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

NCT05952687 | Withdrawn Phase 1 FDA Drug

• 2 other identifiers: iSTARNCI-2023-05552
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

iSTAR is an open-label, multi-center, phase 1b study of oral XPO1 inhibitor selinexor and oral MDM2 inhibitor idasanutlin in children with progressive or recurrent atypical teratoid/rhabdoid tumors (AT/RT), malignant rhabdoid tumors (MRT) and synchronous/metachronous rhabdoid tumors. Primary Objectives

• To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of combination treatment with oral idasanutlin and selinexor in children with recurrent or progressive AT/RT or MRT.
• To characterize the plasma pharmacokinetics of oral idasanutlin and selinexor in children with recurrent or progressive AT/RT or MRT, to assess potential covariates to explain the inter- and intra-individual pharmacokinetic variability. Secondary Objectives
• Evaluate safety of the combination treatment with oral idasanutlin and selinexor in children
• Evaluate efficacy of the combination treatment of idasanutlin and selinexor as measured by objective response (partial response \[PR\] or complete response \[CR\]) rate separately in progressive/relapsed AT/RT and progressive/relapsed MRT
• Estimate progression-free and overall-survival separately in progressive/relapsed AT/RT and progressive/relapsed MRT

Conditions

Rhabdoid Tumor; Atypical Teratoid/Rhabdoid Tumor; Atypical Teratoid/Rhabdoid Tumor of CNS; CNS Tumor

Outcome Measures

Primary Outcomes (3)

• Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of combination treatment with oral idasanutlin and selinexor in children with recurrent or progressive AT/RT or MRT in the dose finding/safety phase.

  The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a DLT and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered at the recommended phase 2 dose (RP2D). The MTD estimate will be limited to evaluable patients and toxicity assessments from course 1 (28 days). The RP2D will be based on the MTD and the totality of the safety/efficacy data.

  1 month after start of idasanutlin and selinexor treatment

• Idasanutlin plasma apparent systemic clearance (CL/F) in children with recurrent or progressive AT/RT or MRT

  For each patient, idasanutlin plasma concentration-time data will be analyzed using non-compartmental methods to estimate the plasma CL/F.

  1 month after start of idasanutlin and selinexor treatment

• Idasanutlin area under the plasma concentration time curve (AUC) in children with recurrent or progressive AT/RT or MRT

  For each patient, idasanutlin plasma concentration-time data will be analyzed using non-compartmental methods to estimate the AUC.

  1 month after start of idasanutlin and selinexor treatment

Secondary Outcomes (6)

• Objective response rate in subjects with progressive/relapsed AT/RT

  Approximately 2 years from start of treatment

• Objective response rate in subjects with progressive/relapsed MRT

  Approximately 2 years from start of treatment

• Progression-free survival in subjects with progressive/relapsed AT/RT

  Approximately 7 years from start of treatment

• Progression-free survival in subjects with progressive/ relapsed MRT

  Approximately 7 years from start of treatment

• Overall survival in subjects with progressive/relapsed AT/RT

  Approximately 7 years from start of treatment

Study Arms (4)

Dose Finding/Safety Phase

EXPERIMENTAL

Patients with progressive/relapsed atypical teratoid/rhabdoid tumors (AT/RT) \& malignant rhabdoid tumors (MRT) or synchronous/metachronous AT/RT \&MRT

Drug: Idasanutlin; Drug: Selinexor

Expansion Phase: Stratum A

EXPERIMENTAL

Patients with progressive/relapsed AT/RT

Drug: Idasanutlin; Drug: Selinexor

Expansion Phase: Stratum B

EXPERIMENTAL

Patients with progressive/relapsed MRT

Drug: Idasanutlin; Drug: Selinexor

Expansion Phase: Stratum C

EXPERIMENTAL

Patients with progressive/relapsed, synchronous/metachronous AT/RT \& MRT

Drug: Idasanutlin; Drug: Selinexor

Interventions

Idasanutlin DRUG

Patients will receive idasanutlin dosed once daily on Days 1-5 of a 28-day cycle starting with 80% of the RP2D determined in the ongoing pediatric iMATRIX trial using single agent idasanutlin.

Also known as: RO5503781

Dose Finding/Safety Phase

Selinexor DRUG

Patients will receive selinexor on Day 4 of each of the first 3 weeks of a 28-day cycle. Selinexor will be skipped on week 4 of each cycle.

Also known as: KPT-330

Dose Finding/Safety Phase; Expansion Phase: Stratum A; Expansion Phase: Stratum B; Expansion Phase: Stratum C

Eligibility Criteria

• Age: 6 Months - 25 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• Significant nausea and vomiting (CTCAEv5 grade 3 or more), chronic diarrhea, malabsorption despite maximal supportive care or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption.
• Known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies). Known active hepatitis B (e.g., hepatitis B surface antigen reactive) or hepatitis C (e.g., hepatitis C virus ribonucleic acid \[qualitative\]). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as the presence of hepatitis B core antibody \[HBc Ab\] and absence of HBsAg) are eligible. HBV DNA test must be performed in these patients prior to study treatment. Patients with a known history of hepatitis C virus infection and positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.
• Clinically significant, uncontrolled heart disease.
• Pregnant or lactating women at the time of enrollment.
• Major surgery within 21 days of the first dose or anticipate need for major surgical procedure during the cycle of the study. Gastrostomy tube placement, ventriculo-peritoneal shunt, ommaya reservoir placement, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery
• Myeloablative therapy with autologous hematopoietic stem cell rescue within 30 days or allogeneic hematopoietic stem cell rescue within 100 days of study treatment initiation
• Received the following within 7 days prior to initiation of study treatment
• Strong CYP2C8 inhibitors
• CYP2C8 substrates
• OATP1B1/3 substrates
• Received strong CYP2C8 and strong CYP3A4 inducers within 14 days prior to the initiation of study treatment
• Patients unable to temporarily interrupt treatment with oral or parenteral anticoagulants/anti-platelet agents (e.g., warfarin, chronic daily treatment with aspirin \[\> 325 mg/day\], clopidogrel, dabigatran, apixaban, rivaroxaban) during the treatment phase. These agents must be discontinued 7 days (or 5 half-lives), whichever is longer prior to the start of study medication.
• Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the patient upon induction of neutropenia, including patients who are, or should be on antimicrobial agents for the treatment of active infection such as the following:
• Fungal infection other than mucosal candidiasis, within \<2 weeks of completing appropriate systemic antifungal therapy
• Bacterial infection with positive cultures in the 7 days prior to dosing

Sponsors & Collaborators

• St. Jude Children's Research Hospital: lead

Related Links

• St. Jude Children's Research Hospital
• Clinical Trials Open at St. Jude
• St. Jude Brain Tumor Studies

MeSH Terms

Conditions

Rhabdoid Tumor; Central Nervous System Neoplasms

Interventions

RG7388; selinexor

Condition Hierarchy (Ancestors)

Neoplasms, Complex and Mixed; Neoplasms by Histologic Type; Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Nervous System Diseases

Study Officials

• Amar Gajjar, MD

  St. Jude Children's Research Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 11, 2023
• First Posted: July 19, 2023
• Study Start: March 1, 2024
• Primary Completion: September 1, 2025
• Study Completion (Estimated): August 1, 2032
• Last Updated: March 27, 2024

Record last verified: 2024-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data will be made available at the time of article publication.
• Access Criteria: Data will be provided to researchers following a formal request with the following information: full name of requestor, affiliation, data set requested, and timing of when data is needed. As an informational point, the lead statistician and study principal investigator will be informed that primary results datasets have been requested.