VICTORY: A Pilot Study to Investigate Safety and Efficacy of Weekly Combination of Intravenous Vinblastine With Oral Type II RAF Inhibitor Tovorafenib in Pediatric Patients With Recurrent/Progressive RAF Altered Low Grade Gliomas
Overview
- Phase
- Early Phase 1
- Intervention
- Tovorafenib
- Conditions
- Low-grade Glioma
- Sponsor
- Daniel Morgenstern
- Enrollment
- 57
- Locations
- 1
- Primary Endpoint
- Safety and Tolerability
- Status
- Recruiting
- Last Updated
- 11 months ago
Overview
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
Detailed Description
Phase A (Feasibility Phase) A feasibility phase will be conducted to establish the maximum tolerated dose (MTD/RP2D) of the combination of vinblastine + tovorafenib using the Rolling 6 design. Patients will receive vinblastine and tovorafenib on Days 1, 8, 15, 22 of each cycle for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days. Treatment cycles will repeat every 28 days for a total of 24 cycles in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3. The RP2D of tovorafenib of 420 mg/m2 once weekly (not exceeding 600 mg) in combination with vinblastine (4mg/m2) will be used as the starting dose and will be de-escalated/escalated as per Table 4. Dose of tovorafenib will not be escalated further. Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression, unacceptable toxicity occurs, or withdrawal from the study occurs. Missed doses of either vinblastine or tovorafenib will not be made up. Phase B (Expansion/Efficacy Phase) Once the MTD/RP2D of the combination, vinblastine + tovorafenib has been established, the expansion/efficacy phase will be initiated at the dose determined in Phase A. Patient will receive vinblastine and tovorafenib weekly on Days 1, 8, 15, 22 of each cycle at dose determined in Phase A for a total duration of 17 cycles followed by 7 additional cycles of tovorafenib alone. One cycle of protocol therapy is 28 days. Treatment cycles will repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients will undergo radiographic evaluation of their disease at the end of every third cycle, starting with the end of Cycle 3. Patients will be treated on protocol therapy for a total of 24 cycles, the vinblastine and tovorafenib for a total duration of 17 cycles followed by 7 additional cycles of alone tovorafenib, unless disease progression or unacceptable toxicity occurs, unless disease progression, unacceptable toxicity or withdrawal from study occurs. Missed doses of either vinblastine or tovorafenib will not be made up.
Investigators
Daniel Morgenstern
Senior Medical Officer
The Hospital for Sick Children
Eligibility Criteria
Inclusion Criteria
- •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.
- •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.
Exclusion Criteria
- •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.
Arms & Interventions
Treatment (single arm study)
Intervention: Tovorafenib
Treatment (single arm study)
Intervention: Vinblastine
Outcomes
Primary Outcomes
Safety and Tolerability
Time Frame: 2 years
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
MTD/RP2D
Time Frame: 2 years
To determine the maximum tolerated dose (MTD/RP2D) of combination of vinblastine + tovorafenib for children with recurrent/progressive LGGs.
Overall response rate
Time Frame: 2 years
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.
Secondary Outcomes
- Pharmacokinetics (AUC of vinblastine and tovorafenib)(5 years (to complete analyses))
- Clinical Benefit rate(3 years)
- Pharmacokinetics (Cmax vinblastine and tovorafenib)(5 years (to complete analyses))
- Duration of response(3 years)
- Progression free survival(3-year)