Neratinib + Valproate for Advanced Solid Cancers

Overseen By Massey IIT Research Operations

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Virginia Commonwealth University

Must be taking: Neratinib, Sodium valproate

Must not be taking: Antacids, PPIs, CYP3A4 drugs

Disqualifiers: Brain metastases, Cardiac disease, others

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

Compensation: Varies

Number of Visits: Unknown

83 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose for a combination of two medicines, neratinib and sodium valproate (also known as divalproex sodium), to treat advanced solid cancers. Researchers seek to evaluate the effectiveness of this combination for specific cancers, such as those with RAS mutations, certain brain tumors, and eye melanoma. Suitable candidates have advanced solid tumors that have not responded to other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new combination therapy.

Do I need to stop taking my current medications to join the trial?

The trial protocol does not specify if you must stop all current medications, but certain medications need to be adjusted or stopped. You cannot take proton pump inhibitors, strong or moderate CYP3A4 inhibitors or inducers, and some other specific drugs. If you've used these, you must stop them at least 2 weeks before starting the trial. Antacids and H2 receptor antagonists need to be timed around neratinib doses. Check with the trial team for details on your specific medications.

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop all current medications, but you cannot take certain drugs that might interact with the study medications. If you're on antacids, H2 receptor antagonists, proton pump inhibitors, or certain other medications, you may need to adjust or stop them. It's best to discuss your current medications with the trial team.

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

Research has shown that neratinib, a drug often used for HER2-positive breast cancer, is generally safe but can cause diarrhea, affecting about 40% of patients. Divalproex sodium, also known as valproate, treats conditions like seizures. Both drugs have been studied separately and are usually well-tolerated.

However, less information exists on their combined use. Current research is in the early stages (Phase 1/2), as scientists work to determine the safest dose. This phase typically involves small groups to ensure side effects remain manageable and to understand how the body processes the drugs. So far, no major safety issues have emerged, but the full effects of the combination are still under investigation. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Neratinib combined with Divalproex Sodium because this treatment duo offers a fresh approach for tackling advanced solid cancers with RAS mutations, such as colon, pancreatic, and glioblastoma. Unlike traditional chemotherapy or targeted therapies like BRAF and MEK inhibitors, Neratinib is a tyrosine kinase inhibitor that blocks the HER2 receptor, which can play a role in cancer growth. Meanwhile, Divalproex Sodium, commonly used to treat seizures, is being repurposed here for its potential to enhance the effects of Neratinib by modulating gene expression. This combination could offer a more targeted attack on cancer cells, potentially leading to better outcomes for patients with specific genetic mutations.

What evidence suggests that this trial's treatments could be effective for advanced solid cancers?

Research has shown that combining neratinib and valproate can slow tumor growth and enhance the immune system's ability to fight tumors. Participants in this trial will receive this combination, which targets specific changes in cancer cells known as RAS mutations and has shown promise in treating solid tumors with these mutations. Neratinib blocks proteins that aid cancer cell growth, while valproate, often used for seizures, can make cancer cells more vulnerable. Together, these treatments offer a new approach to tackling difficult-to-treat cancers like RAS-mutated tumors, certain brain cancers, and eye melanoma. ^{1 3 5 6 7}

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 advanced solid tumors, including specific types such as RAS-mutated colon or pancreatic cancer, ocular melanoma, and glioblastoma with RAS mutation or EGFR alteration. Participants must have progressed after standard treatments or have no effective options available. They should be in good physical condition (ECOG 0-1), not pregnant, willing to use contraception, able to swallow pills without malabsorption issues, and free from serious infections or heart conditions.

Inclusion Criteria

My kidney function, measured by creatinine levels, is within the normal range.

It's been at least 12 weeks since I finished radiation therapy for my brain tumor.

I have not increased my corticosteroid dose for my brain tumor in the last week.

Exclusion Criteria

I have a condition that affects how my body absorbs nutrients, but I can take supplements.

I have severe diarrhea that is not controlled by oral medication.

I cannot swallow pills.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dose Escalation

Participants receive neratinib and divalproex sodium to determine the recommended phase 2 dose (RP2D)

4 weeks

Daily dosing

Phase 2 Expansion

Participants with specific cancer types receive treatment at the RP2D to evaluate antitumor effects

13 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Divalproex Sodium
• Neratinib

Trial Overview The study aims to find the safest dose of neratinib combined with sodium valproate that can be given to patients with advanced solid tumors. It will also assess how well this combination works against certain tumor types like those with RAS mutations and EGFR-altered glioblastomas.

How Is the Trial Designed?

Group I: Pancreatic Cancer Experimental Treatment 2 Interventions

RAS-mutated pancreatic cancer at RP2D

Group II: Other Cancer Experimental Treatment 2 Interventions

"Other Cancer" (RAS-mutated) at RP2D

Group III: Ocular Melanoma (OM) Experimental Treatment 2 Interventions

Phase II dose expansion at RP2D

Group IV: Neratinib + Divalproex Sodium - Dose Escalation Cohort Experimental Treatment 2 Interventions

Neratinib by mouth (PO) once daily + Divalproex Sodium (Valproate) by mouth (PO) twice daily on days 1-28 of each course.

Group V: Glioblastoma (GBM) Experimental Treatment 2 Interventions

Glioblastoma with a RAS-mutation or EGFR alteration at RP2D

Group VI: Colon Experimental Treatment 2 Interventions

Colon Cancer (RAS-mutated) - Phase II dose expansion at recommended phase II dose (RP2D)

Divalproex Sodium is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Divalproex Sodium for:

• Seizure disorders
• Manic episodes associated with bipolar disorder
• Migraine prophylaxis

Approved in European Union as Valproate for:

• Epilepsy
• Mania
• Migraine prophylaxis

Approved in Canada as Depakote for:

• Seizure disorders
• Manic episodes associated with bipolar disorder
• Migraine prophylaxis

Who Is Running the Clinical Trial?

Virginia Commonwealth University

Lead Sponsor

Trials

732

Recruited

22,900,000+

Puma Biotechnology, Inc.

Industry Sponsor

Trials

58

Recruited

10,100+

Published Research Related to This Trial

Neratinib was approved by the FDA for the extended treatment of early-stage HER2-positive breast cancer, showing a significant improvement in invasive disease-free survival (iDFS) with a 2-year rate of 94.2% compared to 91.9% for placebo in a study of 2,840 women.

While neratinib is effective, it is associated with a high incidence of diarrhea (40% grade 3 or 4), which is the most common reason for treatment discontinuation, though most adverse effects are manageable and reversible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. Food and Drug Administration Approval: Neratinib for the Extended Adjuvant Treatment of Early-Stage HER2-Positive Breast Cancer. Singh, H., Walker, AJ., Amiri-Kordestani, L., et al.[2019]

The combination of neratinib and valproate significantly slows the growth of 4T1 mammary tumors in mice, leading to reduced expression of key proteins associated with tumor growth and increased immune cell infiltration.

This drug combination enhances the tumors' sensitivity to immunotherapy by promoting a more favorable immune environment, without causing noticeable damage to normal tissues, indicating a potential safe therapeutic strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Neratinib + Valproate] exposure permanently reduces ERBB1 and RAS expression in 4T1 mammary tumors and enhances M1 macrophage infiltration. Booth, L., Roberts, JL., Rais, R., et al.[2019]

Neratinib is an oral pan HER inhibitor that irreversibly blocks the activity of HER2 and other related receptors, showing promise in improving outcomes for patients with HER2-amplified breast cancer, which affects 20% to 25% of cases.

Current clinical trials are evaluating neratinib's safety and efficacy across various cancer types, including breast cancer, with a focus on its use in different treatment settings such as metastatic and adjuvant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib, A Novel HER2-Targeted Tyrosine Kinase Inhibitor. Tiwari, SR., Mishra, P., Abraham, J.[2019]

Neratinib, an ERBB inhibitor, causes K-RAS to mislocalize in pancreatic tumor cells, and when combined with sodium valproate, it initially reduces the activity of several cancer-related receptors, but resistance mechanisms can develop quickly after treatment cessation.

Knocking down ERBB3 enhances the lethality of the neratinib and valproate combination, suggesting that targeting ERBB3 could improve treatment outcomes, especially when used alongside the PI3Kα/δ inhibitor copanlisib, which also promotes cancer cell death through autophagy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enhanced signaling via ERBB3/PI3K plays a compensatory survival role in pancreatic tumor cells exposed to [neratinib + valproate]. Dent, P., Booth, L., Poklepovic, A., et al.[2021]

Neratinib is an oral, irreversible inhibitor targeting HER1, HER2, and HER4, specifically developed for treating HER2-positive breast cancer, and is approved in the USA for patients who have previously received trastuzumab-based therapy.

The drug is currently in various stages of clinical development for other cancers, including metastatic breast cancer and solid tumors like non-small cell lung cancer and glioblastoma, indicating its potential broader therapeutic applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib: First Global Approval. Deeks, ED.[2019]

Neratinib significantly reduces the risk of invasive disease recurrence or death in women with early-stage HER2-positive breast cancer who have completed trastuzumab therapy, as shown in the ExteNET trial over 12 months, with benefits observed at both 2 and 5 years post-treatment.

Patients with hormone receptor-positive disease and those who start neratinib within 1 year of completing trastuzumab experience greater benefits, leading to its approval in the EU as an extended adjuvant therapy for this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib in Early-Stage Breast Cancer: A Profile of Its Use in the EU. Dhillon, S.[2021]

Neratinib combined with paclitaxel showed a high overall response rate of 73% in patients with HER2-positive breast cancer, indicating its efficacy as a treatment option.

The combination therapy had manageable side effects, with common adverse events including diarrhea and peripheral sensory neuropathy, but no dose-limiting toxicities were observed during the study.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination neratinib (HKI-272) and paclitaxel therapy in patients with HER2-positive metastatic breast cancer. Chow, LW., Xu, B., Gupta, S., et al.[2023]

In a phase I/II trial involving 105 patients, the combination of neratinib and capecitabine was found to have a manageable safety profile, with diarrhea (88%) and palmar-plantar erythrodysesthesia syndrome (48%) being the most common side effects.

The treatment demonstrated promising efficacy, achieving an objective response rate of 64% in patients without prior lapatinib exposure and 57% in those previously treated with lapatinib, indicating its potential as an effective option for HER2-positive metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. Saura, C., Garcia-Saenz, JA., Xu, B., et al.[2022]

In a phase I trial involving 20 patients with specific ERBB or KRAS mutations, the combination of neratinib and trametinib was found to have significant treatment-related toxicities, including 100% incidence of diarrhea at the lowest dose level.

Despite the toxicity, only two patients achieved stable disease for at least 4 months, indicating that the combination therapy had limited clinical efficacy, potentially due to drug-drug interactions affecting optimal dosing.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I trial of the pan-ERBB inhibitor neratinib combined with the MEK inhibitor trametinib in patients with advanced cancer with EGFR mutation/amplification, HER2 mutation/amplification, HER3/4 mutation or KRAS mutation. Piha-Paul, SA., Tseng, C., Tran, HT., et al.[2023]

Neratinib, when combined with capecitabine, has shown effectiveness in treating HER2-positive metastatic breast cancer, particularly in patients with brain metastasis, which is a common complication in this subtype.

The NALA trial, a Phase III randomized study, compares neratinib plus capecitabine to the standard treatment of lapatinib plus capecitabine, indicating potential advancements in treatment options for HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neratinib: the emergence of a new player in the management of HER2+ breast cancer brain metastasis. Nasrazadani, A., Brufsky, A.[2020]

Neratinib, a tyrosine kinase inhibitor, shows promising efficacy in treating HER2-positive breast cancer, with a higher response rate when used in combination with other therapies compared to monotherapy.

While neratinib is associated with a high incidence of adverse events, particularly diarrhea (83.9% of patients), these side effects are generally manageable, and the drug has been linked to improved survival outcomes in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Efficacy Profile of Neratinib: A Systematic Review and Meta-Analysis of 23 Prospective Clinical Trials. Tao, Z., Li, SX., Shen, K., et al.[2021]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03919292

NCT03919292 | Neratinib + Valproate in Advanced Solid ... To determine the recommended phase 2 dose (RP2D) of the combination of neratinib and sodium valproate when given to patients with advanced solid tumors.

2. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2019-02675

Neratinib and Divalproex Sodium in Treating Patients with ... This phase I/II trial studies the best dose of neratinib and divalproex sodium in treating patients with solid tumors that have spread to other places in the ...

3. withpower.com withpower.com/trial/phase-2-neoplasms-4-2019-4b049

Neratinib + Valproate for Advanced Solid Cancers Research shows that the combination of Neratinib and Valproate can slow the growth of certain tumors and make them more responsive to immune system attacks in ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7809886/

RAS-targeted therapies: is the undruggable drugged? - PMC Currently, a phase I/II clinical trial is evaluating the efficacy of neratinib in RAS-mutant solid tumours in combination with the histone deacetylase inhibitor ...

5. ancora.ai ancora.ai/fr/details/NCT03919292

Neratinib + Valproate in Advanced Solid Tumors, w/ ... To determine the recommended phase 2 dose (RP2D) of the combination of neratinib and sodium valproate when given to patients with advanced solid tumors.

6. masseycancercenter.org masseycancercenter.org/clinical-trials/details/phase-12-study-of-neratinib-and-divalproex-sodium-valproate-in-advanced-solid-tumors-with-an-expansi

Phase 1/2 Study of Neratinib and Divalproex Sodium ... Phase 1/2 Study of Neratinib and Divalproex Sodium (Valproate) in Advanced Solid Tumors, with an Expansion Cohort in RAS Mutated Cancers. Objective.

7. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03919292/

Clinical Trial: NCT03919292 This study is a single-arm, open-label, phase 1/2 trial to determine the recommended phase 2 dose of neratinib and sodium valproate when given in combination ...