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Testing the Addition of an Anti-cancer Drug, Selinexor, to the Usual Chemotherapy Treatment (Temozolomide) for Brain Tumors That Have Returned After Previous Treatment

NCT05432804 · National Cancer Institute (NCI)
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Official title
A Phase 1 and Randomized Phase 2 Trial of Selinexor and Temozolomide in Recurrent Glioblastoma
About this study
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of temozolomide followed by selinexor in recurrent glioblastoma patients as determined by dose-limiting toxicities (DLTs) and the total toxicity profile. (Phase I) II. To evaluate the efficacy of sequentially administering temozolomide and selinexor in recurrent glioblastoma as determined by progression-free survival (PFS). (Phase II) SECONDARY OBJECTIVES: I. To evaluate overall response rate as determined by Response Assessment in Neuro-Oncology (RANO) response criteria. II. To evaluate the efficacy of sequentially administering temozolomide and selinexor in recurrent glioblastoma as determined by 6-month PFS (6mPFS) and overall survival (OS). III. To validate signatures of vulnerability to predict response to selinexor through ribonucleic acid (RNA) sequencing for 6 top-scoring gene pairs, whole exome sequencing, P53, EGFR, and Mcl-1. OUTLINE: This is a phase I, dose-escalation study of selinexor in combination with fixed dose temozolomide followed by a phase II study that compares selinexor temozolomide combination therapy vs. temozolomide monotherapy. Patients are randomized to 1 of 2 groups for the phase II part of this trial. GROUP I (Phase II): Patients receive temozolomide orally (PO) once daily (QD) on days 1-5 of each cycle and placebo PO QD on days 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. GROUP II (Phase I and II): Patients receive temozolomide PO QD on days 1-5 of each cycle and selinexor PO QD on days 8 and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. (Phase I completed as of April 2024) Patients undergo magnetic resonance imaging (MRI) throughout the study and blood sample collection while on study. After completion of study treatment, patients are followed up every 2 months up to 2 years.
Eligibility criteria
Inclusion Criteria: * Patients must have histologically confirmed glioblastoma (IDH wild-type, MGMT promoter methylated) that has undergone resection or biopsy upon first recurrence. Recurrence at site of prior involvement is defined by histopathological evidence of viable neoplastic cells associated with any of the following: mitotic activity, increased proliferation rate, micro-endothelial proliferation, or pseudo-palisading necrosis * Prior to resection or biopsy, patients must have measurable disease, defined as at least one bi-dimensional contrast-enhancing lesion with clearly defined margins, with 2 perpendicular diameters of at least 10 mm, visible on \>= 2 axial slices * Patients must have received first-line treatment of temozolomide plus radiotherapy * Patients must not have received any prior therapy aside from resection or biopsy for their recurrent disease * Age \>= 18 years. Because no dosing or adverse event data are currently available on the use of selinexor (KPT-330) in combination with temozolomide in patients \< 18 years of age, children are excluded from this study * Karnofsky performance status \>= 60% (Eastern Cooperative Oncology Group \[ECOG\] =\< 2) * Absolute neutrophil count \>= 1,500/mcL * Platelets \>= 100,000/mcL * Hemoglobin \>= 10 g/dL * Total bilirubin =\< 2 x institutional upper limit of normal (ULN) * Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine transaminase (ALT) (serum glutamic-pyruvic transaminase \[SGPT\]) =\< 3 x institutional ULN * Glomerular filtration rate (GFR) \>= 30 mL/min/1.73 m\^2 * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial * Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better * The effects of selinexor (KPT-330) and temozolomide on the developing human fetus are unknown. For this reason and because selective nuclear export inhibitors as well as deoxyribonucleic acid (DNA) alkylating agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 180 days after the last dose of temozolomide. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 90 days after completion of study treatment administration * Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible Exclusion Criteria: * Patients who have had chemotherapy must have full recovery of organ and marrow function following the nadir of the last chemotherapy cycle * Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia * Patients who are receiving any other investigational agents * Patients who have previously received bevacizumab * History of allergic reactions attributed to compounds of similar chemical or biologic composition to selinexor (KPT-330) or temozolomide * History of hypersensitivity to dacarbazine (DTIC), since both dacarbazine and temozolomide are metabolized to 5-(3-methyltriazen-1-yl)-imidazole-4-carboxamide (MTIC) * Patients with uncontrolled intercurrent illness * Pregnant women are excluded from this study because selinexor (KPT-330) is a selective inhibitor of nuclear export with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with selinexor (KPT-330), breastfeeding is not allowed for mothers during treatment with selinexor (KPT-330) and for 7 days after the last dose. These potential risks may also apply to other agents used in this study * Hospitalized patients with severe coronavirus disease of 2019 (COVID-19) who are \>= 75 years old, or with a high-risk COVID-GRAM score, or with lactate dehydrogenase (LDH) \> 370 (U/L) AND D-Dimer \> 600 mcg/L FEU should not receive low-dose selinexor (KPT-330) pending additional results
Study design
Enrollment target: 97 participants
Allocation: randomized
Masking: triple
Age groups: adult, older_adult
Timeline
Starts: 2023-03-20
Estimated completion: 2027-06-30
Last updated: 2026-05-18
Interventions
Procedure: Biospecimen CollectionProcedure: Magnetic Resonance ImagingDrug: Placebo AdministrationDrug: SelinexorDrug: Temozolomide
Primary outcomes
  • Recommended phase 2 dose (RP2D) (Phase I) (Up to 28 days)
  • Progression-free survival (PFS) (Phase II) (From randomization to date of disease progression (either progression of existing lesions or appearance of new lesions), death, or date of last contact, whichever occurs first, assessed up to 3 years)
Sponsor
National Cancer Institute (NCI) · nih
Contacts & investigators
InvestigatorFrances E Chow · principal_investigator, City of Hope Comprehensive Cancer Center LAO
All locations (36)
Mayo Clinic Hospital in ArizonaRecruiting
Phoenix, Arizona, United States
City of Hope Comprehensive Cancer CenterRecruiting
Duarte, California, United States
UC San Diego Moores Cancer CenterRecruiting
La Jolla, California, United States
Keck Medicine of USC KoreatownRecruiting
Los Angeles, California, United States
Los Angeles General Medical CenterRecruiting
Los Angeles, California, United States
USC / Norris Comprehensive Cancer CenterRecruiting
Los Angeles, California, United States
University of California Davis Comprehensive Cancer CenterRecruiting
Sacramento, California, United States
UCHealth University of Colorado HospitalRecruiting
Aurora, Colorado, United States
UM Sylvester Comprehensive Cancer Center at Coral GablesRecruiting
Coral Gables, Florida, United States
UM Sylvester Comprehensive Cancer Center at Deerfield BeachRecruiting
Deerfield Beach, Florida, United States
Mayo Clinic in FloridaRecruiting
Jacksonville, Florida, United States
University of Miami Miller School of Medicine-Sylvester Cancer CenterRecruiting
Miami, Florida, United States
Moffitt Cancer CenterRecruiting
Tampa, Florida, United States
Emory University Hospital MidtownRecruiting
Atlanta, Georgia, United States
Emory University Hospital/Winship Cancer InstituteRecruiting
Atlanta, Georgia, United States
University of Chicago Comprehensive Cancer CenterRecruiting
Chicago, Illinois, United States
University of Chicago Medicine-Orland ParkRecruiting
Orland Park, Illinois, United States
University of Kentucky/Markey Cancer CenterRecruiting
Lexington, Kentucky, United States
Mayo Clinic in RochesterRecruiting
Rochester, Minnesota, United States
Saint Barnabas Medical CenterRecruiting
Livingston, New Jersey, United States
Rutgers Cancer Institute of New JerseyRecruiting
New Brunswick, New Jersey, United States
Rutgers New Jersey Medical SchoolRecruiting
Newark, New Jersey, United States
Roswell Park Cancer InstituteActive Not Recruiting
Buffalo, New York, United States
Laura and Isaac Perlmutter Cancer Center at NYU LangoneRecruiting
New York, New York, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer CenterActive Not Recruiting
New York, New York, United States
Wake Forest University Health SciencesRecruiting
Winston-Salem, North Carolina, United States
University of Cincinnati Cancer Center-UC Medical CenterRecruiting
Cincinnati, Ohio, United States
Ohio State University Comprehensive Cancer CenterRecruiting
Columbus, Ohio, United States
University of Cincinnati Cancer Center-West ChesterRecruiting
West Chester, Ohio, United States
University of Oklahoma Health Sciences CenterRecruiting
Oklahoma City, Oklahoma, United States
University of Pittsburgh Cancer Institute (UPCI)Recruiting
Pittsburgh, Pennsylvania, United States
Huntsman Cancer Institute/University of UtahActive Not Recruiting
Salt Lake City, Utah, United States
University of Virginia Cancer CenterActive Not Recruiting
Charlottesville, Virginia, United States
VCU Massey Comprehensive Cancer CenterRecruiting
Richmond, Virginia, United States
University of Wisconsin Carbone Cancer Center - Eastpark Medical CenterRecruiting
Madison, Wisconsin, United States
University of Wisconsin Carbone Cancer Center - University HospitalRecruiting
Madison, Wisconsin, United States
Testing the Addition of an Anti-cancer Drug, Selinexor, to the Usual Chemotherapy Treatment (Temozolomide) for Brain Tumors That Have Returned After Previous Treatment · TrialPath