Neoplasms

All Conditions

Heart and Blood Diseases

Rare Diseases

Glioma

Astrocytoma

Oligodendroglioma

Mitral Valve Insufficiency

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

3 Tesla Scanning: MRI/MRS of glioma and non-glioma patients.

Approximately 38 brain tumor patients with IDH mutated gliomas and 50 patients with non-glioma disease will be scanned.

3 Tesla scanning

Changho Choi, PhD

The Investigators will examine the disease specificity of 2-hydroxyglutarate in non-glioma brain lesions, and the clinical utility of 2-hydroxyglutarate, glycine and citrate in IDH mutated gliomas and IDH wild type gliomas.

Malignant gliomas represent the majority of primary brain tumors in adults and are among the most intractable tumors. Cancers reprogram their metabolism to meet the needs of rapid cell growth. Alterations in metabolite abundance may serve as biomarkers of malignancy, and the capability to monitor the changes non-invasively would have significant clinical utility in cancer. Gliomas often contain a specific metabolic activity that is predictive of the genotype and has predictive value with respect to tumor stage and patient survival. A high fraction of gliomas contain mutations in the metabolic enzymes, isocitrate dehydrogenase (IDH) 1 and 2. These heterozygous mutations are confined to the active site of the enzyme and result in a neomorphic activity that causes the mutant enzyme to produce an "oncometabolite", 2-hydroxyglutarate (2HG). Non-invasive identification of this onco-metabolite by MRS is therefore a major breakthrough in cancer research. Beyond simple detection of 2HG, our preliminary data show that 2HG is a remarkably sensitive biomarker for monitoring tumor progression and response to treatment in IDH mutated gliomas. Glycine (Gly) is a biomarker of tumor malignancy, as indicated in prior studies. Our data also indicate that citrate (Cit) is elevated in gliomas.

Over the course of this preliminary study, there has been crucial need for 3D evaluation of these onco-metabolites within the tumor mass. The Investigators will examine the clinical utility of 2HG, Gly and Cit, in a large cohort of subjects using multi-slice 2D MRSI at 3T. The specific aims include, first, an in-vivo MRS study for the disease specificity of 2HG (Aim 1). The Investigators will examine clinically proven non-glioma lesions that mimic glioma in clinical MRI. To increase the clinical applicability of the result, the Investigators will select non-enhancing brain diseases, given that IDH mutation occurs largely in grade-2 and -3 gliomas, which are often non-enhancing. Second, the Investigators will examine the clinical utility of 2HG, Gly, Cit and other metabolites in patients with IDH mutated gliomas (Aim 2). Third, the Investigators will examine the clinical utility of Gly, Cit and other metabolites in patients with IDH wild type gliomas (Aim 3). In Aim 2 and 3, the patients will undergo MRSI scans at multiple time points, and the Investigators will monitor the metabolic changes with tumor progression and in response to treatment. The Investigators anticipate our study will provide significant value in many aspects of management of gliomas. 3D evaluation of the cancer biomarkers using MRSI will provide biological insights for making the diagnosis of gliomas, tracking of infiltrative cells during follow up, and determining response to treatment. Success of the 2HG specificity study in non-glioma neurological diseases will provide an experimental evidence for use of non-invasive 2HG imaging as a triaging tool in the workup of a new brain mass.

Clinical Development of Cancer-Specific MRS Biomarkers in Malignant Gliomas

The investigators anticipate the study will provide significant value in many aspects of management of gliomas. 3D evaluation of the cancer biomarkers using MRSI will provide biological insights for making the diagnosis of gliomas, tracking of infiltrative cells during follow up, and determining response to treatment.

National Institutes of Health (NIH)

National Cancer Institute (NCI)

University of Texas Southwestern Medical Center

Oligoastrocytoma

Antineoplastic Agents

All Drugs and Chemicals

Temozolomide

Antineoplastic Agents, Alkylating

Alkylating Agents

Total resected LGGs treated with early radiation

Total resected LGGs treated without radiation

Residual LGGs treated with early radiation

Radiation therapy

Zhongping Chen, M.D., Ph.D.

Although the prognosis of patients with low-grade glioma (LGG) is generally good, recurrence seems unavoidable in some patients because of the infiltrative growth of the tumors. How to treat LGGs is still under controversy. The role of radiation therapy and chemotherapy in the treatment of LGG need to be further investigated. The purpose of this study is the following:

1. to investigate the role of early radiation therapy in MRI-determined total resected LGGs;
2. to compare the efficacy of early radiation therapy and that of initial chemotherapy in the LGGs without total resection.

Treatment Strategy for Low-grade Gliomas

Sun Yat-sen University

Zhongping CHEN

Diseases and Abnormalities at or Before Birth

Nervous System Diseases

Congenital Abnormalities

Brain Neoplasms

Herbal and Botanical

Sage

Natacha Entz-Werle, MD

At present, diagnosis of oligodendroglioma is made on histological and radiographic criteria in the French Mayo-Ste Anne classification. The less frequent grade A oligodendrogliomas are characterized by no vascular contrast on RMN evaluation comparatively to grade B forms. This benign histological subtype relapses in few cases with a more aggressive histology. To determine these relapsed cases at diagnosis, a collection of tumour begun in February 2004. Then, our study was designed to identify diagnostic molecular and metabolic markers that could eventually be used as a signature characterising grade A versus grade B oligodendrogliomas. The molecular analysis will use genomic techniques like allelotyping study, quantitative real-time PCR, gene sequencing , serial analysis of genomic expression and immunohistochemistry, since the metabolic study will be the spectroscopic examination of in vivo tumour. This study will include paediatric and adult patients followed for oligodendrogliomas, medulloblastomas and gliomas to compare the different tumour signatures. All these results will be correlated to survival and clinical features.

Research of Molecular and Metabolic Markers in Oligodendrogliomas Comparatively to Other Brain Tumours

Research of Molecular and Metabolic Diagnostic Markers in Oligodendrogliomas A and B Comparatively.

University Hospital, Strasbourg, France

Diffuse Astrocytoma

Anti-Infective Agents

Everolimus

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If activation is present, patients will be treated with single-agent everolimus at 10 mg daily continuously for up to 24 cycles, after which patients will be followed with interval MRIs until progression.

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If activation is not present, patients will be treated with combined everolimus and Temozolomide (TMZ). Everolimus will be given at 10 mg daily continuously for up to 24 cycles, and Temozolomide will be dosed initially at 150 mg/m\^2 per day for 5 days out of a 28-day cycle for up to 12 cycles, after which patients will be followed with interval MRIs until progression.

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If 1p/19q co-deletion is present, patients will be treated with single-agent everolimus at 10 mg daily continuously for up to 24 cycles, after which patients will be followed with interval MRIs until progression.

Temozolomide will be dosed initially at 150 mg/m2/day for 5 days out of a 28-day cycle. TMZ will be stopped after 12 cycles

Jennifer Clarke, MD, MPH

The purpose of this study is to find out what effects, good and/or bad, everolimus (RAD001, also known as Afinitor®) alone or with temozolomide has on the patient and the patient's low-grade glioma. Everolimus is being investigated as an anticancer agent based on its potential to prevent tumor cells from growing and multiplying. Specifically, there is a protein called mTOR that we think helps many tumors to grow, and everolimus blocks the effect of mTOR. Temozolomide is also an anticancer agent that prevents tumor cells from growing and multiplying.

PRIMARY OBJECTIVES:

Arm 1: To assess progression-free survival in patients with previously untreated alpha-thalassemia/mental retardation, X-linked (ATRX) lost and/or 1p/19q intact, phosphatidylinositol 3-kinase (PI3K)/Mechanistic target of rapamycin (mTOR) pathway-activated low grade-glioma (LGG) treated with everolimus.

Arm 2: To assess progression-free survival in patients with previously untreated ATRX lost and/or 1p/19q intact, PI3K/mTOR pathway-non-activated LGG treated with everolimus and TMZ.

Arm 3: To assess progression-free survival in patients with previously untreated ATRX intact and/or 1p/19q co-deleted LGG treated with everolimus.

SECONDARY OBJECTIVES:

1. To assess overall and progression-free survival distributions (Arms 1, 2 \& 3).
2. To assess the objective response rate to treatment (Arms 1, 2 \& 3).
3. To further delineate the safety profile of the combination of everolimus and TMZ (Arm 2)
4. To assess whether treatment (Arms 1, 2 \& 3) provides clinical benefit by reducing seizure frequency

EXPLORATORY OBJECTIVES

1. Pending adequate funding, to assess the ability of metabolic and physiologic imaging parameters such as magnetic resonance (MR) spectroscopy, perfusion-weighted imaging, and diffusion-weighted imaging to predict clinically relevant endpoints such as time to progression and survival.
2. To assess for an association between the presence/absence of clonal or subclonal genetic mutations in the PI3K pathway and Median progression-free survival (PFS), Objective Response Rate (ORR), phosphatase and tensin homolog (PTEN) gene methylation, and the immunohistochemical measurements of the PI3K pathway activation in patients treated with everolimus or TMZ and everolimus.
3. To longitudinally assess quality of life (QoL) in low-grade glioma patients over the course of treatment with everolimus (Arms 1 \& 3).

OUTLINE:

Patients will be assigned to one of 3 treatment arms based on two characteristics of their tumor, called "1p/19q" (this is a test of the tumor chromosomes) and "p-PRAS40" (this is a test of a pathway in the tumor called mTOR). If the patient's tumor is 1p/19q intact and the phosphorylation of proline-rich Ak strain transforming (AKT) substrate of 40 kDa, encoded by the gene AKT1S1 (p-PRAS40) positive, the patient will be assigned to Treatment Arm 1. If the patient's tumor is 1p/19q intact and p-PRAS40 negative, the patient will be assigned to Treatment Arm 2. If the patient's tumor is 1p/19q co-deleted, regardless of the p-PRAS40 result, the patient will be assigned to Treatment Arm 3.

All patients will be observed for safety for 30 days following the last dose of everolimus. After completion of study treatment, patients whose tumors have not progressed will be followed with interval MRIs for an additional 2 years, and thereafter as per the discretion of the managing physician. Patients off protocol therapy will continue to be followed for survival only.

Everolimus With and Without Temozolomide in Adult Low Grade Glioma

PI3K/mTOR Pathway Activation Selected Phase II Study of Everolimus (RAD001) With and Without Temozolomide in the Treatment of Adult Patients With Supratentorial Low-Grade Glioma

Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. Based on RANO criteria, a responder is defined using both radiographic and clinical criteria. Complete response (CR) or Partial Response (PR) will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size. In addition, changes in neurologic function and steroid use will be considered. Analyses will be performed after all enrolled participants in arm 1 or arm 2 have completed 33 months on study, or whenever the progression status of all participants has been established, whichever comes first. Kaplan-Meier estimates and the associated 95% confidence intervals (CI) will be calculated for the 33-month PFS separately for the two arms.

Participants will be analyzed based on intention to treat using the Response Assessment in Neuro-Oncology (RANO) criteria for progression. Based on RANO criteria, a responder is defined using both radiographic and clinical criteria. Complete response (CR) or Partial Response (PR) will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size. In addition, changes in neurologic function and steroid use will be considered. Analyses will be performed after all participants enrolled in arm 3 have completed 38 months on study, or whenever the progression status of all participants has been established, whichever comes first. Kaplan-Meier estimates and the associated 95% CIs will be calculated for the 38-month PFS.

Participants will be analyzed based on an intention to treat model. PFS is defined as the time from first objective response to the time of disease progression or death using the Response Assessment in Neuro-Oncology (RANO) criteria to determine progression. If the participant does not have an event of disease progression or recurrence nor has the patient died, the participant's data will be censored at the date of last contact with the patient. Kaplan-Meier estimates and the associated 95% CIs will be calculated.

Participants will be analyzed based on an intention to treat model. Overall survival is defined as the first day of treatment until death or study completion, whichever comes first. Kaplan-Meier estimates and the associated 95% CIs will be calculated by treatment arm.

Overall response rate (ORR) is the percentage of patients who achieved a best response of complete response (CR) or partial response (PR) out of all assigned patients. Based on the best objective status as assessed by the Response Assessment in Neuro-Oncology (RANO) criteria. Using RANO criteria, a responder is defined by radiographic and clinical criteria. Complete response or PR will be first assessed by radiographic changes as determined by an improvement of the bi-dimensional evaluation of the tumor size. In addition, changes in neurologic function and steroid use will be considered. The point estimate and the associated 2-sided 95% CI for the response rate separately for the three arms.

To assess the reduction in seizure rate the investigator will compare the seizure rate on study to that experienced one month prior to enrolling in the study. The RANO low grade gliomas (LGG) guideline will be used to assess reduction of seizures, which calls a 50% or more reduction number of monthly seizures an 'improvement'; a 50% or more increase a worsening'; and anything less than 50% in either direction a 'stable seizure rate'.

Novartis

University of California, San Francisco

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If activation is present, patients will be treated with single-agent everolimus at 10 mg daily continuously for up to 24 cycles.

Arm 1: Everolimus

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If activation is not present, patients will be treated with combined everolimus and temozolomide (TMZ). Everolimus will be given at 10 mg daily continuously for up to 24 cycles, and Temozolomide will be dosed initially at 150 mg/m\^2 per day for 5 days out of a 28-day cycle for up to 12 cycles.

Arm 2: Everolimus and Temozolomide

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the PI3K/mTOR pathway. If 1p/19q co-deletion is present, patients will be treated with single-agent everolimus at 10 mg daily continuously for up to 24 cycles.

Arm 3: Everolimus (1p/19q Co-deletion Present)

Total

20-29 years old

30-39 years old

40-49 years old

50-59 years old

60-69 years old

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Study was closed prematurely due to slow accrual and loss of drug support.

Dr. Jennifer Clarke, MD MPH

One participant in Arm 2 went off treatment after only a few days of beginning therapy but was included in the analysis as part of the ITT population

Progression-Free Survival Rate (PFS) (Arms 1 and 2)

Progression-Free Survival Rate (PFS) (Arm 3)

Median Progression Free Survival (PFS)

Overall Survival Rate (OS)

Objective Response Rate (ORR)

One participant in Arm 2 went off treatment after only a few days of beginning therapy, so monthly seizure data could not be collected.

Rate of Reduction in Seizures

If the tumor is 1p/19q intact, then patients will be further selected by whether or not their tumor demonstrates activation of the phosphatidylinositol 3-kinase (PI3K)

/Mechanistic target of rapamycin (mTOR) pathway. If activation is present, patients will be treated with single-agent everolimus at 10 mg daily continuously for up to 24 cycles.

Overall Study

Symptoms and General Pathology

Recurrence

Glioblastoma

LB100

LB-100 will be infused over 2 hours via intravenous (IV) infusion 2 to 4 hours before surgery. The dose established from a Phase I study will be 2.33 mg/m\^2.

LB-100

Eric C Burton, M.D.

Background:

The brain is separated from the rest of the blood stream by the blood-brain barrier. This is like a filter that protects the brain. But is also a challenge when medicines need to get into the brain. Researchers want to give the new drug LB100 to people before brain tumor surgery. They will measure how much LB100 is in the blood and how much gets into the brain. This may help with the use of LB100 to treat brain tumors in the future.

Objective:

To see if LB100 can pass into the brain.

Eligibility:

People at least 18 years old with a brain tumor that requires surgery.

Design:

Participants will be screened with:

Physical exam

Medical history

Blood tests

Neurosurgery evaluation

Scans

Heart tests

Tumor sample. This can be from a previous procedure.

Participants will have their brain surgery at the Clinical Center.

Participants will get a dose of the study drug through a plastic tube in a vein for 2 hours during surgery.

Participants will have blood taken 7 times in the 8 hours after getting the study drug.

Tumor samples will be taken during surgery.

Participants will have a heart test after getting the study drug. Sticky pads on the skin will measure electrical activity of the heart.

Two-three weeks after leaving the hospital, participants will have a follow-up visit. They will have a physical exam and blood tests.

One month after surgery, they will be contacted in person or by phone to see how they are doing.

Background:

* Primary gliomas are an incurable disease in spite of aggressive multimodality therapy consisting of craniotomy, irradiation, and chemotherapy. Therapeutic options for patients with recurrent glioma are limited, and there is an unmet need to identify more effective agents.
* LB100, a water-soluble small molecule novel protein phosphatase 2A (PP2A) inhibitor, was commercially developed through a Cooperative Research and Development Agreement (CRADA) based on our previous intramural research. This compound has shown to be effective in a variety of cancer types in both in vitro and in vivo models. Preclinical studies indicate LB100 has in vitro and in vivo activity as a single agent as well as potentiating the effect of cytotoxic agents including temozolomide, docetaxel, doxorubicin, and ionizing radiation. LB100 is active in combination with temozolomide or doxorubicin against xenografts of glioblastoma, neuroblastoma, pheochromocytoma, breast cancer, fibrosarcoma, and melanoma.
* A complete phase I study of LB100 has established its safety and the recommended phase II dose (2.33 mg/m\^2, daily for three days every 3 weeks).
* Although it is a polar compound, rodent studies suggest LB100 has activity in the brain.
* Whether LB100 can across the human blood brain barrier (BBB), and at what concentration relative to the plasma level is not known. Characterizing these parameters is important because:

  * 1) Our ongoing in vitro studies indicate that LB100 has distinct mechanisms of action at different drug concentrations (e.g., nM versus uM);
  * 2) There are other brain tumors lacking effective medical therapies but without a BBB. Characterizing the LB100 BBB penetration profile will assist in defining its optimal clinical indication.

Objective:

-To determine the pharmacokinetic (PK) properties of LB100 in glioma tumor tissues.

Eligibility:

* Patients with histologically proven glioblastoma and grades II-III astrocytomas and oligodendrogliomas.
* A clear clinical indication for another surgical resection must be present.
* Subjects must be greater than or equal to 18 years old.
* Karnofsky performance status of greater than or equal to 60%.
* Patients must have adequate organ function.

Design:

* This is a two stage Phase II, open label, single institution study to determine the PK and pharmacodynamic (PD) profile of LB100.
* The dose (established from a Phase I study) will be 2.33 mg/m\^2 delivered intravenously over 2 hours.
* PK and PD effect of LB100 treated tissues will only be evaluated with pathologic confirmation of recurrent tumor. Resected material demonstrating chemoradiation treatment effect or inflammatory response will not be included in the analysis.
* PK will be determined by quantitating LB100 in tumor tissues removed at various time points.
* The primary endpoint is PK response, defined as a binary variable indicating the presence/absence of LB100 in tumor tissues.
* PD effect is defined as statistically significant elevation of phospho-proteins in treated tumor tissues compared to untreated glioma specimens. Untreated inter-patient baseline variance and standard deviation (SD) will be calculated. Post-treatment PD effect difference greater than 2.5 times the baseline SD is statistically significant at the .05 significance level. Due to relatively small sample size, t-distribution is to be used to calculate the cutoff defining the PD response.
* Up to 25 patients may be enrolled to obtain 8 evaluable subjects. A two-stage design will be used. Five patients will be initially treated. If at least one of five demonstrates PK activity, 3 additional subjects will be enrolled. PK effect will be declared to be significant if at least 2 of the 8 patients demonstrate a PK response (presence of LB100 in tumor tissue).

Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

Phase II Trial of LB100, a Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

All individual participant data (IPD) recorded in the medical record will be shared with intramural investigators upon request.

Here is the number of participants with serious and/or non-serious adverse events assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life-threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.

Participants tumor tissue was examined to determine the presence of drug in the tumor tissue.

Blood samples for the determination of plasma levels of LB-100 will be obtained from each participant. Plasma concentrations of LB100 will be determined at each time point. LC-MS-MS assay that can measure LB-100 in human plasma. Assay range is 2.0 -1000 ng/mL. A higher value is better because it would have made it more likely drug could penetrate the blood brain barrier at therapeutic levels.

Concentration of LB100 in glioma tumor tissue when a known non-toxic dose of LB100 is delivered intravenously. Glioma tissue sampling to detect and quantify LB100 will be performed by assaying phospho-protein expression in glioma tissue resected prior to and after infusion of LB100. These are values for the LB100 in the tumor which was done at one timepoint.

Changes in phospho-protein expression in circulating PBMC. Pharmacodynamic (PD) response is defined as statistically significant elevation of phospho-protein expression in treated tumor tissues compared to untreated glioma specimens. Post-treatment PD effect (as measured by increase in tumor tissue phospho-protein expression) difference greater than 2.5 times the baseline standard deviation (SD) is statistically significant at the .05 significance level.

The maximum observed analyte concentration in serum was reported.

AUC is a measure of the serum concentration of LMB100 over time. It is used to characterize drug absorption.

Plasma decay half-life is the time measured for the plasma concentration of the drug to decrease by one half.

Time to maximum observed plasma concentration of LMB100 (Tmax).

The CL is a quantitative measure of the rate at which a drug substance is removed from the body.

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug.

Drug amount in brain as a percent of drug in plasma.

Concentration of drug in brain tumor tissue. Brain penetration is measured as "drug amount in a brain as a percent of drug in plasma.

Principal Investigator

Treatment with LB100

LB-100: LB-100 will be infused over 2 hours via intravenous (IV) infusion 2 to 4 hours before surgery. The dose established from a Phase I study will be 2.33 mg/m\^2.

1/LB100 Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma

Age, Categorical

Age, Continuous

Dr. Eric Burton

2/7 were not analyzed because no tumor was found on analysis.

Number of Participants With the Presence of Drug in the Tumor Tissue

Pre-dose

End of infusion (2 hours post-start)

30 minutes post LB100 infusion completion

1 hour post LB-100 infusion completion

2 hours post LB100 infusion completion

4 hours post LB100 infusion completion

8 hours post LB100 infusion completion

Plasma Concentration and Calculated LB100

Concentration of LB100

Changes in Phospho-protein Expression in Circulating Peripheral Blood Mononuclear Cells (PBMC)

Maximum Observed Plasma Concentration of LB100 (Cmax)

Area Under the Plasma Concentration vs. Time Curve Extrapolated to Infinity (AUC(INF)

Plasma Half-Life of Drug LB100

Time to Maximum Observed Plasma Concentration of LMB100 (Tmax)

Total Clearance (CL) of LMB100

Volume of Distribution (Vd) of LMB100

Brain Concentration

Brain Penetration

Number of Participants With Serious and/or Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)

Participants who required surgery received up to 3 doses of oral selinexor tablets 60 milligrams (mg) twice weekly (BIW) on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until progression of disease (PD) or development of unacceptable toxicities.

Participants who were not eligible for surgery received selinexor tablets 50 mg per square meter (mg/m\^2) BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.

Participants who were not eligible for surgery received selinexor tablets 60 mg BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.

Participants who were not eligible for surgery received selinexor tablets 80 mg once weekly (QW) during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.

Selinexor

This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas.

This is an open-label, multicenter, Phase 2 study to evaluate the efficacy and safety of oral selinexor in participants with recurrent gliomas.

Initially, the study included 2 arms: an exploratory Surgical Arm (Arm A) with sequential enrollment for participants who require surgery and a medical arm (Arm B) for participants who are not eligible for surgery.

Enrollment in Arm B was stopped to explore alternative dosing in Protocol Versions ≥ 4.0 to potentially improve tolerability. Four arms (Arms C, D, E, and F) were added to the Medical Arm in Protocol Version 4.0. Arms E and F were eliminated in protocol version 6.0 and no participants were ever enrolled in these arms.

Participants in the primary population enrolled under Protocol Version ≥ 4.0 will be randomized to Arm C and Arm D (approximately 30 participants per arm) to explore alternative dosing to potentially improve tolerability.

After screening and registration/randomization in the study, participants enrolling in Arm A or randomized to Arm C will receive 60 mg selinexor orally twice weekly. Participants randomized to Arm D will receive 80 mg selinexor orally weekly.

Participants will be treated until progression of disease or the development of unacceptable toxicities. All participants will then undergo the End of Treatment (EOT) visit.

Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Participants With Recurrent Gliomas

A Phase 2 Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Patients With Recurrent Gliomas

The analysis of 6mPFS was performed by calculating the estimated survival probability of having PFS ≥ 6 months based on Kaplan-Meier method, where PFS was defined as the time from the start of study treatment until first documented progression based on Response Assessment in Neuro-Oncology (RANO) criteria, or death from any cause. Progressive disease occurs when either of the criteria was present: greater than or equal to (≥) 25 percentage (%) increase in T1 gadolinium enhancing disease, increase in T2/ Fluid-attenuated inversion recovery (FLAIR), detection of new lesions, or decreased clinical status.

The ORR was determined as percentage of participants who had either complete response (CR) or partial response (PR) using the RANO criteria. CR: No T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, no corticosteroid use and stable, or increasing clinical status. PR: ≥50% decrease in T1 gadolinium enhancing disease, stable or decreasing T2/FLAIR, no new lesions, stable or decreased use of corticosteroids, and stable or increased clinical status.

The OS was calculated from the date of start of study treatment to the date of death. Participants who were still alive prior to the data cut-off for final efficacy analysis, or who dropout prior to study end, were censored on the day they were last known to be alive. The OS was estimated using Kaplan-Meier method.

The PFS was calculated from the date of start of study treatment to the date of disease progression based on RANO criteria, or date of death should progression not have occurred. Progressive disease occurs when either of the criteria was present: ≥25% increase in T1 gadolinium enhancing disease, increased T2/FLAIR, detection of new lesions, or decreased clinical status.

An adverse event (AE) was defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was defined as an AE that was fatal; life threatening (places the participant at immediate risk of death); requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; was a congenital anomaly/birth defect; and other important medical events. TEAE was defined as any AE with onset or worsening of a pre-existing condition on or after the first administration of study medication through 30 days following last dose or any event considered drug-related by the Investigator through the end of the study. TEAEs included both serious and non-serious TEAEs.

Karyopharm Therapeutics Inc

Participants who required surgery received up to 3 doses of oral selinexor tablets 60 mg BIW on Day 1, Day 3 and between 2 and 48 hours prior to surgery, subsequently underwent surgery for resection of their tumor and resumed selinexor tablets 60 mg BIW after recovery, during Week 1 to 4 of each 4-week cycle, until PD or development of unacceptable toxicities.

Arm A: Selinexor 60 mg and Surgery

Participants who were not eligible for surgery received selinexor tablets 50 mg/m\^2 BIW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.

Arm B: Selinexor 50 mg/m^2

Arm C: Selinexor 60 mg

Participants who were not eligible for surgery received selinexor tablets 80 mg QW during Week 1 to 4 of each 4-week cycle until PD or development of unacceptable toxicities.

Arm D: Selinexor 80 mg

Safety population consisted of all participants who had received any amount of study treatment.

Study was terminated due to Sponsor decision (all except 1 patient were off-treatment and 2 patients were in survival follow-up).

Jatin Shah, MD

Modified intent-to-treat (mITT) population consisted of all enrolled participants in Arms B, C and D who had received at least 1 dose of study medication and have at least 1 post-baseline efficacy follow-up assessment, unless the participant discontinued treatment prior to the first post baseline assessment due to death, toxicity, or PD. Data for this outcome measure was not planned to be collected and analyzed for Arm A: Selinexor 60 mg and Surgery.

6-Month Progression-Free Survival (PFS) Rate

mITT population consisted of all enrolled participants in Arms B, C and D who had received at least 1 dose of study medication and have at least 1 post-baseline efficacy follow-up assessment, unless the participant discontinued treatment prior to the first post baseline assessment due to death, toxicity, or disease progression. Data for this outcome measure was not planned to be collected and analyzed for Arm A: Selinexor 60 mg and Surgery.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical Development of Cancer-Specific MRS Biomarkers in Malignant Gliomas	NCT02388659	Malignant Gliom... Oligodendroglio... Astrocytomas	3 Tesla scannin...	18 Years -	University of Texas Southwestern Medical Center
Treatment Strategy for Low-grade Gliomas	NCT00897377	Astrocytomas Oligodendroglio... Oligoastrocytom...	Radiation thera... Temozolomide	18 Years - 60 Years	Sun Yat-sen University
Clinical Development of Cancer-Specific MRS Biomarkers in Malignant Gliomas	NCT02388659	Malignant Gliom... Oligodendroglio... Astrocytomas	3 Tesla scannin...	18 Years -	University of Texas Southwestern Medical Center
Research of Molecular and Metabolic Markers in Oligodendrogliomas Comparatively to Other Brain Tumours	NCT00213876	Oligodendroglio...		1 Year -	University Hospital, Strasbourg, France
Everolimus With and Without Temozolomide in Adult Low Grade Glioma	NCT02023905	Low Grade Gliom... World Health Or... Oligodendroglio... Mixed Oligoastr...	Everolimus Temozolomide	18 Years -	University of California, San Francisco
Protein Phosphatase 2A Inhibitor, in Recurrent Glioblastoma	NCT03027388	Astrocytoma, Gr... Glioblastoma Mu... Giant Cell Glio... Glioma Oligodendroglio...	LB-100	18 Years -	National Institutes of Health Clinical Center (CC)
Study Evaluating the Efficacy and Safety of Selinexor (KPT-330) in Participants With Recurrent Gliomas	NCT01986348	Glioblastoma Glioma	Selinexor	18 Years -	Karyopharm Therapeutics Inc

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