Ensayo Clínico de Fase 1, de Cohortes Secuenciales con Escalada de Dosis para Determinar la Seguridad, Tolerabilidad y Dosis Máxima Tolerada de la Administración Oral Diaria de AV-412 en Pacientes con Tumores Sólidos Malignos Refractarios o en Recaída

Criterios de inclusión

• Criteria for Inclusion:
• ≥ 18 year old males or females
• Documented measurable or evaluable solid tumor malignancy that is relapsed, refractory, locally advanced, or metastatic
• 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
• Disease that is currently refractory to, or not amenable to, standard therapy
• Disease that is currently not amenable to surgical intervention, due to either medical contraindications or nonresectability of the tumor
• Karnofsky performance status ≥ 70%, life expectancy ≥ 3 months
• 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
• Ability to give written informed consent
• Criteria for Exclusion:
• Pregnant or lactating women
• Primary CNS malignancies; active CNS metastases
• Hematologic malignancies (includes: leukemia, any form; lymphoma; and multiple myeloma)
• 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)
• Any of the following hematologic abnormalities:
• Hemoglobin ≤ 9.0 g/dL
• ANC \< 1,500 per mm3
• Platelet count \< 100,000 per mm3
• 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)
• 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
• Significant gastrointestinal abnormalities, including:
• Requirement for IV alimentation
• Prior surgical procedures affecting absorption
• Active peptic ulcer disease
• ≥Grade 2 diarrhea due to any etiology
• 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
• Serious/active infection; infection requiring parenteral antibiotics
• Inadequate recovery from prior antineoplastic therapy
• Inadequate recovery from any prior surgical procedure; major surgical procedure within 2 weeks
• Life-threatening illness or organ system dysfunction compromising safety evaluation
• Psychiatric disorder, altered mental status precluding informed consent or necessary testing
• Inability to comply with protocol requirements