Vinblastine + Tovorafenib for Brain Tumors

(VICTORY Trial)

Overseen By Aiman Siddiqi

Age: < 65

Sex: Any

Trial Phase: Phase < 1

Sponsor: Daniel Morgenstern

Must not be taking: CYP2C8, CYP3A4 inhibitors

Disqualifiers: Neurofibromatosis Type 1, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

57 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications. However, you cannot take medications that strongly affect certain liver enzymes (CYP2C8 or CYP3A4) or those with a narrow safety margin within 14 days before starting the trial.

What data supports the effectiveness of the drug Vinblastine + Tovorafenib for brain tumors?

Research shows that vinblastine alone has been effective in stabilizing disease in children with low-grade glioma, with a good survival rate and minimal side effects. Tovorafenib has shown promise in treating relapsed or refractory pediatric low-grade glioma with BRAF alterations, achieving a significant response rate. ^{1 2 3 4 5}

Is the combination of Vinblastine and Tovorafenib safe for humans?

Vinblastine has been used safely in humans for various conditions, but it can cause side effects like neurotoxicity (nerve damage) and hepatotoxicity (liver damage). In mice, using a special delivery method reduced its toxicity in the brain. There is no specific safety data available for Tovorafenib in this context. ^{6 7 8 9 10}

What makes the drug combination of Vinblastine and Tovorafenib unique for treating brain tumors?

The combination of Vinblastine and Tovorafenib is unique because Vinblastine has shown promising results with a low-toxicity profile in treating pediatric low-grade glioma, and Tovorafenib, a novel agent, may enhance this effect. This combination could offer a new approach for brain tumors, especially in cases where standard treatments are limited or have failed. ^{1 5 11 12 13}

What is the purpose of this trial?

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

Research Team

Daniel Morgenstern

Principal Investigator

The Hospital for Sick Children

Eligibility Criteria

This trial is for pediatric patients aged 25 or younger with recurrent or progressive low-grade gliomas (a type of brain tumor) that have specific genetic changes in the BRAF or CRAF genes. These genetic alterations must be confirmed by certified labs.

Inclusion Criteria

Patients must have at least 1 measurable lesion as defined by RANO-LGG criteria

I am 25 years old or younger.

I can start treatment within 14 working days after my screening.

Exclusion Criteria

Patients with other reasons making them unsuitable for enrollment, as determined by the investigator, are excluded

I do not have specific eye conditions or surgeries.

Patients with known or suspected diagnosis of neurofibromatosis Type 1 (NF-1) are excluded

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Feasibility Phase (Phase A)

Establish the maximum tolerated dose (MTD/RP2D) of vinblastine + tovorafenib using the Rolling 6 design

24 cycles (28 days each)

Weekly visits on Days 1, 8, 15, 22 of each cycle

Efficacy Phase (Phase B)

Expansion/efficacy phase initiated at the dose determined in Phase A

24 cycles (28 days each)

Weekly visits on Days 1, 8, 15, 22 of each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 years

Treatment Details

Interventions

• Tovorafenib
• Vinblastine

Trial Overview The study tests Vinblastine and Tovorafenib in two phases: Phase A to find a safe dose combination, followed by Phase B to assess how effective this combination is at the determined safe dosage for treating these brain tumors.

Participant Groups

Group I: Treatment (single arm study) Experimental Treatment 2 Interventions

Tovorafenib is already approved in United States for the following indications:

Approved in United States as Ojemda for:

• Pediatric low-grade glioma with BRAF gene mutations

Who Is Running the Clinical Trial?

Daniel Morgenstern

Lead Sponsor

Trials

2

Recruited

80+

The Hospital for Sick Children

Collaborator

Trials

724

Recruited

6,969,000+

Findings from Research

Vinblastine, given weekly for 70 weeks, is well tolerated and shows promising efficacy in therapy-naïve children with pediatric low-grade glioma (PLGG), achieving a 94.4% overall survival rate and 53.2% progression-free survival rate.

The treatment resulted in disease stabilization in 87% of patients, with visual improvements in 20% of those with optic pathway glioma, and patients with neurofibromatosis type 1 (NF1) had significantly better progression-free survival compared to those without NF1.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study. Lassaletta, A., Scheinemann, K., Zelcer, SM., et al.[2018]

Vinblastine (VLB) nanoparticles significantly inhibited the growth of glioma C6 cells and induced more apoptosis compared to VLB in physiologic saline solution over a 7-day treatment period, indicating stronger cytotoxic effects.

The study found that while VLB in saline allowed for better clone formation of glioma cells, VLB nanoparticles led to more pronounced morphological changes and a greater reduction in cell numbers, suggesting that nanoparticles may enhance the delivery and effectiveness of VLB in treating glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of vinblastine nanoparticles on growth and apoptosis of glioma cell line C6]. Liu, Y., Ouyang, W., Zhang, Z., et al.[2013]

In a phase III clinical trial involving 325 patients with recurrent glioblastoma, cediranib did not significantly improve progression-free survival compared to lomustine alone, whether used as a monotherapy or in combination.

Despite not meeting the primary endpoint, cediranib demonstrated some clinical benefits in secondary outcomes, such as delaying neurological deterioration and reducing the need for corticosteroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. Batchelor, TT., Mulholland, P., Neyns, B., et al.[2022]

In the phase 2 FIREFLY-1 trial, tovorafenib demonstrated a high overall response rate of 67% in treating pediatric low-grade glioma (pLGG) with BRAF alterations, with a median duration of response of 16.6 months.

While tovorafenib shows promise as an effective therapy, it is associated with notable treatment-related adverse events, including hair color changes (76%) and elevated creatine phosphokinase (56%), with 42% of patients experiencing grade ≥3 adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. Kilburn, LB., Khuong-Quang, DA., Hansford, JR., et al.[2023]

In a phase II study involving 51 pediatric patients with recurrent low-grade glioma, vinblastine treatment resulted in a 36% response rate, indicating its potential efficacy as an alternative to radiation for patients who have failed previous treatments.

The study reported a 5-year overall survival rate of 93.2% and a 5-year progression-free survival rate of 42.3%, suggesting that vinblastine is a viable option for managing low-grade gliomas in children, with manageable toxicity primarily affecting blood cell counts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. Bouffet, E., Jakacki, R., Goldman, S., et al.[2022]

This study is the first to report long-term survival in two patients with primary angiosarcoma of the breast treated with adjuvant vinblastine sulfate (Velban), with both patients remaining disease-free for 10 and 12 years after treatment.

The use of Velban as adjuvant therapy was based on previous evidence of its effectiveness in treating similar tumors, suggesting it may significantly improve the clinical outcomes for patients with breast angiosarcoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiosarcoma of the breast: long-term survival following adjuvant chemotherapy. Rosner, D.[2019]

Vinblastine (VBL) was used to treat a 7-month-old girl with progressive low-grade glioma, resulting in a significant increase in liver enzymes (grade IV toxicity) that resolved after treatment ended.

The case suggests that younger patients may experience different toxicity profiles with VBL, indicating a need for age-specific toxicity screening in future treatment protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transient Hepatotoxicity Induced by Vinblastine in a Young Girl with Chiasmatic Low Grade Glioma. Franke, NE., Blok, GJ., Voll, ML., et al.[2021]

Vinblastine sulfate (VLB) delivered within a collagen matrix (CM) significantly enhances antitumor activity in mouse models, showing a threefold increase in drug exposure to tumors compared to free VLB.

The CM formulation of VLB not only reduces acute toxicity in normal brain tissue but also results in less tumor presence in the brain compared to free VLB, indicating a safer and more effective delivery method for treating brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reduction of vinblastine neurotoxicity in mice utilizing a collagen matrix carrier. Sutton, R., Yu, N., Luck, E., et al.[2019]

In a study of 37 non-small cell lung cancer patients, the combination of vinorelbine, paclitaxel, and carboplatin resulted in a 35% response rate, with one complete remission and 12 partial remissions, indicating potential efficacy for this treatment regimen.

The treatment was associated with significant toxicity, including grade III or IV neutropenia in 30% of patients and neuropathy in 16%, but the median survival was 11 months, suggesting that while the combination is feasible, careful monitoring for side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of carboplatin, paclitaxel plus vinorelbine in non-small cell lung cancer patients. Schmittel, A., Siehl, JM., Schulze, M., et al.[2018]

Vinblastine nanoparticles (VLB-PBCA-NP) demonstrated a stronger antiproliferation effect on human glioma cell lines (BT325) compared to vinblastine in water solution, with higher cell growth inhibition rates observed at various concentrations.

The study found that glioma cells treated with vinblastine nanoparticles showed more advanced stages of apoptosis than those treated with the water solution, indicating that the nanoparticles may enhance the drug's effectiveness in inducing cell death.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effect of vinblastine nanoparticles on antiproliferation in human glioma cell lines BT325]. Liu, YM., Ouyang, WQ., Zhang, ZQ., et al.[2013]

The combination of vinblastine and the mTOR inhibitor sirolimus is safe for pediatric patients with advanced solid tumors, with manageable toxicities such as myelosuppression and one case of grade 3 mucositis.

This treatment led to a significant reduction in serum levels of soluble vascular endothelial growth factor receptor (sVEGFR2), indicating effective inhibition of angiogenesis, and resulted in clinical responses in some patients, including one partial response and three cases of stable disease for over three months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors. Morgenstern, DA., Marzouki, M., Bartels, U., et al.[2013]

Vinblastine-isoleucinate (V-LEU) demonstrated comparable antitumor activity to vinblastine in most tested human tumor xenografts, showing superior effectiveness in malignant melanoma and small cell lung carcinoma, while vinblastine was more effective against colorectal carcinomas.

The study involved nine human tumor xenografts in nude mice, and while V-LEU showed promise, further confirmation of its efficacy and a thorough evaluation of its toxicity compared to other vinca alkaloids are necessary before advancing to clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts. Hendriks, HR., Langdon, S., Berger, DP., et al.[2019]

Vinblastine and rapamycin, when used together, significantly enhance the inhibition of neuroblastoma cell proliferation and induce more apoptosis compared to either drug alone, suggesting a synergistic effect.

In mouse models, the combination treatment not only inhibited tumor growth and angiogenesis but also improved survival rates, indicating its potential as an effective therapeutic strategy against neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined therapeutic effects of vinblastine and rapamycin on human neuroblastoma growth, apoptosis, and angiogenesis. Marimpietri, D., Brignole, C., Nico, B., et al.[2013]

References

1. United States pubmed.ncbi.nlm.nih.gov

Phase II Weekly Vinblastine for Chemotherapy-Naïve Children With Progressive Low-Grade Glioma: A Canadian Pediatric Brain Tumor Consortium Study. [2018]

2. China pubmed.ncbi.nlm.nih.gov

[Effects of vinblastine nanoparticles on growth and apoptosis of glioma cell line C6]. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

The type II RAF inhibitor tovorafenib in relapsed/refractory pediatric low-grade glioma: the phase 2 FIREFLY-1 trial. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. [2022]

6. United States pubmed.ncbi.nlm.nih.gov

Angiosarcoma of the breast: long-term survival following adjuvant chemotherapy. [2019]

7. United Arab Emirates pubmed.ncbi.nlm.nih.gov

Transient Hepatotoxicity Induced by Vinblastine in a Young Girl with Chiasmatic Low Grade Glioma. [2021]

8. United States pubmed.ncbi.nlm.nih.gov

Reduction of vinblastine neurotoxicity in mice utilizing a collagen matrix carrier. [2019]

9. Greece pubmed.ncbi.nlm.nih.gov

Phase II trial of carboplatin, paclitaxel plus vinorelbine in non-small cell lung cancer patients. [2018]

10. China pubmed.ncbi.nlm.nih.gov

[Effect of vinblastine nanoparticles on antiproliferation in human glioma cell lines BT325]. [2013]

11. United States pubmed.ncbi.nlm.nih.gov

Phase I study of vinblastine and sirolimus in pediatric patients with recurrent or refractory solid tumors. [2013]

12. England pubmed.ncbi.nlm.nih.gov

Comparative antitumour activity of vinblastine-isoleucinate and related vinca alkaloids in human tumour xenografts. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Combined therapeutic effects of vinblastine and rapamycin on human neuroblastoma growth, apoptosis, and angiogenesis. [2013]