Ignite Creation Date:
2024-05-06 @ 3:56 PM
Last Modification Date:
2024-10-26 @ 2:00 PM
Study NCT ID:
NCT04811196
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-03-18
First Post:
2021-01-25
Brief Title:
A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients
Sponsor:
University Health Network Toronto
Organization:
University Health Network Toronto
Study Overview
Official Title:
A Phase 1 Study of Metronomic Selinexor in Select Soft Tissue Sarcomas and Split Dosing of Selinexor in All Soft Tissue Sarcomas
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
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
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
Detailed Description:
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 eg 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 advancedunresectable 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 65mgm2 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 n3 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 mgm2 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 25mg 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 175mg 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 25mg DL1 Three patients will be assessed per cohort for at least 1 cycle and dose escalation or de-escalation rules will follow 33 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 nauseavomiting 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 Gilberts 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 05x109L on Cycle 2 Day 1 that does not resolve to G1 within 7 days Grade 4 neutropenia absolute neutrophil count ANC 05x109L 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 25x109L 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 25mg 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 andor neutropenic infection erythropoietin for anemia andor 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 eg 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 medications 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 11 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 50 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
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 eg 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 advancedunresectable 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 65mgm2 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 n3 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 mgm2 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 25mg 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 175mg 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 25mg DL1 Three patients will be assessed per cohort for at least 1 cycle and dose escalation or de-escalation rules will follow 33 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 nauseavomiting 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 Gilberts 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 05x109L on Cycle 2 Day 1 that does not resolve to G1 within 7 days Grade 4 neutropenia absolute neutrophil count ANC 05x109L 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 25x109L 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 25mg 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 andor neutropenic infection erythropoietin for anemia andor 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 eg 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 medications 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 11 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 50 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None