Symptoms and General Pathology

All Conditions

Neoplasms

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Recurrence

Lymphoma, Large B-Cell, Diffuse

Lymphoma

Lymphoma, B-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Lymphosarcoma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Everolimus

Tin Fluorides

Panobinostat

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Immunosuppressive Agents

Immunologic Factors

Histone Deacetylase Inhibitors

Part 1a: Sequential single agent therapy with RAD001 and LBH589. Each agent will be given for four-six 28-day cycles.

Subjects with less than a CR after 4 cycles of study drug should proceed to the next study drug(s) after the prescribed washout period.

Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease.

There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest.

Part 1b: Sequential single agent therapy with LBH589 and RAD001 . Each agent will be given for four-six 28-day cycles.

Subjects with less than a CR after 4 cycles of study drug should proceed to the next study drug(s) after the prescribed washout period.

Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease.

There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest.

Subjects will receive the doublet of RAD001 and LBH589 given in two to thirteen, 28-day cycles. Subjects will be evaluated for the disease status after completion of cycle two and then after every 4 cycles. Subjects with progressive disease will stop after 2 cycles. Subjects with stable disease or better may receive up to 13 cycles. LBH589 will start at 15mg po three days a week at least 2 days apart such as on days M/W/F or T/Th/Sat and RAD001 will start at 7.5mg po daily.

RAD001

40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial

LBH589

RAD001 7.5 mg by mouth daily and LBH589 15 mg by mouth on Monday/Wednesday/Friday during Part 2.

Doublet (RAD001 and LBH589)

Anne W. Beaven, MD

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.

Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

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

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.

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.

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.

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.

Novartis

Anne Beaven, MD

Assistant Professor of Medicine

Part 1a: Sequential single agent therapy with RAD001 and LBH589. Each agent will be given for four-six 28-day cycles.

Subjects with less than a CR after 4 cycles of study drug should proceed to the next study drug(s) after the prescribed washout period.

Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease.

There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest.

RAD001: 10 mg/day for Part 1 of the trial

LBH589: 40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial

Arm 1a (RAD001 Followed by LBH589)

Part 1b: Sequential single agent therapy with LBH589 and RAD001 . Each agent will be given for four-six 28-day cycles.

Subjects with less than a CR after 4 cycles of study drug should proceed to the next study drug(s) after the prescribed washout period.

Subjects with a CR may receive up to 6 cycles of study drug and will not receive the next study drug(s) until there is evidence of progressive disease.

There will be a 1-6 week 'washout' period between stopping and starting each agent in Part 1, unless rapid progression suggests holding therapy would not be in the patient's best interest.

RAD001: 10 mg/day for Part 1 of the trial

LBH589: 40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial

Arm 1b (LBH589 Followed by RAD001)

Subjects will receive the doublet of RAD001 and LBH589 given in two to thirteen, 28-day cycles. Subjects will be evaluated for the disease status after completion of cycle two and then after every 4 cycles. Subjects with progressive disease will stop after 2 cycles. Subjects with stable disease or better may receive up to 13 cycles. LBH589 will start at 15mg po three days a week at least 2 days apart such as on days M/W/F or T/Th/Sat and RAD001 will start at 7.5mg po daily.

Doublet (RAD001 and LBH589): RAD001 7.5 mg by mouth daily and LBH589 15 mg by mouth on Monday/Wednesday/Friday during Part 2.

Doublet (Combination RAD001 and LBH589)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

Patients have to be on each drug for at least 2 cycles to be evaluable for response.

Overall Response Rate

The number of responses to treatment were so few that we did not think we could get enough meaningful data for analysis. Therefore, molecular analysis was not performed and no results are available.

Assessment of Association Between Observed Response to RAD001 and LBH589 and the Response Predicted by Molecular Signatures Developed in Our Pre-clinical Model

Blood and lymphatic AEs

Gastrointestinal AEs

General Disorder AEs

Investigation (Lab) AEs

Metabolism and Nutrition AEs

Musculoskeletal and Connective Tissue AEs

Nervous System AEs

Renal and Urinary AEs

Reproductive System AEs

Respiratory, thoracic and mediastinal AEs

Skin and Subcutaneous Tissue AEs

Vascular AEs

Participants who consented to the study and took study drug were analyzed for this outcome measure. Total number of events per CTCAE v4 category per arm are reported if more than one event occurred.

Summary of Adverse Events (AEs)

The number of responses to treatment were so few that we did not think we could get enough meaningful data for analysis. Therefore, serum marker analysis was not performed and no results are available.

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.

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.

Spots Global Cancer Trial Database for doublet (rad001 and lbh589)