Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Sarcoma

Histiocytoma, Malignant Fibrous

Liposarcoma

Fibrosarcoma

Histiocytoma

Histiocytoma, Benign Fibrous

Leiomyosarcoma

Sarcoma, Synovial

Nerve Sheath Neoplasms

Neurofibrosarcoma

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Soft Tissue Sarcoma

Undifferentiated Pleomorphic Sarcoma

Synovial Sarcoma

Malignant Peripheral Nerve Sheath Tumor

Epithelioid Sarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Doxorubicin

Liposomal doxorubicin

Fluorodeoxyglucose F18

Ifosfamide

Isophosphamide mustard

Mesna

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Antineoplastic Agents, Alkylating

Alkylating Agents

Radiopharmaceuticals

Subjects with soft tissue sarcoma who are receiving pegylated liposomal doxorubicin hydrochloride, Ifosfamide with mesna and pegfilgrastim - Repeat every 28 days for 4 cycles total

Subjects with soft tissue sarcoma who are receiving Doxorubicin hydrochloride, Ifosfamide with mesna and pegfilgrastim - Repeat every 28 days for 4 cycles total

will be given at 6 mg subcutaneously (SC) at the end of the mesna infusion

pegfilgrastim

65 mg/m\^2 by continuous intravenous (IV) infusion over 7 days beginning on day 1

doxorubicin hydrochloride

9 g/m\^2 by continuous intravenous (IV) infusion over 6 days beginning on day 1 with mesna 10.5 g/m\^2 by continuous IV infusion over 7 days beginning on day 1

ifosfamide

45 mg/m2 intravenous (IV) Day 1, repeat every 28 days.

pegylated liposomal doxorubicin hydrochloride

The surgical procedure will be decided by the treating physician and independent of study participation

conventional surgery

FDG is a radioactive sugar equal to a uniform whole-body exposure of approximately 1.5 rem for each scan. Post-operative radiation therapy may be given according to institutional guidelines in patients felt to have close surgical margins.

fludeoxyglucose F 18

Edward Cheng, MD

RATIONALE: Diagnostic procedures, such as positron emission tomography (PET) scan and computated tomography (CT) scan, may help doctors predict a patient's response to treatment and may help plan the best treatment. Drugs used in chemotherapy, such as doxorubicin and ifosfamide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving chemotherapy before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This clinical trial is studying how well PET scan combined with CT scan predicts response in patients undergoing chemotherapy and surgery for soft tissue sarcoma.

OBJECTIVES:

Primary

* Determine whether measurements of fludeoxyglucose (FDG) positron emission tomography (PET)/CT imaging can accurately predict disease-free survival of patients with soft tissue sarcoma who are receiving neoadjuvant chemotherapy.

Secondary

* Correlate histological response to neoadjuvant chemotherapy for soft tissue sarcomas with FDG-PET/CT imaging findings.

Tertiary

* Determine the changes in FDG-PET/CT imaging over time as each course of chemotherapy is given.

OUTLINE: Patients receive 1 of 2 standard chemotherapy regimens:

* Preferred regimen: Patients receive pegylated doxorubicin HCl liposome IV on day 1, ifosfamide IV continuously on days 1-6, and pegfilgrastim subcutaneously (SC) on day 8. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.
* Alternative regimen: Patients receive doxorubicin hydrochloride IV continuously on days 1-7. Patients also receive ifosfamide and pegfilgrastim as in the preferred regimen. Treatment repeats every 28 days for up to 4 courses in the absence of disease progression or unacceptable toxicity.

All patients undergo a fludeoxyglucose positron emission tomography/CT scan at baseline, after course 1, and after completion of chemotherapy. Patients undergo surgery within 4-6 weeks after completion of chemotherapy.

After completion of study treatment and surgery, patients are followed every 6 months for 5 years.

PROJECTED ACCRUAL: A total of 62 patients will be accrued for this study.

PET CT as Predictor of Response in Preoperative Chemotherapy for Soft Tissue Sarcoma

An Evaluation of PET/CT Imaging as a Predictor of Disease Free Survival Following Neo-Adjuvant Chemotherapy for Soft Tissue Sarcoma

Compare changes in baseline and follow-up fludeoxyglucose (FDG) positron emission tomography (PET)/CT imaging with disease-free survival by peak SUV and max SUV calculations. Changes in baseline and follow-up PET/CT, based on max SUV calculations, will be compared with disease free survival. Disease free survival will be measured in months from the time of study enrollment until the time that disease recurrence/relapse/progression is recorded.

The overall histologic response will be defined as:

% histologic response = 100 - % viable tumor in the central slice as assessed histologically It should be noted that the % histologic response is different from % tumor necrosis as it includes an assessment of the % tumor necrosis along with the degenerative changes

Changes in PET/CT from baseline will be compared to PET/CT done after one cycle and after completion of chemotherapy treatment before surgical excision using max SUV calculations.

Masonic Cancer Center, University of Minnesota

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Diseases and Abnormalities at or Before Birth

Sarcoma, Endometrial Stromal

Neoplasms, Nerve Tissue

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Peripheral Nervous System Diseases

Neuromuscular Diseases

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neurofibromatoses

Neurofibroma

Endometrial Stromal Tumors

Endometrial Neoplasms

Uterine Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endometrial Stromal Sarcoma

Neurofibromatosis

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.

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.

Selinexor

Albiruni Razak, M.D.

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.

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.

A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients

A Phase 1 Study of Metronomic Selinexor in Select Soft Tissue Sarcomas and Split Dosing of Selinexor in All Soft Tissue Sarcomas

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.

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.

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.

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.

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.

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.

Descriptive statistics will be used to summarize AUC of Selinexor. Only the first 3 patients per dose level will be included for AUC analysis.

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.

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.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
PET CT as Predictor of Response in Preoperative Chemotherapy for Soft Tissue Sarcoma	NCT00346125	Sarcoma	pegfilgrastim doxorubicin hyd... ifosfamide pegylated lipos... conventional su... fludeoxyglucose...	16 Years -	Masonic Cancer Center, University of Minnesota
A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients	NCT04811196	Soft Tissue Sar... Malignant Perip... Leiomyosarcoma Endometrial Str...	Selinexor	18 Years -	University Health Network, Toronto
A Study of Different Dosing Schedules of Selinexor in Sarcoma Patients	NCT04811196	Soft Tissue Sar... Malignant Perip... Leiomyosarcoma Endometrial Str...	Selinexor	18 Years -	University Health Network, Toronto
PET CT as Predictor of Response in Preoperative Chemotherapy for Soft Tissue Sarcoma	NCT00346125	Sarcoma	pegfilgrastim doxorubicin hyd... ifosfamide pegylated lipos... conventional su... fludeoxyglucose...	16 Years -	Masonic Cancer Center, University of Minnesota

Spots Global Cancer Trial Database for malignant peripheral nerve sheath tumor (mpnst)