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Neratinib and Divalproex Sodium in Treating Patients with Advanced Solid Tumors or RAS-Mutated Cancers

Trial Status: Active

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 body (advanced) or advanced cancers that have a genetic mutation in the RAS gene. Neratinib and divalproex sodium may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Inclusion Criteria

  • Tumor Characteristics: * 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 approved therapies or for which there is no standard effective therapy available: ** Colon cancer ** Pancreatic cancer ** Other solid tumor
  • Measurable or evaluable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Absolute neutrophil count (ANC) >= 1500/mm^3
  • Platelets >= 100,000/mm^3
  • Hemoglobin > 9 g/dL (untransfused)
  • Creatinine =< 1.5 x upper limit of normal (ULN) for the laboratory or calculated or actual creatinine clearance >= 60 mL/min
  • 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
  • Left ventricular ejection fraction (LVEF) within 3 months prior to initiation of study treatment indicates an LVEF of >= 50%
  • 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
  • A 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

Exclusion Criteria

  • 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 medication other than sodium valproate
  • 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
  • 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 Food and Drug Administration (FDA) website: ** 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


Virginia Commonwealth University / Massey Cancer Center
Status: ACTIVE
Contact: Andrew Poklepovic
Phone: 804-628-2321


I. To determine the recommended phase 2 dose (RP2D) of the combination of neratinib maleate (neratinib) and divalproex sodium (sodium valproate) when given to patients with advanced solid tumors.


I. To evaluate the safety and toxicity of the neratinib and sodium valproate combination.

II. To explore the antitumor effects of the neratinib and sodium valproate combination, with attention to RAS-mutated tumors as part of an expansion cohort.

III. To evaluate progression-free survival (PFS) in patients with >= stable disease (SD) receiving the neratinib and sodium valproate combination.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive neratinib orally (PO) once daily (QD) and divalproex sodium PO twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days. Patients who complete treatment with SD, partial response, or complete response are then followed every 2 months.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
Virginia Commonwealth University / Massey Cancer Center

Principal Investigator
Andrew Poklepovic

  • Primary ID MCC-17-13821
  • Secondary IDs NCI-2019-02675
  • ID NCT03919292