The purpose of this study is: 1. To determine the optimal recommended phase II dose of two investigational study drugs, LBH589 and RAD001, given in combination in all solid tumors (With enrichment for EBV-Driven tumors). 2. To determine the pharmacokinetic profile of RAD001 in combination with two schedules of LBH589. 3. To assess the preliminary anti-tumor activity of RAD001 and LBH589. This study will also be exploring the hypothesis that HDACi and mTOR inhibitors abrogate the effects of key viral proteins, and switch the virus from a latent proliferative phase to a lytic phase. Immunologic correlates will also be examined to ascertain T-cell subpopulations and expression of HLA class molecules. DCE-MRI will be subsequently employed in dose expansion to examine antiangiogenic effects.
Dose escalation phase 1B of the study will evaluate the safety and tolerability of RAD001 in combination with LBH589 in all solid tumors, lymphomas; and enriched for EBV driven tumors. The phase 2 component will be a single arm, non-randomized study restricted to nasopharyngeal carinoma only (endemic type). A "3+3" dose escalation design will be adopted. Patients will start taking LBH589 three times a week and will have a run in period of one week, followed by continous administration of RAD001 from week 2. Pharmacokinetic assessments will be done on day 1 of LBH589 administration and day 1 of concurrent administration of LBH589 + RAD001. ON day 31, there will be a one week drug holiday. This is done to explore the eliminaition kinetics from steady state,as well as the durability of target modulation. AEs of patients will be monitored closely. In the event of grade 3/4 toxicity, the cohort will be expanded to 6. Dose escalation of LBH589/RAD001 may proceed until the maximum tolerated dose (MTD)is reached. Once the MTD is established, an expasion cohort comprising 20 EBV driven tumors will open at two different LBH589 dose schedules. Treatment will be continued until progression of disease, unacceptable toxcity, or discontinuation criterion is met.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
OTHER
Masking
NONE
Enrollment
49
Dose escalation of LBH589 tablets (5 and 10 mg) and RAD001 tablets (2.5, 5 mg and 10mg)
National Cancer Center Singapore
Singapore, Singapore
Safety and tolerability
Patients will be followed closely for toxicities in the first cycle where they would have weekly consultations visit. After the first cycle, consultation visits will be once every 2 weeks or once a month depending on how well the patient is tolerating the treatment. The following safety assesments will be done on every visit; Vital signs and physical examination Haematology and blood chemistry Cardiac monitoring EBV DNA titre (for patients with EBV Driven tumors recording of adverse events and serious adverse events.
Time frame: Weekly evaluation for the first 5 weeks (DLT period), and continued follow up until patients come off trial due to toxicity or progressive disease
Tumor response
Tumor response will be evaluated at the end of every 8-weeks of treatment. Treatment will continue until one of the following occur; disease progression, unacceptable toxicity, death, or withdrawal from study. Best response (according to RECIST), as well as progression free survival will be reported.
Time frame: Every 2 months until disease progression or withdrawal from study - average of 6 - 12 months
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