product limit method will be used to estimate PFS of the median PFS and PFS rates at clinically relevant time point will be provided with the 95% CI.

  2. Objective Response Rate (ORR) of metronomic Selinexor [ Time Frame: From date of first dose of selinexor until the date of first documented progression, assessed up to 12 months. ]
    Defined as the proportion of patients who achieved a complete response (disappearance of all target tumors) or a partial response (PR) (≥30% decrease in the sum of longest diameters of target tumors) based on RECIST Version 1.1. The ORR, along with exact two-sided 95% confidence intervals based on binomial distribution will be reported.

  3. Clinical Benefit Rate (CBR) of metronomic Selinexor [ Time Frame: From date of first dose of selinexor until the date of first documented progression, assessed up to 12 months. ]
    Defined as the proportion of patients who achieved a complete response (disappearance of all target tumors) or a partial response (≥30% decrease in the sum of the longest diameters of target tumors) or stable disease (Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD) for greater than 16 weeks based on RECIST Version 1.1. The CBR, along with exact two-sided 95% confidence intervals based on binomial distribution will be reported.

  4. Peak Plasma Concentration (Cmax) of metronomic Selinexor [ Time Frame: Prior to dose on day 1, and at 1, 2, 4, and 24 hours post dose of Cycle 1, and prior to dose on Day 1 of Cycle 2 (each cycle is 28 days). ]
    Descriptive statistics will be used to summarize Selinexor concentration at each sampling time point and Cmax. Only the first 3 patients per dose level will be included for Cmax analysis.

  5. Area under the plasma concentration versus time curve (AUC) of metronomic Selinexor [ Time Frame: Prior to dose on day 1, and at 1, 2, 4, and 24 hours post dose of Cycle 1, and prior to dose on Day 1 of Cycle 2 (each cycle is 28 days). ]
    Descriptive statistics will be used to summarize AUC of Selinexor. Only the first 3 patients per dose level will be included for AUC analysis.

  6. Characterization of the toxicity of metronomic Selinexor [ Time Frame: Up to 14 days after completion of study treatment ]
    Analyses will be performed for all patients having received at least one dose of study drug. The study will use the NCI CTCAE v5.0. Serious adverse events, AEs, AEs leading to withdrawal/dose interruptions/dose modification will be summarized using descriptive statistics.

  7. Quality of life assessment using Quality of Life Questionnaire [ Time Frame: Screening and then pre-dose Cycles 1, 6, and 12 (each cycle is 28 days). ]
    To better define the toxicity of Selinexor, patient reported outcomes using 'European Organization for Research and Treatment of Cancer' (EORTC) 'Quality of Life Questionnaire' (QLQ-C30) will be investigated. The score ranges from 1 to 4, with 1 being the worst outcome and 4 being the best. Mean score of individual item numbers of interest will be analyzed with descriptive and mixed effect model methods.



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. Written informed consent in accordance with federal, local, and institutional guidelines
  2. Age > 18 years.
  3. Patients must have histologically confirmed locally advanced/unresectable or metastatic STS

    1. For Arm A the acceptable histologies are MPNST, ESS and LMS
    2. For Arm B arm all STS histologies are eligible
  4. Patients must fall into one of the three following categories:

    1. Show evidence of progressive disease on study entry; or
    2. Be treatment naïve, but have progressed since diagnosis; or
    3. Newly diagnosed patients with de novo metastatic measurable disease.
  5. Patient must have measureable disease as defined by RECIST 1.1.
  6. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  7. Adequate hematopoietic function within 7 days prior to C1D1:

    1. absolute neutrophil count (ANC) ≥1.0x109/L
    2. hemoglobin ≥ 90 g/L
    3. platelet count ≥100 x 109/L
    4. Patients receiving hematopoietic growth factor support, including erythropoietin, darbepoetin, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF), and platelet stimulators (eg, eltrombopag, romiplostim, or interleukin-11) must have a 2-week interval between growth factor support and the Screening assessments, but they may receive growth factor support during the study.
    5. Patients must have:

    i. At least a 2-week interval from the last red blood cell (RBC) transfusion prior to the Screening hemoglobin assessment, and

    ii. At least a 1-week interval from the last platelet transfusion prior to the Screening platelet assessment.

    iii. However, patients may receive RBC and/or platelet transfusions as clinically indicated per institutional guidelines during the study.

  8. Adequate hepatic function within 28 days prior to C1D1:

    1. Bilirubin <1.5 times the upper limit of normal (ULN) (except patients with Gilbert's syndrome who must have a total bilirubin of < 3 times ULN)
    2. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <2 X ULN. In the case of known (radiological and/or biopsy documented) liver metastasis, ALT/AST <5.0 X ULN is acceptable;
  9. Adequate renal function within 28 days prior to C1D1: estimated creatinine clearance of ≥20 mL/min calculated using the formula of Cockcroft and Gault: (140-Age)(Weight in kg)(Constant)/(serum creatinine µmol/L); where constant is 1.23 for men and by 1.04 for women.
  10. Female patients of childbearing potential must agree to use two methods of contraception (including one highly effective and one effective method of contraception) and have a negative serum pregnancy test at Screening. Male patients must use an effective barrier method of contraception if sexually active with a female of childbearing potential. For both male and female patients, effective methods of contraception must be used throughout the study and for 3 months following the last dose of study treatment.
  11. Ability to swallow pills

Exclusion Criteria:

  1. Has received selinexor or another XPO1 inhibitor previously
  2. Patients who are pregnant or lactating
  3. Radiation (except planned or on-going palliative radiation outside of the region of measurable disease), chemotherapy, immunotherapy, any other systemic anticancer therapy, or participation in an investigational anti-cancer study ≤3 weeks prior to initiation of therapy. Mitomycin C and radio-immunotherapy within 6 weeks prior to cycle 1 day 1.
  4. Major surgery within 4 weeks before initiation of therapy
  5. Active, ongoing or uncontrolled active infection within one week prior to first dose
  6. Patients with any gastrointestinal dysfunctions that could interfere with the absorption of Selinexor or patients with significantly diseased or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea;
  7. Inability or unwillingness to take supportive medications such as anti-nausea and anti anorexia agents as recommended by the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines for Antiemesis and Palliative Care.
  8. In the opinion of the Investigator, patients who are significantly below their ideal body weight (Body Surface Area ≤ 1.2m2)
  9. Concurrent therapy with approved or investigational anticancer therapeutic agents
  10. Any condition that, in the opinion of the Investigator, would interfere with evaluation of the study regimen or interpretation of patient safety or study results

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): NCT04811196


Contacts
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Contact: Albiruni Razak, M.D. 416-586-5371 Albiruni.Razak@uhn.ca

Locations
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Canada, Ontario
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Albiruni Razak, M.D.    416-586-4800 ext 3883      
Principal Investigator: Albiruni Razak, M.D.         
Sponsors and Collaborators
University Health Network, Toronto
Investigators
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Principal Investigator: Albiruni Razak, M.D. Princess Margaret Cancer Centre
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Responsible Party: University Health Network, Toronto
ClinicalTrials.gov Identifier: NCT04811196    
Other Study ID Numbers: METSSAR
First Posted: March 23, 2021    Key Record Dates
Last Update Posted: March 30, 2021
Last Verified: March 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 University Health Network, Toronto:
Selinexor, Sarcoma
Additional relevant MeSH terms:
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Sarcoma
Leiomyosarcoma
Nerve Sheath Neoplasms
Neurofibrosarcoma
Sarcoma, Endometrial Stromal
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Muscle Tissue
Neoplasms, Nerve Tissue
Peripheral Nervous System Neoplasms
Nervous System Neoplasms
Nervous System Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Fibrosarcoma
Neoplasms, Fibrous Tissue
Neoplasms, Connective Tissue
Neurofibroma
Neoplasms, Complex and Mixed
Endometrial Stromal Tumors
Endometrial Neoplasms
Uterine Neoplasms
Uterine Diseases
Genital Neoplasms, Female
Urogenital Neoplasms