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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if the combination of two drugs, Tovorafenib (a new potential drug) and Vinblastine, can effectively treat brain tumors known as low-grade gliomas in children and young adults. These tumors must have specific genetic changes called BRAF or CRAF alterations. The study consists of two parts: the first part identifies the best dose, and the second part evaluates the treatment's effectiveness. Individuals with these specific genetic changes in their brain tumor who have not succeeded with other treatments might be suitable candidates. As an Early Phase 1 trial, this research focuses on understanding the treatment's effects in people, offering participants the opportunity to be among the first to receive this new potential drug.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that tovorafenib, a treatment for certain brain tumors, is generally well-tolerated, though some serious side effects have occurred. In one study, a patient experienced a fatal tumor hemorrhage, which is bleeding within the tumor. Additionally, 7% of patients discontinued the medication due to side effects.

Vinblastine, another cancer treatment, also carries potential side effects. Serious side effects are less common but may include allergic reactions, heart problems, breathing issues, and blood disorders. Some patients may also face a risk of developing a new, unrelated cancer.

Both treatments have risks but are already used for other medical conditions, indicating that doctors have some understanding of their safety. As this trial is in the early stages of testing, safety remains a key focus. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for brain tumors that typically focus on surgery, radiation, and chemotherapy, Tovorafenib and Vinblastine offer a novel approach. Tovorafenib is a new drug that works by targeting specific pathways in cancer cells, potentially leading to more effective tumor inhibition. Vinblastine, an established chemotherapy drug, is being used in combination to enhance the overall anti-tumor effect. Researchers are excited about these treatments because combining a targeted therapy with chemotherapy could provide a more potent and precise attack on tumor cells, potentially improving outcomes for patients with brain tumors.

What evidence suggests that this treatment might be an effective treatment for brain tumors?

Research has shown that vinblastine effectively controls disease in children with low-grade glioma, maintaining a good survival rate with few side effects. Tovorafenib has also shown promise, particularly when other treatments have failed, by targeting specific genetic changes in the tumor. Studies suggest that tovorafenib could effectively treat BRAF-altered, relapsed, or hard-to-treat pediatric low-grade gliomas. This trial will combine vinblastine and tovorafenib in a single treatment arm to enhance effectiveness by leveraging the strengths of both drugs. ^{6 7 8 9 10}

Who Is on the Research Team?

Daniel Morgenstern

Principal Investigator

The Hospital for Sick Children

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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-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]

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]

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]

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]

Citations

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Tovorafenib for Relapsed or Refractory BRAF-altered ... The primary efficacy data supporting approval of tovorafenib were derived from 76 patients enrolled in Arm 1 of FIREFLY-1, an open-label, multicenter trial ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT05566795

Study Details | NCT05566795 | DAY101 vs. Standard of ... This is a 2-arm, randomized, open-label, multicenter, global, Phase 3 trial to evaluate the efficacy, safety, and tolerability of tovorafenib monotherapy ...

3. nature.com nature.com/articles/s41591-023-02668-y

The type II RAF inhibitor tovorafenib in relapsed/refractory ... These data indicate that tovorafenib could be an effective therapy for BRAF-altered, relapsed/refractory pLGG.

4. withpower.com withpower.com/trial/early-phase-1-glioma-2-2024-00e15

Vinblastine + Tovorafenib for Brain Tumors (VICTORY Trial) 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 ...

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10826080/

a phase 3, randomized trial of tovorafenib vs. chemotherapy in ... Importantly, this study also includes endpoints to evaluate improvements in neurologic outcomes, visual function in patients with optic pathway ...

6. ojemda.com ojemda.com/safety-and-side-effect-management/side-effect-management

Safety and side effects OJEMDA is a prescription medicine used to treat certain types of brain tumors (cancers) called gliomas in patients 6 months and older: that is a pediatric ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2024/218033s000lbl.pdf

OJEMDA (tovorafenib) - accessdata.fda.gov A fatal adverse reaction of tumor hemorrhage occurred in 1 patient (1%). Permanent discontinuation of OJEMDA due to an adverse reaction occurred in 7% of ...

8. ir.dayonebio.com ir.dayonebio.com/news-releases/news-release-details/day-ones-ojemdatm-tovorafenib-receives-us-fda-accelerated

Day One's OJEMDA™ (tovorafenib) Receives US FDA ... Arm 2 provided additional safety data ... OJEMDA is a prescription medicine used to treat certain types of brain tumors (cancers) called gliomas ...

9. ojemdahcp.com ojemdahcp.com/safety

Safety | OJEMDA™ (tovorafenib) Based on nonclinical data in NF1 models without BRAF alterations, OJEMDA may promote tumor growth in patients with NF1 tumors · Confirm evidence of a BRAF ...

10. clinicaltrials.gov clinicaltrials.gov/study/NCT03429803

NCT03429803 | DAY101 In Gliomas and Other Tumors The purpose of this study is to test the safety DAY101 in children and adolescent participants with brain tumors. The investigators want to find out what ...