Inclusion Criteria:
* 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
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 (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
