What side effects are associated with this type of intervention?

Common side effects of treatments for solid tumors, particularly those involving tyrosine kinase inhibitors like Neratinib and HDAC inhibitors, include diarrhea, rash, hepatotoxicity, gastrointestinal disturbances, fatigue, and hematologic toxicities. These adverse events are important considerations when evaluating the risk-benefit profile of such therapies.

What prior FDA approvals exist?

FDA-approved treatments for solid tumors that involve tyrosine kinase inhibitors (TKIs) include drugs like Lapatinib and Erlotinib, which are used for breast cancer and non-small cell lung cancer, respectively. Histone deacetylase inhibitors (HDAC inhibitors) such as Vorinostat have been approved for cutaneous T-cell lymphoma. While the combination of TKIs and HDAC inhibitors is still under investigation, these approvals highlight the potential of targeting multiple pathways in cancer treatment.

What other types of research exist?

Promising novel alternatives for solid tumor patients include: 1) Dabrafenib plus Trametinib for BRAFV600E-mutated tumors, which has shown efficacy in various solid tumors. 2) Oncolytic virotherapy, such as oncolytic herpes simplex virus type 1 (HSV-1) combined with lenalidomide, which has shown potential in plasma cell neoplasms. 3) Regorafenib, which has demonstrated efficacy in metastatic osteosarcoma and other solid tumors. These alternatives represent advancements in targeted and combination therapies for solid tumors.

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Histone Deacetylase Inhibitor

Neratinib + Valproate for Advanced Solid Cancers

Q: What is the mechanism of action of this treatment?

Tyrosine kinase inhibitors (TKIs) and histone deacetylase (HDAC) inhibitors are common treatments for solid tumors. TKIs, such as Neratinib, block the enzyme tyrosine kinase, which is crucial for cell division and survival signaling pathways, thereby inhibiting cancer cell growth and spread. HDAC inhibitors, like Sodium Valproate, modify histones to alter gene expression, leading to the reactivation of tumor suppressor genes and induction of cancer cell death. These targeted therapies are significant for solid tumor patients as they specifically address dysregulated pathways in cancer cells, potentially offering more effective and less toxic treatment options compared to traditional chemotherapy.

Phase 1 & 2

Recruiting

Led By Andrew Poklepovic, MD

Research Sponsored by Virginia Commonwealth University

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

All patients must meet all of the following inclusion criteria to be eligible to participate in the study: Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, Adequate bone marrow function, Absolute neutrophil count (ANC) ≥ 1500/mm3, Platelets ≥ 100,000/mm3, Hemoglobin > 9 g/dL (untransfused), Adequate renal function, Creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance ≥ 60 mL/min, Adequate hepatic function, Total bilirubin ≤ 1.5 x ULN for the laboratory Exception: If a patient has documented Gilbert's syndrome and a total bilirubin is > 1.5 x ULN for the laboratory, the total bilirubin requirement may be waived provided the direct bilirubin is within normal limits (WNL) for the laboratory, Aspartate aminotransferase (AST) ≤ 3.0 x ULN for the laboratory, Alanine aminotransferase (ALT) ≤ 3.0 x ULN for the laboratory, Note: For the expansion cohorts, in patients with documented liver metastasis, the AST and ALT requirements will be ≤ 5 x ULN for the laboratory, Non-hematologic toxicities from previous cancer therapies resolved to ≤ grade 1 except chronic residual toxicities that in the opinion of the investigator are not clinically relevant given the known safety/toxicity profiles of neratinib and sodium valproate (eg, alopecia, changes in pigmentation, stable endocrinopathies, neuropathy, skin toxicities), International normalized ratio (INR) is ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 x ULN for the laboratory, A woman of childbearing potential (WCBP), defined as a woman who is < 60 years of age and has not had a hysterectomy, must have a documented negative serum pregnancy test within 7 days prior to initiating study treatment, WCBP and a male patient with a partner who is a WCBP must agree to use a medically accepted method for preventing pregnancy for the duration of study treatment and for 2 months following completion of study treatment, Ability to understand and willingness to sign a written informed consent document

Creatinine ≤ 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance ≥ 60 mL/min

Must not have

Active or clinically significant cardiac disease including any of the following: Unstable angina (eg, anginal symptoms at rest) or onset of angina within 3 months prior to initiating study treatment, Myocardial infarction diagnosed within 6 months prior to initiating study treatment, Cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers, New York Heart Association (NYHA) class III or IV congestive heart failure, Seizure disorder requiring an enzyme inducing antiepileptic medication (EIAED), Serious (ie, ≥ grade 3) uncontrolled infection, Chronic or active hepatitis B or C infection with elevated transaminase levels, Pleural effusion or ascites that causes respiratory compromise (ie, ≥ grade 2 dyspnea), Known mitochondrial disorder caused by mutations in mitochondrial DNA polymerase gamma (γ), Known urea cycle disorders, Planned ongoing treatment with other drugs thought to potentially have adverse interactions with either of the medications included in the study treatment: Cosyntropin, Proton pump inhibitors (PPIs), High-risk P-glycoprotein (P-gp) substrates (eg, digoxin, dabigatran, fexofenadine). Other anticoagulants are not considered high-risk P-gp substrates, Strong or moderate CYP3A4 inhibitors and/or Strong or moderate CYP3A4 inducers. Examples of clinical inhibitors and clinical inducers for P450-mediated metabolism and classification of strong, moderate, and weak interactions are available through the FDA website, Tables 3-2 and 3-3: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm093664.htm Note: If such medications have been used, patients must have discontinued these agents ≥ 2 weeks prior to initiating study treatment, Pregnancy or breastfeeding, Medical, psychological, or social condition that, in the opinion of the investigator, may increase the patient's risk or limit the patient's adherence with study requirements

Active uncontrolled diarrhea leading to dehydration or electrolyte disturbances not easily controlled with oral repletion

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 13 months

Awards & highlights

Summary

This trial is testing a combination of neratinib and sodium valproate to treat advanced cancers. It focuses on patients with specific hard-to-treat tumors. Neratinib blocks proteins that help cancer grow, and sodium valproate may make cancer cells more sensitive to treatment.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects include diarrhea which could lead to dehydration if uncontrolled; blood pressure changes; possible interactions leading to cardiac issues; risk of seizures for those on certain antiepileptic medications; and liver function alterations due to hepatitis B/C.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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

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

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I am a woman under 60, have not had a hysterectomy, and tested negative for pregnancy recently.

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My cancer is advanced, has a RAS mutation or specific changes, and has not responded to standard treatments.

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I am fully active or can carry out light work.

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My cancer is advanced, has a RAS mutation, and has not responded to standard treatments.

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My bone marrow is working well.

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My advanced cancer has worsened despite treatment, or there's no effective treatment for it.

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My solid tumor can be measured or evaluated by standard criteria.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

Select...

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

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I cannot swallow pills.

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I do not have brain membrane cancer spread.

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I have been treated with neratinib before.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 13 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~13 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 13 months for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Determination of Recommended Phase 2 Dose (RP2D)

Secondary study objectives

Sodium valproate

Glioblastoma Antitumor Effects

Progression Free Survival (PFS)

+1 more

Side effects data

From 2022 Phase 2 trial • 11 Patients • NCT03094052

100%

Diarrhea

100%

Constipation

82%

Nausea

45%

Abdominal distension

45%

Fatigue

36%

Dizziness

36%

Headache

27%

Dyspnea

27%

Hot flashes

27%

Anorexia

27%

Vomiting

27%

Pruritus

27%

Weight loss

18%

Skin and subcutaneous tissue disorders - Other, specify

18%

Dysgeusia

18%

Bloating

18%

Fever

18%

Abdominal pain

18%

Gastrointestinal disorders - Other, specify

18%

Aspartate aminotransferase increased

18%

Alanine aminotransferase increased

18%

Sinus bradycardia

Neck pain

Rash maculo-papular

Muscle weakness upper limb

Lymphedema

Rash acneiform

Back pain

Vaginal dryness

Anal hemorrhage

Paresthesia

Gastroesophageal reflux disease

Pain

Infections and infestations - Other, specify

Urinary tract pain

Flu like symptoms

Fracture

Flatulence

Mucositis oral

Chills

General disorders and administration site conditions - Other, specify

Ejection fraction decreased

Oral dysesthesia

Peripheral sensory neuropathy

Creatinine increased

Upper respiratory infection

Vaginal infection

Stomach pain

Bruising

Fall

Joint range of motion decreased

Musculoskeletal and connective tissue disorder - Other, specify

Arthralgia

Vaginal discharge

Vaginal hemorrhage

Wheezing

Anxiety

Insomnia

Cholecystitis

100%

80%

60%

40%

20%

Study treatment Arm

Treatment (Neratinib)

Trial Design

6Treatment groups

Experimental Treatment

Group I: Pancreatic CancerExperimental Treatment2 Interventions

RAS-mutated pancreatic cancer at RP2D

Group II: Other CancerExperimental Treatment2 Interventions

"Other Cancer" (RAS-mutated) at RP2D

Group III: Ocular Melanoma (OM)Experimental Treatment2 Interventions

Phase II dose expansion at RP2D

Group IV: Neratinib + Divalproex Sodium - Dose Escalation CohortExperimental Treatment2 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 Treatment2 Interventions

Glioblastoma with a RAS-mutation or EGFR alteration at RP2D

Group VI: ColonExperimental Treatment2 Interventions

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

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Neratinib

2014

Completed Phase 2

~1970

Divalproex Sodium

2006

Completed Phase 4

~560

0 / 15Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Tyrosine kinase inhibitors (TKIs) and histone deacetylase (HDAC) inhibitors are common treatments for solid tumors. TKIs, such as Neratinib, block the enzyme tyrosine kinase, which is crucial for cell division and survival signaling pathways, thereby inhibiting cancer cell growth and spread. HDAC inhibitors, like Sodium Valproate, modify histones to alter gene expression, leading to the reactivation of tumor suppressor genes and induction of cancer cell death. These targeted therapies are significant for solid tumor patients as they specifically address dysregulated pathways in cancer cells, potentially offering more effective and less toxic treatment options compared to traditional chemotherapy.

Breast Cancer Resistance to Cyclin-Dependent Kinases 4/6 Inhibitors: Intricacy of the Molecular Mechanisms.