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

Inclusion Criteria

• •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
• •4. Disease that is currently refractory to, or not amenable to, standard therapy
• •5. Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor
• •6. Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months
• •7. 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
• •8. 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)
• •5. Any of the following hematologic abnormalities:
• •* Hemoglobin ≤ 9.0 g/dL
• •* ANC \< 1,500 per mm3
• •* Platelet count \< 100,000 per mm3
• •6. 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)
• •7. 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
• •8. Significant gastrointestinal abnormalities, including:
• •* Requirement for IV alimentation
• •* Prior surgical procedures affecting absorption
• •* Active peptic ulcer disease
• •* ≥Grade 2 diarrhea due to any etiology
• •9. 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
• •10. Serious/active infection; infection requiring parenteral antibiotics
• •11. Inadequate recovery from prior antineoplastic therapy
• •12. Inadequate recovery from any prior surgical procedure; major surgical procedure within 2 weeks
• •13. Life-threatening illness or organ system dysfunction compromising safety evaluation
• •14. Psychiatric disorder, altered mental status precluding informed consent or necessary testing
• •15. Inability to comply with protocol requirements