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A Safety and Tolerability Study of RAD001 (mTOR Inhibitor) in Combination With Two Dosing Schedules of LBH589B (Histone Deacetylase Inhibitor) in Solid Tumors/ Lymphomas With Enrichment for EBV-Driven Tumors

Phase 1
21 Years
Open (Enrolling)
Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid Tumour

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Trial Information

A Safety and Tolerability Study of RAD001 (mTOR Inhibitor) in Combination With Two Dosing Schedules of LBH589B (Histone Deacetylase Inhibitor) in Solid Tumors/ Lymphomas With Enrichment for EBV-Driven Tumors

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.

Inclusion 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 ≤

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:

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.

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label

Outcome Measure:

Safety and tolerability

Outcome Description:

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.

Outcome 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

Safety Issue:


Principal Investigator

Daniel Tan Shao Weng

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Center Singapore


Singapore: Centralised Institutional Review Board B

Study ID:




Start Date:

January 2011

Completion Date:

June 2013

Related Keywords:

  • Nasopharyngeal Carcinoma, Lymphomas, Any EBV+ Solid Tumour
  • Nasopharyngeal carcinoma, antiangiogenesis, HDACi, mTOR, Phase Ib
  • Carcinoma
  • Lymphoma
  • Neoplasms
  • Nasopharyngeal Neoplasms