Phase I/II Umbrella Trial of Ulixertinib, Tovorafenib, and Vinblastine Sulfate in Pediatric Patients with Progressive, Relapsed, or Refractory Low-Grade Glioma

Trial ID: 2024-516896-34-00
Protocol: KiTZ-EPILOGUE-2024
Sponsor: Universitaetsklinikum Heidelberg AöR

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Diseases & Conditions

Glioma

Objectives

The primary objective of this phase I/II multi-arm umbrella trial is to identify effective single-agent or combination-based treatment regimens for pediatric low-grade glioma. The study utilizes an intra-individual dose escalation design to establish the optimal dose regarding efficacy and safety for each participant.

Participants

This study involves 22 participants diagnosed with pediatric low-grade glioma. The study population consists of children and adolescents, specifically those aged 6 to 21 years, of both sexes. Participants must present with progressive, relapsed, or refractory disease following first or second-line therapies, such as chemotherapy, targeted therapy, or radiotherapy. Inclusion requires a histopathologic diagnosis of a grade 1 or grade 2 tumor and the presence of a genetic activating RAF alteration. Eligible subjects must demonstrate adequate hematologic and organ function, a body surface area of at least 0.9 m², and a life expectancy exceeding 3 months. Furthermore, a minimum performance status as measured by the Lansky scale or Karnofsky scale of 70 is required.

Plans and Procedures

This Phase I/II combination umbrella trial is designed to evaluate single agent or combination-based treatment regimens for patients with progressive/relapsed/refractory pediatric low-grade glioma. The methodology utilizes an intra-individual dose escalation concept to determine the optimal dose regarding safety and activity for each participant. The study employs several investigational products, including ulixertinib, tovorafenib, and vinblastine sulfate. The research process begins with a screening period to confirm eligibility based on molecular profiles, such as RAF alterations, and specific clinical criteria. Following screening, participants may undergo treatment cycles, with the study treatment period lasting a maximum of 12 cycles. Clinical assessments, including response evaluations based on RAPNO-LGG criteria, are conducted every 8 weeks through central review. Primary objectives include the assessment of dose-limiting toxicity and the best response. Secondary endpoints encompass duration of response, disease control rate, progression-free survival, and overall survival. The trial is expected to conclude its recruitment and activity by February 2030.

Treatment

The experimental treatment includes vinblastine sulfate, administered as an injection via the intravenous route.

The experimental treatment includes ulixertinib, administered in tablet form through an oral route.

The experimental treatment includes tovorafenib, administered in tablet form through an oral route.

Efficacy

The primary efficacy assessment focuses on the dose-limiting toxicity (DLT) of the combination treatment regimens. The best response, categorized as complete response (CR) or partial response (PR), is evaluated using RAPNO-LGG criteria. This assessment is performed via central review every 8 weeks for a maximum of 12 cycles.

Secondary efficacy parameters include:

Duration of response (DOR) and disease control rate (DCR).
Progression-free survival (PFS) and overall survival (OS).
Response rate (RR) in the population reaching the maximum tolerated dose (MTD).
Objective response rate (ORR2), DOR2, DCR2, and PFS2 following re-challenge for rebound tumor growth.
Minimal response (MR) based on RAPNO-LGG.
Time to response (TTR) and time to best response.
Comparison of best response between treatment arms.

Additionally, plasma pharmacokinetics (PK) for ulixertinib and tovorafenib are evaluated.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Children and adolescents with progressive/relapsed/refractory pLGG and an indication for treatment, post first or maximum second line therapy (chemotherapy, targeted therapy, radiotherapy).
Histopathologic diagnosis of glioma or glioneuronal tumor (Grade 1 or 2, according to 2021 WHO Classification for CNS tumors).
DNA methylation classification in accordance with pLGG diagnosis.
Presence of a genetic activating RAF alteration (e.g. KIAA1549::BRAF fusion, BRAF V600E mutation, RAF1-fusions).
Molecular analysis performed per LOGGIC Core BioClinical Databank (DRKS00019035) or equivalent.
Transfer of molecular data (Panel, DNA methylation and optional RNA sequencing) to EPILOGUE trial (if not in LOGGIC Core BioClinical Databank).
Age at the time of signing informed consent ≥ 6 to ≤ 21 years.
In case of enrollment shortly after tumor operation (including stereotactic biopsy), postoperative MRI must be performed within 72 hours following surgery.
Disease that is measurable according to RAPNO-LGG criteria.
Patients receiving steroids for tumor-associated symptoms must be on a stable dose (e.g., no initial/loading dose or no increase) for 14 days prior to start of treatment.
Life expectancy > 3 months, sufficient general condition score (Lansky scale ≥ 70 or Karnofsky scale ≥ 70). Transient states like infections can be accepted, and also stable disabilities resulting from disease/surgery (hemiparesis etc.) can be accepted (they can be ignored for purposes of Lansky/Karnofsky assessments).
Participant is able and willing to swallow and retain oral study medication.
Adequate hematologic and organ function within 14 days before the first study treatment on Day 1 of Cycle 1, as defined by the following: - Hematology: Absolute granulocytes ≥ 1.0 × 109/L (unsupported) Platelets ≥ 100 × 109/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to start of treatment, need to be stable) Hemoglobin ≥ 8 g/dl or ≥ 4.96 mmol/L (transfusions allowed per institutional guidelines; last transfusion > 2 weeks prior to start of treatment) - Biochemistry: Total bilirubin ≤ 1.5 x upper limit of normal (ULN) AST (SGOT) ≤ 3 x ULN ALT (SGPT) ≤ 3 x ULN Serum creatinine ≤ 1.5 x ULN. Patients with documented Gilbert’s Disease may be enrolled provided total bilirubin ≤ 2.0 × ULN and in the opinion of the Investigator, patient can safely participate in the study.
ECG: normal QTc interval according to Bazett formula < 440 ms within 28 days prior to initiation of treatment.
BSA ≥ 0.9 m2 (Calculated by Mosteller formula).
Females of childbearing potential must have a negative serum or urine pregnancy test within 7 days prior to initiation of treatment.
Sexually active women of childbearing potential must agree to use two acceptable methods of contraception during heterosexual intercourse in which one method must be a barrier method (a condom is preferred) in addition to one of the acceptable highly effective birth control methods during the study and for at least 180 days after the last study treatment administration.
Sexually active male patients with a female partner of reproductive potential must agree to use a condom in addition to one of the highly effective contraception methods for at least 120 days after the last study treatment administration.
Willingness and ability to complete all study-related assessments, including electronic patient-reported outcome (ePRO) (PROMIS) assessments, in the investigator’s judgment.
Ability of patient and/or legal representative(s) to understand the character and individual consequences of clinical trial.
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.
Written informed consent, also concerning data, tumor and blood sample transfer, must be obtained according to International Conference on Harmonization of Technical Requirements (ICH)/Good Clinical Practice (GCP), and to national/local regulations, before patient screening and registration.
„Treat-Biopsy“ group only: Patients requiring partial resection/biopsy either immediately before enrollment or upon progression under trial treatment as part of their standard of care.

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Exclusion Criteria

Patients with high-grade gliomas or tumors of unknown malignant potential including tumors with histone H3 mutation, isocitrate dehydrogenase (IDH) 1/2 mutation and/or cyclin-dependent kinase inhibitor (CDKN)2A/B deletion.
Patients with known or suspected by investigator diagnosis of NF-1.
Patients with CNS tumors or metastases who are neurologically unstable despite adequate treatment (e.g. convulsions).
Patients with any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate drug absorption.
Participants who have clinically significant, uncontrolled heart disease.
Participants who have received any anticancer therapy (e.g., chemotherapy, immunotherapy, targeted therapy, biological response modifiers, endocrine anticancer therapy, bevacizumab) within 2 weeks or at least 5 half-lives (whichever is longer) of study drug administration.
Patients received radiotherapy within 12 weeks of study drug administration.
Patients previously treated with ulixertinib.
Patients undergone through major surgical procedure unrelated to pLGG within 21 days prior to randomization or anticipation of the need for major surgery during study treatment. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of an investigational drug is administered.
Concomitant treatment with a strong cytochrome P450 2C8 (CYP2C8) or 3A4 (CYP3A4), 1A2 (CYP1A2) and CYP2D6 inhibitor/inducer, or treatment with medications that are substrates of breast cancer resistance protein (BCRP) with a narrow therapeutic index to tovorafenib, other than those allowed per Section 5.8.1 and Section 5.8.2, within 14 days before initiation of therapy. Medications that are substrates of CYP2C8 or CYP3A4 are allowed but should be used with caution.
Traditional herbal medicines; these therapies are not fully studied and their use may result in unanticipated drug-drug interactions that may cause or confound the assessment of toxicity. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product. For information on CYP inhibitors or inducers and P-glycoprotein inhibitors or inducers see Section 5.8.1 and Section 5.8.2.
Patients with history of hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any excipient present in the pharmaceutical form (including benzamide) of the investigational medicinal product.
Pregnant or lactating females.
Patient is held in an institution by legal or official order.
Patient is financially dependent on the Sponsor, Investigator or trial site.
Participation in other ongoing clinical trials.
Previous participation in this clinical trial.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Austria	Not Yet Recruiting	28 Feb 2026	3
Czechia	Recruiting	28 Feb 2026	3
Denmark	Not Yet Recruiting	28 Feb 2026	3
Germany	Recruiting	28 Feb 2026	22
Sweden	Not Yet Recruiting	28 Feb 2026	3