This study is a single-arm, open-label, phase 1/2 trial to determine the recommended phase 2
dose of neratinib and sodium valproate when given in combination to patients with advanced
solid tumors in 28 day cycles. The phase II portion of the study will evaluate the
combination at the RP2D in 3 cohorts of RAS mutated tumors, KRAS mutant colorectal cancer,
KRAS mutant pancreatic cancer, and K or N RAS mutant solid tumors.
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 approved therapies or
for which there is no standard effective therapy available: :
- Colon Cancer
- Pancreatic Cancer
- Other Solid Tumor
- Measurable or evaluable 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
- 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
- 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
(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/DrugInteracti
onsLabeling/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
