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

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: Advanced solid tumor: One of the following advanced solid tumors that 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 Response Evaluation Criteria in Solid Tumors version 1.1
• Age >= 18 years
• 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
• 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 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
• 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