The purpose of this study is evaluate the response, safety and tolerability in subjects receiving the investigational drugs, RAD001 and LBH589. Subjects in Part 1 will receive one drug for four cycles followed by 4 cycles of the second drug unless they achieve complete remission. Subjects in a complete remission may receive up to 6 cycles of study drug and will not receive the next study drug until there is evidence of disease progression. Subjects in Part 2 will receive both drugs together for at least 2 cycles and up to 13 if tolerated.
This will be a prospective, non-randomized, un-blinded phase 2 efficacy trial using a mechanistic target of rapamycin (mTOR) inhibitor and a histone deacetylase (HDAC) inhibitor for epigenetic targeted therapies. Subjects will receive RAD001 and LBH589 given in two to thirteen, 28-day cycles. Subjects will be assessed for disease status after 2 cycles and then after every 4 cycles. Subjects with progressive disease will stop after 2 cycles. Subjects with stable disease or better les may receive up to 13 cycles. LBH589 was given at 40mg when the study first opened and was changed to 20mg po shortly thereafter. LBH589 is taken on days M/W/F. RAD001 was given at 10mg po daily for Part 1. In Part 2, LBH589 is given at 15mg and RAD001 is given at 7.5mg. Treatment will be administered on an outpatient basis. Patients will be followed for up to 2 years after completion of therapy or until progression of disease or death.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Duke University Medical Center
Durham, North Carolina, United States
Overall Response Rate
Overall Response Rate is the number of participants with a partial and complete response assessed by the Updated Cheson criteria for lymphoma. A complete response is complete disappearance of all detectable clinical and radiographic evidence of disease and disappearance of all disease-related symptoms if present before therapy and normalization of those biochemical abnormalities. If a subject has residual lesions on CT scan and the disease was fluorodeoxyglucose (FDG) avid pre-treatment, then that subject will be considered to be in a complete response. Partial response is a greater than or equal to 50% decrease in the sum of the products of the greatest diameters of 6 largest dominant nodes or nodal masses. No increase in size of nodes, liver or spleen and no new sites of disease
Time frame: after 2 cycles of each study drug or after 2 cycles of doublet, up to 24 weeks
Assessment of Association Between Observed Response to RAD001 and LBH589 and the Response Predicted by Molecular Signatures Developed in Our Pre-clinical Model
We will estimate the association of the molecular signature-predicted response to the doublet (CR+PR) with the observed response. All evaluable patients will be used in estimating response. The chi-square test with one-sided alpha of 0.10 will be used to test for the association between predicted and observed responses. Contingency tables will be used to present these associations.
Time frame: From the start of combination therapy until a maximum of 2 years after completion of therapy
Summary of Adverse Events (AEs)
Counts of adverse events or treatment-emergent adverse events (TEAE, defined as newly occurring or worsening after first dose) experienced by patients on study drug(s). National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE version 3.0) is used to assess severity. Relatedness to study drug is assessed by the investigator.
Time frame: From the time of first dose of study drug until 4 weeks after participant has stopped study drug; up to 1 year
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Distribution of Change Across Time of mTOR and HDAC-I Inhibition From Baseline Until After the 1st 2 Cycles of Study Drug in Patients Who Received LBH and RAD.
Serum markers will be measured on the first day of cycle 1 and on the first day of cycle 3. The distribution of change across time in a marker will be summarized.
Time frame: after 2 cycles of study therapy; up to 8 weeks
Evaluate the Association of Observed Response to the Doublet With the Response Predicted by Molecular Signatures for Activated B Cell Like (ABC) DLBCL and for Germinal Center B Cell Like (GCB) DLBCL.
Response rates seen in subjects with activated B cell like DLBCL and for Germinal center B cell like DLBCL will be reported and assessed to see if GCB is associated with improved outcomes compared to ABC in subjects with relapsed disease who have received RAD + LBH. We will estimate the association of the ABC and GCB with the observed response. All evaluable patients will be used in estimating response. The chi-square test with one-sided alpha of 0.10 will be used to test for the association between predicted and observed responses. The number of responses to treatment were so few that we did not think we could get enough meaningful data for analysis.
Time frame: up to 13 cycles of therapy; approximately 1 year