Pilot Study of Vinblastine and Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas

NCT06381570 | Recruiting Early Phase 1 DMC

• 1 other identifier: VICTORY/OZM-138
• Study Type: interventional
• Target: 57
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Pilot, multicenter, open-label study of patients less than or equal to 25 years, with recurrent or progressive LGG harboring a CRAF or BRAF alteration, including BRAF V600 mutations and KIAA1549: BRAF fusions. Patients with BRAF or CRAF alterations will be identified through molecular assays as routinely performed at Clinical Laboratory Improvement Amendments (CLIA) of 1988 or other similarly certified laboratories. The study will be conducted in two sequential phases: Phase A: A Feasibility (combination dose finding) phase, followed by Phase B: An Efficacy phase. The maximum tolerated dose (MTD)/Recommended Phase 2 Dose (RP2D) of the combination as determined in Phase A would be the dose used in Phase B. The patients on Phase A who were below the MTD/RP2D would be eligible for intra-patient dose escalation to MTD/RP2D subject to criteria outlined later

Conditions

Low-grade Glioma

Keywords

RAF altered; non-NF1

Outcome Measures

Primary Outcomes (3)

• MTD/RP2D

  To determine the maximum tolerated dose (MTD/RP2D) of combination of vinblastine + tovorafenib for children with recurrent/progressive LGGs.

  2 years

• Safety and Tolerability

  To assess safety and tolerability of combination of vinblastine and tovorafenib in pediatric patients with recurrent/progressive LGG through documentation of number of participants with treatment-related adverse events as assessed by CTCAE v5.0

  2 years

• Overall response rate

  To determine overall response rate (ORR) of CR, PR and MR in patients with LGG treated with combination of vinblastine + tovorafenib by RANO-LGG criteria.

  2 years

Secondary Outcomes (5)

• Pharmacokinetics (Cmax vinblastine and tovorafenib)

  5 years (to complete analyses)

• Pharmacokinetics (AUC of vinblastine and tovorafenib)

  5 years (to complete analyses)

• Progression free survival

  3-year

• Duration of response

  3 years

• Clinical Benefit rate

  3 years

Study Arms (1)

Treatment (single arm study)

EXPERIMENTAL

Drug: Tovorafenib; Drug: Vinblastine

Interventions

Tovorafenib DRUG

Tovorafenib for oral dosing is provided as an immediate-release tablet in 100 mg strength. The 100 mg tablets are red to yellowish red oval tablets. All products are labeled tovorafenib. In addition, tovorafenib is provided as a powder for reconstitution (PfR) in bottles (430mg per bottle to deliver 300 mg dose). Upon reconstitution with water, the concentration is 25 mg/mL. Vinblastine is administered by intravenous route as IV push, sites to follow local administration guidelines, once weekly (central line, but peripheral line is also permitted)

Also known as: Vinblastine

Treatment (single arm study)

Vinblastine DRUG

vinblastine in combination with tovorafenib

Treatment (single arm study)

Eligibility Criteria

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

You may qualify if:

• Age
• a) Patients must be less than or equal to 25 years of age at the time of enrollment.
• Study Group
• a) Progressive/Recurrent LGG (non-NF1) with documented BRAF or CRAF alteration as identified through molecular assays as routinely performed at CLIA or other similar certified laboratories.
• Diagnosis
• All patients must have pathological confirmation of low-grade glioma with BRAF or CRAF alteration.
• Patient must have progressive or recurrent LGG.
• Must have at least 1 measurable lesion, as defined by RANO-LGG criteria.
• Eligible histologies will include all tumors considered low-grade glioma or low-grade astrocytoma (WHO grade I and II) by WHO classification of Tumors of the Central Nervous system -5th edition revised with exception of subependymal giant cell astrocytoma.
• Prior Therapy
• Must have received at least 1 line of systemic therapy prior (at least a vinca alkaloid and/or single agent carboplatin and/or a MEK or BRAF inhibitor) and have documented evidence of radiographic progression.
• Patients must have fully recovered from the acute toxic effects (≤ Grade I) of all prior anticancer chemotherapy and have undergone the following washout periods, as applicable.
• i. Myelosuppressive chemotherapy: At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea) ii. Radiation therapy (XRT): Radiation therapy to the measurable lesion(s) must be completed at least 6 months prior to administration of combination therapy. Patients who have documented radiographic progression less than 6 months from radiotherapy in 1 or more measurable lesions are eligible. At least 2 weeks after the last dose fraction of XRT to the non-target lesion.
• iii. Investigational agent or any other anticancer therapy not defined above: At least four weeks prior to planned start of combination therapy, or five half-lives, whichever is shorter.
• iv. Patients must have recovered from acute effects of any prior surgery. v. Chronic toxicities from prior anticancer therapy must be stable as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 Grade ≤ 2, except ongoing retinopathy which must be ≤ Grade 1.

You may not qualify if:

• Patients meeting any of the following criteria are to be excluded from study participation:
• Patient's tumor has additional previously known activating molecular alterations, other than BRAF or CRAF.
• Known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) via genetic testing or current diagnostic clinical criteria.
• History of any major disease, other than the diagnosis of LGG, that might interfere with safe protocol participation.
• Patient with a history or current evidence of central serous retinopathy (CSR), retinal vein occlusion (RVO), or ophthalmopathy present at baseline who would be considered a risk factor for CSR or RVO. Ophthalmological findings secondary to long-standing optic pathway glioma (such as visual loss, optic nerve pallor, or strabismus) will NOT be considered a significant abnormality for the purposes of this study.
• Major surgery within 14 days (2 weeks) prior to enrollment (does not include central venous access, cyst fenestration or cyst drainage, or ventriculoperitoneal shunt placement or revision).
• Clinically significant active cardiovascular disease, or history of myocardial infarction, or deep vein thrombosis/pulmonary embolism within 6 months prior to enrollment, ongoing cardiomyopathy, or current prolonged QT interval corrected for heart rate by Fridericia's formula (QTcF) interval \> 470 ms based on triplicate ECG average.
• Concomitant medications that are strong inhibitors or inducers of CYP2C8 or CYP3A4 within 14 days before initiation of therapy. Concomitant medications that are substrates of BCRP with a narrow therapeutic index within 14 days before initiation of therapy
• Current enrollment in any other investigational treatment study. Participation on a concurrent observational or bio-sampling study is allowed.
• Active systemic bacterial, viral, or fungal infection.
• Nausea and vomiting ≥ National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 Grade 2 (for those not controlled by supportive care), malabsorption requiring supplementation, or significant bowel or stomach resection that would preclude adequate absorption of tovorafenib.
• Patient has CTCAE v5.0 Grade 3, creatine phosphokinase (CPK) elevation (\> 5 × ULN - 10 × ULN).
• Patients who are neurologically unstable despite adequate treatment (e.g., uncontrolled seizures).
• Pregnancy or lactation.
• History of drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome or Stevens Johnsons syndrome (SJS). Patients with hypersensitivity to the investigational medicinal product or to any drug with similar chemical structure or to any other excipient present in the pharmaceutical form of the investigational medicinal product.

Sponsors & Collaborators

• Daniel Morgenstern: lead
• The Hospital for Sick Children: collaborator

Study Sites (1)

The Hospital for Sick Children

Toronto, Ontario, M5G 1X8, Canada

RECRUITING

MeSH Terms

Interventions

tovorafenib; Vinblastine

Intervention Hierarchy (Ancestors)

Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Officials

• Daniel Morgenstern

  The Hospital for Sick Children

  STUDY DIRECTOR

Central Study Contacts

Nirav Thacker

CONTACT

613-737-7600; nthacker@cheo.on.ca

Aiman Siddiqi

CONTACT

aiman.siddiqi@sickkids.ca

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Senior Medical Officer

Study Record Dates

• First Submitted: April 10, 2024
• First Posted: April 24, 2024
• Study Start: March 21, 2024
• Primary Completion (Estimated): March 21, 2027
• Study Completion (Estimated): March 21, 2029
• Last Updated: May 15, 2025

Record last verified: 2025-05

Locations

CA (1)