Trial of Idasanutlin and Selinexor Therapy for Children With Progressive/Relapsed AT/RT or Extra-CNS Malignant Rhabdoid Tumors

Inclusion Criteria

• •Participant and/or guardian can understand and will sign a written informed consent document according to institutional guidelines.
• •Before patient screening and registration, written informed consent, also concerning data and sample transfer, must be given according to ICH/GCP and national/local regulations
• •Children, adolescents, and young adults with relapsed/progressive AT/RT, MRT, or synchronous/metachronous rhabdoid tumor that is histologically confirmed by the enrolling institution. Patients must have failed at least one frontline therapy other than surgery to be eligible.
• •Age at enrollment ≥ 6 months to 25 years
• •Tumor sample is available from the time of diagnosis or relapse. If tumor sample is not available for deposition but molecular analysis was performed using a non-INFORM registry or non-CLINGEN molecular pipeline, transfer of molecular data (DNA methylation, whole exome and RNA sequencing) must be completed prior to enrollment. However, these tests will have to be completed in a CLIA certified facility.
• •Patient has fully recovered from the acute toxic effects of chemotherapy, immunotherapy, or radiation therapy or is anticipated to do so prior to enrolling on this study:
• •* Myelosuppressive chemotherapy: patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (4 and 6 weeks if prior temozolomide and nitrosourea, respectively).
• •* Hematopoietic growth factors: at least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim or biosimilar growth factor.
• •* Biologic anti-neoplastic agent (except monoclonal antibodies): at least 7 days must have elapsed since completion of therapy with a biologic agent prior to enrollment. For agents that have known adverse events occurring beyond 7 days after administration, this period prior to enrollment must be extended beyond the 7 days, during which adverse events are known to occur, up to a maximum of 30 days prior to initiation of study treatment.
• •* Monoclonal antibodies: Thirty days or at least three half-lives must have elapsed since prior therapy that included a monoclonal antibody, whichever is later prior to initiation of study treatment.
• •* Treatment with cellular therapy (e.g., CAR-T cell infusion) for anti-neoplastic intent within 30 days prior to initiation of study treatment
• •* Radiation therapy: at least 3 months must have elapsed since any previous irradiation to the site of disease prior to study enrollment, unless measurable disease is confirmed by biopsy or is present at a site separate from the irradiated area or meets CSF criteria for enrollment
• •Disease that is measurable as defined by RAPNO criteria or RECIST v1.1 (as appropriate). A patient who has no measurable disease will be allowed to enroll if one of the following criteria is met:
• •* there is evidence of leptomeningeal disease
• •* CSF presence of tumor cells by cytology confirmed on 2 separate occasions at least 1 week apart.
• •Adequate performance status:
• •* Patients \<16 years of age: Lansky ≥50%
• •* Patients ≥16 years of age: Karnofsky ≥50%
• •* Transient states like infections can be accepted, stable disabilities resulting from disease/surgery (posterior fossa syndrome, hemiparesis, amputations, etc.) can be accepted and will not be considered for Lansky/ Karnofsky assessments.
• •Stable neurologic deficits on a stable dose of corticosteroids (if applicable) for at least 1 week before study enrollment.
• •Patient can swallow oral study medication or should have a nasogastric for minimum size of the NG tube that may be used) or G-tube for the administration of the medication.
• •Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to enrollment.
• •For females of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse or use contraception, agreement to refrain from donating eggs
• •For males: agreement to remain abstinent (refrain from heterosexual intercourse or use a condom, and agreement to refrain from donating sperm
• •Absence of any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
• •No prior therapy with the combination of MDM2 inhibitors and XPO1 inhibitors.
• •Adequate end-organ function defined by the following laboratory results obtained within 14 days prior to initiation of study drug:
• •* Bone marrow function: normal bone marrow function as defined by:
• •* a hemoglobin concentration \>8 g/dL (with or without support);
• •* absolute neutrophil count (ANC) \> 1,000/mm3, and
• •* platelet count \>75,000/ mm3 (unsupported for 72 hours)
• •* Adequate renal function as defined by CrCl ≥60 mL/min/1.73 m2
• •* Adequate liver function as defined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentration ≤ 3 x upper limit of normal (ULN) per institutional practice and total bilirubin ≤ 1.5 × ULN for age. Serum albumin ≥ 2 g/dL
• •* Adequate Pancreatic Function defined as:
• •* Serum amylase ≤ 1.5 x ULN as per institutional practice
• •* Serum lipase ≤ 1.5 x ULN as per institutional practice
• •Adequate cardiac function as defined by:
• •* ECG with normal QTc interval \< 450 ms as determined by Fridericia correction
• •* Fractional shortening (FS) ≥28% or left ventricular ejection fraction (LVEF) ≥50% as determined by echocardiography or multigated acquisition scan (MUGA)within 28 days prior to initiation of study therapy.
• •* Depending on institutional standard, either FS or LVEF is adequate for enrollment if only one value is measured; if both values are measured, then both values must meet the above criteria.
• •Life expectancy ≥ 3 months, in the investigator's judgment