Safety/Tolerability Study of AV-412 in Subjects With Refractory or Relapsed Solid Tumor Malignancies

Criteria for Inclusion:

1. ≥ 18 year old males or females
2. Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic
3. Patients entered to MTD Cohort B must have:

• Histologically or cytologically confirmed NSCLC
• No prior therapy with erlotinib, gefitinib, or any other EGFR-kinase inhibitor
• Previously documented exon 19 deletion and/or exon 21 L858R mutations
• Measurable disease according to RECIST

1. Disease that is currently refractory to, or not amenable to, standard therapy
2. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor
3. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months
4. No childbearing potential or use of effective contraception by all fertile male and female patients, during the study and for 3 months after the last dose of study drug
5. Ability to give written informed consent

Criteria for Exclusion:

1. Pregnant or lactating women
2. Primary CNS malignancies; active CNS metastases
3. Hematologic malignancies (includes: leukemia, any form; lymphoma; and multiple myeloma)
4. Active second malignancy or history of another malignancy within 2 years with the exception of:

• Treated, non-melanoma skin cancers
• Treated CIS of the breast or cervix
• Controlled, superficial bladder carcinoma
• T1a or b prostate carcinoma involving < 5% of resected tissue and PSA within normal limits (WNL)

1. Any of the following hematologic abnormalities:

• Hemoglobin ≤ 9.0 g/dL
• ANC < 1,500 per mm3
• Platelet count < 100,000 per mm3

1. Any of the following serum chemistry abnormalities:

• Total bilirubin > 1.5 × the ULN
• AST or ALT ≥ 3 × the ULN (≥ 5 × if due to hepatic involvement by tumor)
• Serum albumin < 2.5 g/dL
• Creatinine ≥ 1.5 × ULN (or calculated CLCR < 50 mL/min/1.73 m2)

1. Significant cardiovascular disease, including:

• CHF requiring therapy
• Ventricular arrhythmia requiring therapy
• Any conduction disturbance (including patients with QTc interval prolongation > 0.47 sec, history of a severe arrhythmia, or history of a familial arrhythmia [eg, WPW])
• Angina pectoris requiring therapy
• LVEF < 50% by MUGA or Echocardiogram
• Uncontrolled HTN
• MI within 6 months of study entry
• NYHA > Class I

1. Significant gastrointestinal abnormalities, including:

• Requirement for IV alimentation
• Prior surgical procedures affecting absorption
• Active peptic ulcer disease
• ≥Grade 2 diarrhea due to any etiology

1. Known history of significant ophthalmologic abnormalities, including:

• Severe dry-eye syndrome
• Keratoconjunctivitis sicca
• Sjogren's syndrome
• Severe exposure keratopathy
• Disorders increasing risk for epithelium-related complications

1. Serious/active infection; infection requiring parenteral antibiotics
2. Inadequate recovery from prior antineoplastic therapy
3. Inadequate recovery from any prior surgical procedure; major surgical procedure within 2 weeks
4. Life-threatening illness or organ system dysfunction compromising safety evaluation
5. Psychiatric disorder, altered mental status precluding informed consent or necessary testing
6. Inability to comply with protocol requirements