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

NCT03919292 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: MCC-17-13821
• Study Type: interventional
• Target: 83
• Locations: 1 country
• Sites: 1

Brief 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 GBM, and ocular melanoma, as part of the phase 2 expansion cohort.

Conditions

Solid Tumor, Adult

Keywords

Colon Cancer; Pancreatic Cancer; Other solid tumor; Advanced solid tumor; Tumor progression

Outcome Measures

Primary Outcomes (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).

  28 Days

Secondary Outcomes (4)

• Evaluation of Treatment Related Adverse Events of Neratinib combined with Sodium Valproate

  13 Months

• Solid Tumor Antitumor Effects

  13 Months

• Glioblastoma Antitumor Effects

  13 Months

• Progression Free Survival (PFS)

  13 Months

Study Arms (6)

Neratinib + Divalproex Sodium - Dose Escalation Cohort

EXPERIMENTAL

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

Drug: Neratinib; Drug: Divalproex Sodium

Colon

EXPERIMENTAL

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

Drug: Neratinib; Drug: Divalproex Sodium

Glioblastoma (GBM)

EXPERIMENTAL

Glioblastoma with a RAS-mutation or EGFR alteration at RP2D

Drug: Neratinib; Drug: Divalproex Sodium

Ocular Melanoma (OM)

EXPERIMENTAL

Phase II dose expansion at RP2D

Drug: Neratinib; Drug: Divalproex Sodium

Other Cancer

EXPERIMENTAL

"Other Cancer" (RAS-mutated) at RP2D

Drug: Neratinib; Drug: Divalproex Sodium

Pancreatic Cancer

EXPERIMENTAL

RAS-mutated pancreatic cancer at RP2D

Drug: Neratinib; Drug: Divalproex Sodium

Interventions

Neratinib DRUG

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.

Also known as: Nerlynx

Colon; Glioblastoma (GBM); Neratinib + Divalproex Sodium - Dose Escalation Cohort; Ocular Melanoma (OM); Other Cancer; Pancreatic Cancer

Divalproex Sodium DRUG

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

Also known as: Depakote, Valproate

Colon; Glioblastoma (GBM); Neratinib + Divalproex Sodium - Dose Escalation Cohort; Ocular Melanoma (OM); Other Cancer; Pancreatic Cancer

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Virginia Commonwealth University: lead
• Puma Biotechnology, Inc.: collaborator

Study Sites (1)

Virginia Commonwealth University Massey Cancer Center

Richmond, Virginia, 23298, United States

RECRUITING

Related Publications (1)

• 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.

  PMID: 34482636 DERIVED

MeSH Terms

Conditions

Colonic Neoplasms; Pancreatic Neoplasms; Disease Progression

Interventions

neratinib; Valproic Acid

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Study Officials

• Andrew Poklepovic, MD

  Massey Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Massey IIT Research Operations

CONTACT

804-628-6430; masseysiit@vcu.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 10, 2019
• First Posted: April 18, 2019
• Study Start: May 1, 2019
• Primary Completion (Estimated): December 31, 2029
• Study Completion (Estimated): January 31, 2031
• Last Updated: April 21, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)