Safety and Tolerability Study of RAD001 and LBH589 in All Solid Tumors With Enrichment for EBV Driven Tumors

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.

Eligibility Criteria:
Inclusion criteria

1. Patients with histologically or cytologically confirmed solid malignancy or lymphoma that is metastatic or unresectable, and for which standard curative or palliative measures do not exist or are no longer effective.

   For enrichment and dose expansion phase only:

   Only patients with EBV-related tumors, including all nasopharyngeal carcinoma, as well as tumors known to be EBV-related which include (but are not limited to) gastric carcinoma (10-15%), lymphoma. These tumors (NPC excluded) should have:

   i)EBER in situ hybridisation on paraffin samples/ circulating tumor cells; or ii)Elevated pre-treatment serum EBV viral titres
2. Patients who have had prior treatment with mTOR inhibitors and HDAC inhibitors will be allowed ONLY in the dose escalation phase
3. Age ≥ 21 years old.
4. Performance status of ≤ 2 (ECOG scale).
5. Target lesion on spiral CT or MRI scan must have at least one diameter \> 1 cm (on conventional CT scan the indicator lesion must have at least one diameter \> 2 cm) (for dose expansion).
6. Adequate bone marrow reserve: absolute granulocyte count \> 1 x 109/L, hemoglobin \> 8 g/dL and platelet count \>100,000/dL.
7. Adequate hepatic function (serum total bilirubin level \< 1.5 x ULN; alanine transaminase (ALT) and aspartate transaminase (AST) less than 3 times ULN.
8. Adequate renal function (creatinine \< 1.5 times ULN).
9. Normal ECG at baseline - with no significant conduction abnormalities and a QTc ≤ 450.
10. Left Ventricular Ejection Fraction ≥ 50% as assessed by MUGA scan or echocardiography at screening.
11. No concurrent use of investigational antineoplastic therapy.
12. No medical problems severe enough to prevent compliance with the study requirements
13. Negative pregnancy test (urinary β-HCG) at screening (applicable to women of child bearing potential who are sexually active).
14. Subjects must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study.

Exclusion Criteria:

1. Known brain metastases (locally advanced NPC with direct extension to central nervous system is permissible).
2. Chemotherapy (in the case of nitrosoureas and mitomycin C within 6 weeks), radiotherapy, immunotherapy within 4 weeks before study drug administration.
3. Patients receiving chronic immunosuppressive treatment with high dose corticosteroids (tailing doses or low doses are acceptable) or another immunosuppressive agent;
4. Patients with uncontrolled diabetes (fasting glucose \> 2x ULN);
5. History of uncontrolled heart disease (unstable angina, congestive heart failure, myocardial infarction within preceding 12 months, clinically significant rhythm or conduction abnormality such as second and third degree heart block, congenital long QT syndrome, obligate use of a cardiac pacemaker. Patients with QTc at screening \> 450 ms.
6. Subjects taking medications known to have a risk of causing causing QTc prolongation and Torsades de Pointes (risk group 1 as indicated on webpage: http://www.torsades.org).
7. Patients who will need valproic acid for any medical condition during the study or within 5 days prior to the first panobinostat treatment.
8. Patients with impairment of GI function or GI disease that may significantly alter panobinostat absorption.
9. Patients with unresolved diarrhea of grade 2 and above.
10. Patients with a known history of Hepatitis B, C and HIV seropositivity.
11. Patients with an active bleeding diathesis;
12. Subjects with Grade ≥ 2 neuropathy at baseline.
13. For patients undergoing magnetic resonance imaging (MRI) studies (including DCE-MRI, BOLD-MRI and DWI-MRI) in the expansion cohort:

    1. Contraindications to MRI, e.g. contraindicated metal implants
    2. Patients with poor antecubital fossa venous access.