OBJECTIVES:
I. To determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of RAD001 and once daily PTK787 when given in combination. (Cohort IA) II. To describe the toxicities associated with the combination of RAD001 and once daily PTK787. (Cohort IA) III. To evaluate the therapeutic antitumor activity of the combination of once daily PTK787 with RAD001. (Cohort IA) IV. To determine the dose limiting toxicity (DLT) and maximally tolerated dose (MTD) of RAD001 and twice daily PTK787 when given in combination. (Cohort IB) V. To describe the toxicities associated with the combination of RAD001 and twice daily PTK787. (Cohort IB) VI. To evaluate the therapeutic antitumor activity of the combination of twice daily PTK787 with RAD001. (Cohort IB) VII. To determine the MTD-Recommended Phase 2 Dose (RP2D) based on the MTD for Cohorts IA and IB. (Cohorts IA \& IB) VIII. To investigate the biological activity of the combination of PTK787 with RAD001 at the MTD-RP2D. (Cohort II) IX. To evaluate the therapeutic antitumor activity of the combination of PTK787 with RAD001 at the MTD-RP2D. (Cohort II) X. To evaluate pharmacogenetic, metabolic and clinical markers that may predict for hypertension induced by anti-VEGF therapy. (Cohort II) XI. To obtain pilot data on efficacy outcomes in patients with metastatic kidney cancer, neuroendocrine cancer, NSCLC or melanoma. (Cohort II)
OUTLINE:
Patients are assigned to 1 of 4 cohorts, according to their disease (cohort IA, IB, or IIA \[any histopathologic diagnosis\] vs cohort IIB \[metastatic kidney cancer, neuroendocrine cancer, melanoma, or non-small cell lung cancer). Patients are initially enrolled into cohorts IA and IB until the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) are determined. Once the MTD/RP2D of everolimus and vatalanib are determined, subsequent patients are enrolled and treated in expansion cohorts IIA or IIB.
Cohorts 1A or 1B (dose escalation cohorts; closed to enrollment as of 12/6/06): Patients receive oral vatalanib once (cohort 1A) or twice (cohort 1B) daily on days 1-28 and oral everolimus once daily on days 15-28 of course 1. For all subsequent courses, patients receive oral vatalanib once (cohort 1A) or twice (cohort 1B) daily and oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohort IIA (expansion cohort treated at the MTD/RP2D): Patients receive oral everolimus once daily for 14 days followed by a 7-day rest period. Patients then receive oral vatalanib twice daily on days 1-28 and oral everolimus once daily on days 15-28 of course 1. For all subsequent courses, patients receive oral vatalanib twice daily and oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Cohort IIB (expansion cohort treated at the MTD/RP2D): Patients receive oral vatalanib twice daily on days 1-28 and oral everolimus once daily on days 15-28 of course 1. For all subsequent courses, patients receive oral vatalanib twice daily and oral everolimus once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed at 3 months.
