Phase I/II combination umbrella trial in progressive/relapsed/refractory pediatric low-grade glioma (pLGG) (EPILOGUE)

Prior treatment

• 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.
• Previous participation in this clinical trial.
• 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 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.

Other illness

• 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 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.
• Participants who have clinically significant, uncontrolled heart disease.

Other

• 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.
• 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).

• Children and adolescents with progressive/relapsed/refractory pLGG and an indication for treatment, post first or maximum second line therapy (chemotherapy, targeted therapy, radiotherapy).
• 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.
• Histopathologic diagnosis of glioma or glioneuronal tumor (Grade 1 or 2, according to 2021 WHO Classification for CNS tumors).
• 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.
• 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.