A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients
A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients
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.
Background:

 Soft tissue sarcomas (STS):

 STS are a group of heterogeneous mesenchymal derived tumors with many histological types that
 account for approximately 1% of adult tumors and 15% of pediatric tumors. STS can be divided
 into those with simple genetic alterations (e.g. translocations or activating mutations) or
 karyotypic complex lesions. However, most subclasses are treated in the same manner. Surgery
 is the primary treatment for localized STS, with or without radiation therapy (RT), but
 approximately 10% of patients will present with metastatic disease.

 For patients who present with metastatic disease, or those with locally advanced/unresectable
 or have failed primary therapy, cytotoxic chemotherapy is usually the treatment of choice
 which may provide meaningful palliation or prolong survival. Traditionally, doxorubicin
 containing regimens, in combination with ifosfamide or as a single agent are standard first
 line therapies. Combination based doxorubicin containing regimens have shown higher response
 rates and progression free survival at the expense of more toxicity when compared to
 doxorubicin alone. However, no combination regimen has been associated with increased overall
 survival compared to doxorubicin alone.

 In the metastatic setting, STS carry a poor prognosis related to a lack of chemo-sensitivity
 and a lack of systemic therapeutic options. Exportin 1 (XPO1 or chromosome region maintenance
 1 [CRM1]) is the sole nuclear exporter of some tumor suppressor proteins (TSP). XPO1 is
 over-expressed 2-4 fold in a variety of solid and hematological tumors with higher levels
 correlating with poorer outcomes.

 Selinexor:

 Selinexor is a novel, oral, small-molecule XPO1 inhibitor which forces reactivation of TSPs
 and thus leads to apoptosis of tumor cells. Preclinical data of Selinexor has shown promising
 in-vitro tumor regression in sarcoma. In two phase I studies, single agent clinical activity
 in the form of prolonged stable disease was seen in STS. Twice weekly dosing aided
 tolerability with a MTD declared at 65mg/m2 for solid tumors and 60mg flat dosing was the
 RP2D based on better tolerability given problems related to gastrointestinal toxicity however
 these doses were still difficult for patients to take due to the toxicity profile. A Phase 1b
 study has been performed combining Selinexor once weekly oral dosing with doxorubicin given
 at the standard 3 weekly dose in advanced soft tissue sarcoma.

 Previous studies have provided a signal of increased likelihood of benefit to particular
 subtypes including metastatic malignant peripheral nerve sheath tumors (MPNST) and
 endometrial stromal sarcomas (ESS). In the early phase studies, objective responses or
 prolonged stable disease were demonstrated (n=3 for both MPNST and ESS). In this study, the
 investigator also plans to include leiomyosarcoma (LMS) - such strategy will allow not only
 seamless recruitment, but also generate treatment efficacy data for other rare types of
 sarcomas.

 Additionally, preclinical data has shown efficacy in using metronomic dosing of Selinexor.
 The investigator hypothesizes that low dose Selinexor will improve tolerability of the drug
 without impacting the clinical benefit that has been seen in other studies for patients with
 particular histological subtypes of STS.

 Rationale:

 Biological Rationale:

 More than 2500 patients with advanced cancers have received Selinexor orally in Phase 1 and
 Phase 2-3 studies as of 31 May 2019. Based on the preclinical and clinical findings to date,
 Selinexor dosing is limited to ≤70 mg/m2 (≤120 mg) maximum dose in adults. The plan going
 forward is that Selinexor will be administered primarily as fixed milligram doses, as
 analyses of Phase 1 pharmacokinetic (PK) data indicated that exposure is not strongly
 correlated with Body Surface Area (BSA).

 An interim analysis of preliminary results was performed to determine the RP2D for future
 studies. The results of this analysis suggest that, overall, Selinexor doses > 65 mg do not
 appear to provide additional efficacy responses beyond those seen with the 60 mg dose
 (described herein as 45-65 mg dose level, median 60 mg) with the exception of activity in
 refractory multiple myeloma (MM), where the RP2D is Selinexor 80 mg in combination with 20mg
 dexamethasone. Importantly, response results with Selinexor 45-65 mg twice weekly were
 comparable for both hematologic malignancies (excluding MM) and solid tumors.

 The currently available selinexor formulation (20 mg tablet) and dosage is quite toxic
 particularly in terms of gastrointestinal disturbance, particularly nausea and vomiting. As a
 result of these difficulties it might be beneficial to investigate alternate formulations of
 selinexor or a different dosing schedule of the currently available selinexor formulation. A
 PK study in male Beagle dogs has been completed by Karyopharm investigating a new extended
 release (ER) formulation of Selinexor 20 mg tablets showing favorable results.

 Dose Schedule Rationale:

 In the present study, Selinexor will be given using two different schedules according to
 Schema for Arm A (metronomic) and Schema for Arm B (split dosing).

 In Arm A Selinexor will be administered at a fixed oral dose as per dose level (starting at
 2.5mg PO 4 days on, 3 days off repeated weekly) of each 4-week (28-day) cycle a total of 16
 doses per cycle. The maximum dose for Selinexor in this study will be 17.5mg PO flat dosing 4
 days on, 3 days off, weekly. This arm of the study will be aimed at identifying the RP2D and
 toxicity profile of this new selinexor dosing schedule.

 In Arm B patients will be treated with Selinexor 40mg in the morning, 20mg in the afternoon
 and 20mg at night on days 1, 8, 15 and 22 of a 28-day cycle. The hope is that this alternate
 dosing schedule will improve the tolerability of this formulation of selinexor without
 impacting its clinical benefit.

 Intervention and mode of delivery:

 In Arm A patients will receive Selinexor orally as described above. The initial 3 patients
 will be enrolled to the first Selinexor dose level of 2.5mg (DL1). Three patients will be
 assessed per cohort for at least 1 cycle and dose escalation or de-escalation rules will
 follow 3+3 dosing. The first dose of study treatment for the first two patients will be
 staggered by 7 days. Intra-patient dose escalation is not permitted at any time during the
 treatment plan.

 In Arm B also patients will receive selinexor orally as described above.

 Duration of Intervention and Evaluation:

 Treatment in both arms with Selinexor will be repeated on a 28-day cycle until radiographic
 or symptomatic progression on imaging or the development of unacceptable toxicity. Patients
 will be restaged every 2 cycles until unacceptable toxicity or disease progression.
 Subsequent follow-up for disease progression will continue by telephone or review of patient
 medical records for up to 2 years after the completion of trial treatment.

 Number of Patients:

 A total of up to 36 patients will be accrued in Arm A. Up to 20 patients will be enrolled in
 Arm B with an anticipated accrual period of 12 to 18 months.

 Definition of dose limiting toxicity (DLT):

 DLT is defined as any of the following occurring in the first 28 days of each dose level that
 is considered at least possibly related to drug administration:

 ≥ 4 missed doses (out of 16) due to a toxicity that is at least possibly study drug related.

 Discontinuation of a patient due a toxicity that is at least possibly study drug related
 before completing cycle 1

 Non-Hematologic:

 Grade ≥ 3 nausea/vomiting, dehydration or diarrhea while taking optimal supportive
 medications Grade 3 fatigue lasting for ≥ 7 days while taking optimal supportive care and
 with correction of dehydration, anorexia, anemia, endocrine, or electrolyte abnormalities.

 Grade 3 AST or ALT elevation lasting longer than 7 days OR Grade 3 AST or ALT elevation in
 the setting of bilirubin elevation > 2x ULN (> 2X baseline for patients with Gilbert's
 syndrome) OR any grade 4 AST or ALT elevation.

 Any other clinically significant Grade ≥ 3 non-hematological toxicity except alopecia or
 electrolyte abnormalities correctable with supportive therapy Any cardiac disorder ≥ CTCAE
 Grade 3

 Hematologic:

 Grade 4 neutropenia [absolute neutrophil count (ANC) < 0.5x109/L] on Cycle 2 Day 1 that does
 not resolve to G1 within 7 days Grade 4 neutropenia [absolute neutrophil count (ANC) <
 0.5x109/L] within the first 28 days lasting ≥ 7 days Grade 3 Febrile neutropenia Grade ≥ 3
 thrombocytopenia associated with clinically significant bleeding Grade 4 thrombocytopenia
 within the first 28 days (platelets < 25x109/L) lasting > 7days

 Other:

 Any hematologic or non-hematologic toxicity that results in the inability to administer day 1
 of the next planned cycle within 14 days of the planned end of the previous cycle.

 Treatment related death During the dose escalation portion of the study, patients who missed
 >1 dose of Selinexor during Cycle 1 for reasons unrelated to study drug are not evaluable for
 DLT and will be replaced.

 Treatment Discontinuation Criteria:

 Disease progression Noncompliance with protocol Need for treatment with medications not
 allowed by the study protocol Consent withdrawal Intercurrent illness Incidence or severity
 of AEs Investigator discretion

 Duration:

 The treatment period for an individual patient is expected to be approximately between 2 and
 12 months, however there is no maximum treatment duration.

 Study procedures:

 For Arm A the starting dose of Selinexor will be 2.5mg given 4 days on 3 days off on a weekly
 basis as part of a 28-day cycle. For Arm B patients will receive oral Selinexor 40 mg in the
 morning, 20 mg in the afternoon, 20 mg in the evening. Patients will be assessed for response
 after ever 2 cycles. Treatment will be given until disease progression or unacceptable
 toxicity.

 Safety data:

 Overall safety profile as per NCI CTCAE version 5.

 Concomitant Medications:

 Patients will receive best supportive care, including anti-emetics, appetite stimulants and
 growth factors, blood product transfusions, antimicrobials and (as appropriate) granulocyte
 colony-stimulating factors (G-CSF) for neutropenia and/or neutropenic infection,
 erythropoietin for anemia, and/or platelet-stimulating factors for thrombocytopenia. Patients
 will not be dosed with G-CSF in the first cycle for primary prophylaxis of febrile
 neutropenia.

 If clinically indicated and as required by protocol, patients may receive red blood cell or
 platelet transfusions, acetaminophen, serotonin (5-HT3) receptor subtype antagonists (e.g.,
 ondansetron) megestrol acetate, and olanzapine in addition to ondansetron. Patients
 intolerant to 5-HT3 antagonists may receive D2-antagonists instead. Additional anti-nausea
 and anti-anorexia agents may be given as needed. Patients may continue to receive baseline
 medication(s), and may receive concomitant medications that are medically necessary as
 standard care to treat co-morbid diseases, AEs, and intercurrent illnesses.

 Concurrent therapy with any other approved or investigative anticancer therapy is not
 allowed.

 Pharmacokinetic and Pharmacodynamic assessments:

 PK will be determined at various times following administration of Selinexor in Arm A.

 Pharmacokinetics:

 In the metronomic arm for the first 3 patients in each dose level, blood samples just before
 Selinexor administration (C1D1), and at 1hr, 2hr, 4hr, 24hr and a trough level pre C2 will be
 collected.

 Response:

 Objective disease response assessment will be made according to standard, international
 RECIST 1.1 criteria for solid tumors.

 Safety Variables and Analysis:

 The safety and tolerability of Selinexor will be evaluated by means of drug related DLT, AE
 reports, physical examinations, and clinically significant laboratory safety evaluations. NCI
 CTCAE version 5.0 will be used for grading of AEs.

 Investigators will provide their assessment of causality as: unrelated, possibly related, or
 probably or definitely related for all AEs.
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