Triple Drug Therapy for Brain Tumor

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Virginia Commonwealth University

Must be taking: Valproic acid

Must not be taking: EIAEDs, Strong CYP3A4 inhibitors

Disqualifiers: Cardiac disease, Hypertension, HIV, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three drugs—sorafenib, valproic acid, and sildenafil—to determine their safety and effectiveness in treating high-grade glioma, a type of brain tumor. Researchers aim to discover how well these drugs work together to slow or stop tumor growth. Individuals with a confirmed diagnosis of high-grade glioma that has progressed or recurred might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot participate if you are on certain strong medications that affect liver enzymes (CYP3A4 and CYP2C9). If you are taking enzyme-inducing antiepileptic drugs, your doctor might try to switch you to a different medication before you join the study.

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

Research has shown that combining sorafenib, valproic acid, and sildenafil has been somewhat safe in earlier studies. The most common side effects were mild to moderate, including skin rash, low calcium levels, reduced white blood cells, and indigestion. Although these side effects can be uncomfortable, they are usually manageable. It is important to note that this combination remains under study, with ongoing research to fully understand its safety and effectiveness in treating brain tumors. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the triple drug therapy involving Sildenafil, Sorafenib, and Valproic Acid for brain tumors because it combines three different mechanisms of action to tackle the disease from multiple angles. Unlike traditional treatments that might focus solely on inhibiting tumor growth, Sorafenib blocks specific proteins to prevent cancer cell proliferation, while Valproic Acid modifies gene expression to potentially make cancer cells more susceptible to treatment. Additionally, Sildenafil, commonly known for treating erectile dysfunction, enhances the delivery of these drugs to the brain, potentially increasing their effectiveness. This multifaceted approach has the potential to improve outcomes by attacking the tumor on several fronts at once.

What evidence suggests that this trial's treatments could be effective for high-grade glioma?

Research has shown that a combination of three drugs—sorafenib, valproic acid, and sildenafil—might help treat high-grade glioma, a type of brain tumor. In this trial, participants will receive this combination therapy. Studies have found that sildenafil can increase the amount of sorafenib that reaches the brain, potentially enhancing its effectiveness against tumors. Some patients using this combination have shown positive results against high-grade glioma, suggesting that these drugs together could be beneficial for this condition. However, this treatment is still under study, so its full safety and effectiveness remain unconfirmed. ^{1 2 3 5 6}

Who Is on the Research Team?

Andrew Poklepovic, MD

Principal Investigator

Massey Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with high-grade glioma, a serious brain tumor that has come back after treatment. They must understand the study and agree to use birth control. Their blood counts and organ functions need to meet specific levels, they should be relatively active (able to care for themselves), and not have used certain drugs recently or have conditions that could interfere with the treatments.

Inclusion Criteria

It has been over 12 weeks since I finished radiation therapy of 50 Gray or more.

My brain tumor has worsened or come back, confirmed by tests or biopsy.

Your AST and ALT levels must be within a certain range as determined by the lab test.

Exclusion Criteria

Investigational agent within 4 weeks of first dose of study treatment

I have seizures and take specific seizure medicines that might not be allowed.

I do not have conditions that would make antiangiogenic agents unsafe for me.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sorafenib, valproic acid, and sildenafil in 4-week cycles

6 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Long-term follow-up

Participants are monitored for overall survival and progression-free survival

Up to 4 years

What Are the Treatments Tested in This Trial?

Interventions

• Sildenafil
• Sorafenib
• Valproic Acid

Trial Overview The trial tests if combining three drugs—sorafenib (Nexavar®), valproic acid (Depakote®), and sildenafil (Viagra®)—is safe and effective against recurrent high-grade glioma. It checks how well patients tolerate this mix of medications and observes their impact on the brain tumor's progression.

How Is the Trial Designed?

Group I: Treatment (sorafenib tosylate, valproic acid, sildenafil) Experimental Treatment 3 Interventions

* Sorafenib 400 mg orally twice a day; * Valproic acid (to levels ≥ Lower Level of Normal (LLN) orally twice a day; * Sildenafil 50 mg orally twice a day A cycle consists of 4 weeks. \*The first 6 patients evaluable for qualifying toxicity assessment will be treated as a safety lead-in; enrollment will be gated (the first 3 evaluable patients must complete 4 weeks of the combination therapy before the next 3 patients start combination treatment on protocol)

Sildenafil is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in European Union as Viagra for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in United States as Revatio for:

• Pulmonary arterial hypertension

Approved in Canada as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Approved in Japan as Sildenafil for:

• Erectile dysfunction
• Pulmonary arterial hypertension

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

A treatment regimen combining thiotepa, topotecan, and carboplatin was administered to ten pediatric patients with recurrent central nervous system tumors, showing potential to consolidate remission in this challenging group.

Out of the ten patients, four are long-term survivors, particularly those with no evidence of disease at the time of stem cell rescue, suggesting that the extent of disease prior to treatment significantly influences outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Thiotepa/topotecan/carboplatin with autologous stem cell rescue in recurrent/refractory/poor prognosis pediatric malignancies of the central nervous system. Gilheeney, SW., Khakoo, Y., Souweidane, M., et al.[2013]

ImuVert, a biologic response modifier derived from Serratia marcescens, has been granted orphan drug status by the FDA and is currently being tested in a multicenter clinical trial for recurrent malignant astrocytoma, a type of brain tumor with a poor prognosis.

In phase I and II trials, ImuVert showed manageable toxicities, including mild local reactions and some cases of hypotension, indicating that while it has potential as a treatment, careful monitoring of side effects is necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ImuVert therapy in the treatment of recurrent malignant astrocytomas: nursing implications. Cress, NB., Owens, BM., Hill, FH.[2019]

Temozolomide (TMZ) combined with the ribonucleotide reductase inhibitors Trimidox (TX) and Didox (DX) showed synergistic cytotoxic effects against human malignant glioma cell lines, indicating a promising approach for enhancing treatment efficacy in brain tumors.

The study found that these drug combinations could potentially reduce the required doses of each drug while maintaining effectiveness, although some combinations also exhibited additive or antagonistic effects depending on the specific cell line and drug ratios used.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined effects of temozolomide and the ribonucleotide reductase inhibitors didox and trimidox in malignant brain tumor cells. Figul, M., Söling, A., Dong, HJ., et al.[2018]

Valproate (VPA) shows promise in treating glioblastoma multiforme by inhibiting tumor growth through mechanisms such as histone deacetylase inhibition, which leads to gene transcription changes that promote cell differentiation and reduce invasion.

VPA may enhance the effectiveness of traditional treatments like chemotherapy and radiation by inhibiting DNA repair, suggesting that combining VPA with these therapies could be a beneficial strategy for glioblastoma patients, warranting further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valproic acid for the treatment of malignant gliomas: review of the preclinical rationale and published clinical results. Berendsen, S., Broekman, M., Seute, T., et al.[2013]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT01817751

Sorafenib, Valproic Acid, and Sildenafil in Treating Patients ... The purpose of this research study is to test the safety, tolerability, and effectiveness of the combination of three drugs, sorafenib (Nexavar®), valproic ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11071549/

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in ... Inhibition of the ABCG2 transporter with sildenafil may increase sorafenib drug concentrations in the brain, improving sorafenib anti-tumor ...

3. cancertherapyadvisor.com cancertherapyadvisor.com/reports/sorafenib-plus-valproic-acid-and-sildenafil-proves-active-in-high-grade-glioma/

Sorafenib Plus Valproic Acid and Sildenafil Proves Active ... The combination of sorafenib tosylate, valproic acid, and sildenafil demonstrated activity in a phase 2 trial of patients with high-grade ...

4. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/51/NCT01817751/ICF_001.pdf

Informed Consent Form The combination of sorafenib, valproic acid, and sildenafil is investigational, which means that its safety and effectiveness is not known. The study is being ...

5. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38712133/

Phase 2 Study of Sorafenib, Valproic Acid, and Sildenafil in ... Here we report the results of a single-center phase 2 clinical trial combining sorafenib tosylate, valproic acid, and sildenafil for the ...

6. cdek.pharmacy.purdue.edu cdek.pharmacy.purdue.edu/trial/NCT01817751/

Trial | NCT01817751 The purpose of this research study is to test the safety, tolerability, and effectiveness of the combination of three drugs, sorafenib (Nexavar®), valproic ...