Neratinib + Valproate In Advanced Solid Tumors, W/Expansion Cohort In Ras-Mutated Ca

Study Overview

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

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.

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.

Solid Tumor, Adult

DRUG: Neratinib
DRUG: Divalproex Sodium

MCC-17-13821

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2019-04-10	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2025-04-15
First Submitted that Met QC Criteria 2019-04-15	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2025-04-16
First Posted (ACTUAL) 2019-04-18	Results First Posted N/A	Last Verified 2025-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Non Randomized

Interventional Model:
Sequential

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Neratinib + Divalproex Sodium - Dose Escalation Cohort Neratinib by mouth (PO) once daily + Divalproex Sodium (Valproate) by mouth (PO) twice daily on days 1-28 of each course.	DRUG: Neratinib 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 expans DRUG: Divalproex Sodium Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).
EXPERIMENTAL: Colon Colon Cancer (RAS-mutated) - Phase II dose expansion at recommended phase II dose (RP2D)	DRUG: Neratinib 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 expans DRUG: Divalproex Sodium Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).
EXPERIMENTAL: Glioblastoma (GBM) Glioblastoma with a RAS-mutation or EGFR alteration at RP2D	DRUG: Neratinib 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 expans DRUG: Divalproex Sodium Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).
EXPERIMENTAL: Ocular Melanoma (OM) Phase II dose expansion at RP2D	DRUG: Neratinib 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 expans DRUG: Divalproex Sodium Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).
EXPERIMENTAL: Other Cancer "Other Cancer" (RAS-mutated) at RP2D	DRUG: Neratinib 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 expans DRUG: Divalproex Sodium Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).
EXPERIMENTAL: Pancreatic Cancer RAS-mutated pancreatic cancer at RP2D	DRUG: Neratinib 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 expans DRUG: Divalproex Sodium Combination of Neratinib and Divalproex Sodium (Valproate) will be given to patients with advanced solid tumors (dose escalation) and Ras-mutated cancers (dose expansion).

Primary Outcome Measures	Measure Description	Time Frame
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).	28 Days

Secondary Outcome Measures	Measure Description	Time Frame
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.	13 Months
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.	13 Months
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	13 Months
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.	13 Months

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Name: Massey IIT Research Operations

Phone Number: 804-628-6430

Email: masseysiit@vcu.edu

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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
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

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
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Puma Biotechnology, Inc.

Investigators

PRINCIPAL_INVESTIGATOR: Andrew Poklepovic, MD, Massey Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General 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.

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Clinical Trial Record