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Solid Tumor, AdultPhase 1/2NCT03919292

Neratinib + Valproate in Advanced Solid Tumors, w/Expansion Cohort in Ras-Mutated Ca

A Phase 1/2 study testing Neratinib and Divalproex Sodium in people with Solid Tumor, Adult, run by Virginia Commonwealth University at 1 site in United States.

Suspended

Paused. Enrolment is on hold for now and may resume.

Official record
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Trial summary

To determine the recommended phase 2 dose (RP2D) of the combination of neratinib and sodium valproate when given to patients with advanced solid tumors. Then to explore the antitumor effects of the neratinib and sodium valproate combination in advanced solid tumors with attention to RAS-mutated tumors, EGFR-altered… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Solid Tumor, Adult
What is being tested?
Neratinib and Divalproex Sodium
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
80 participants
Where
1 siteUnited States
Study dates
1 May 2019to 31 Jan 2031
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Phase 1 - Dose Escalation Phase: Advanced solid tumor that has progressed during or after treatment with approved therapies or for which there is no standard effective therapy available
  • Phase 2 - Dose Expansion Phase: One of the following advanced solid tumors that is RAS-mutated and has progressed during or after treatment with at least one approved therapy or for which there is no standard effective therapy available: :
  • Colon Cancer with a RAS mutation
  • Pancreatic Cancer with a RAS mutation
  • Other Solid Tumor with RAS Mutation
  • Ocular melanoma, which includes melanoma that develops in the sclera, retina, uvea (iris, choroid layer, and ciliary layer), or conjunctiva or other cancers with a GNAQ or GNA11 mutation
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  • Measurable disease by RECIST v1.1
  • 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

Who cannot join

  • Current or prior known meningeal metastases Known brain metastases that are symptomatic or untreated Note: Patients with known brain metastases who are asymptomatic and have had post-treatment imaging that indicates stable brain disease are eligible. Note that brain imaging in patients with known brain metastases is required within 8 weeks prior to initiation of study therapy.
  • Any investigational agent within 4 weeks prior to initiating study treatment
  • Previous therapy with neratinib
  • Active uncontrolled diarrhea leading to dehydration or electrolyte disturbances not easily controlled with oral repletion
  • Inability to swallow medication
  • Known or suspected malabsorption condition or obstruction. Note: Use of pancreatic enzyme supplements is allowed to control malabsorption
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  • Inability to shift medications as follows: Antacids (eg, calcium carbonate): dose at least 3 hours after dosing with neratinib. H2 receptor antagonists: dose must be taken at least 2 hours after or 10 hours before dosing with neratinib
  • Resting systolic blood pressure (BP) < 100 mmHg
  • 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

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Virginia Commonwealth University Massey Cancer Center

    Richmond, Virginia, 23298

Other trials in United States

About this study

Official title: Phase 1/2 Study of Neratinib and Divalproex Sodium (Valproate) in Advanced Solid Tumors, With an Expansion Cohort in Ras-Mutated Cancers

To determine the recommended phase 2 dose (RP2D) of the combination of neratinib and sodium valproate when given to patients with advanced solid tumors. Then to explore the antitumor effects of the neratinib and sodium valproate combination in advanced solid tumors with attention to RAS-mutated tumors, EGFR-altered GBM, and ocular melanoma, as part of the phase 2 expansion cohort.

Read the detailed description

The purpose of this trial is to test the safety of combining 2 drugs, neratinib (Nerlynx) and divalproex sodium (Depakote DR), also commonly called valproate, when treating patients with advanced cancer.

In an earlier stage of this trial the purpose was to test different doses of neratinib in combination with divalproex sodium to see which doses should be used in future research trials. This trial will also help us to learn how advanced tumors respond to the combination of neratinib and divalproex sodium.

Being tested
Neratinib, Divalproex Sodium
Keywords
Colon Cancer, Pancreatic Cancer, Other solid tumor, Advanced solid tumor, Tumor progression
Medical subject headings
Colonic Neoplasms, Pancreatic Neoplasms, Disease Progression

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NeratinibDrug

    Also called Nerlynx

    Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion). Doses of Neratinib are escalated in small groups of patients during the dose expansion portion of the study.

  • Divalproex SodiumDrug

    Also called Depakote, Valproate

    Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).

Study groups in NCT03919292
Study groupRoleWhat they receive
Neratinib + Divalproex Sodium - Dose Escalation CohortExperimentalNeratinib by mouth (PO) once daily + Divalproex Sodium (Valproate) by mouth (PO) twice daily on days 1-28 of each course.
Receives: Drug: Neratinib; Drug: Divalproex Sodium
ColonExperimentalColon Cancer (RAS-mutated) - Phase II dose expansion at recommended phase II dose (RP2D)
Receives: Drug: Neratinib; Drug: Divalproex Sodium
Glioblastoma (GBM)ExperimentalGlioblastoma with a RAS-mutation or EGFR alteration at RP2D
Receives: Drug: Neratinib; Drug: Divalproex Sodium
Ocular Melanoma (OM)ExperimentalPhase II dose expansion at RP2D
Receives: Drug: Neratinib; Drug: Divalproex Sodium
Other CancerExperimental"Other Cancer" (RAS-mutated) at RP2D
Receives: Drug: Neratinib; Drug: Divalproex Sodium
Pancreatic CancerExperimentalRAS-mutated pancreatic cancer at RP2D
Receives: Drug: Neratinib; Drug: Divalproex Sodium

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Determination of Recommended Phase 2 Dose (RP2D)

    RP2D for the combination of neratinib and sodium valproate that is less than or the same as the maximum tolerated dose (MTD).

    Measured: 28 Days

Secondary outcomes (4)

  1. Evaluation of Treatment Related Adverse Events of Neratinib combined with Sodium Valproate

    Determine the safety and toxicity of the combination of neratinib and sodium valproate by the number of participants with serious adverse events, and types of events as assessed by utilizing the Common Terminology Criteria for Adverse Events (CTCAE) Version 5.

    Measured: 13 Months

  2. Solid Tumor Antitumor Effects

    Phase 2 advanced solid tumor cohorts only: Evaluate number of participants with tumor response based on Response Evaluation Criteria in Solid Tumors (RECIST v1.1), in patients evaluable for response.

    Measured: 13 Months

  3. Glioblastoma Antitumor Effects

    Phase 2 GBM cohort only: Evaluate number of participants with tumor control based on objective response based on Response Assessment in Neuro-Oncology (RANO) criteria or Macdonald criteria, or disease control defined as PFS ≥ 6-month in patients evaluable for response

    Measured: 13 Months

  4. Progression Free Survival (PFS)

    Evaluate the number of participants with progression free survival (PFS) defined as the duration of time from start of combination treatment (Cycle 1, Day 1) to date of progression.

    Measured: 13 Months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Apr 2019
  2. Study start1 May 2019
  3. Primary completion31 Dec 2029 (estimated)
  4. Study completion31 Jan 2031 (estimated)

Why it stopped: Pending amendment approval

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
80 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03919292
Sponsor's protocol ID
MCC-17-13821
Status last verified
Oct 2026
First submitted
10 Apr 2019
Last updated
21 Oct 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No: There is no plan to make individual participant data available to other researchers at this time.

Publications

  • Dent P, Booth L, Poklepovic A, Kirkwood JM. Neratinib kills B-RAF V600E melanoma via ROS-dependent autophagosome formation and death receptor signaling. Pigment Cell Melanoma Res. 2022 Jan;35(1):66-77. doi: 10.1111/pcmr.13014. Epub 2021 Sep 4.

    PubMed 34482636

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Neratinib and Divalproex Sodium in people with Solid Tumor, Adult, run by Virginia Commonwealth University at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 24 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: paused, as of the sponsor's last update on 21 Oct 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determination of Recommended Phase 2 Dose (RP2D) (time frame: 28 Days). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03919292, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Oct 2026.

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