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

• Sponsor: Anne Beaven, MD (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00978432
• Collaborator: Novartis (Industry)
• Enrollment: 50
• Location: 1
• Arms: 3
• Duration (Months): 49
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Diffuse Large B-cell Lymphoma	Drug: RAD001; Drug: LBH589; Drug: Doublet (RAD001 and LBH589)	Phase 2

Detailed Description

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 Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Apr 1, 2015
• Actual Study Completion Date: Mar 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1a (RAD001 followed by LBH589) 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.	Drug: RAD001; 10 mg/day for Part 1 of the trial; Other Names: Everolimus ; Drug: LBH589; 40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial; Other Names: panobinostat
Experimental: Arm 1b (LBH589 followed by RAD001) 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.	Drug: RAD001; 10 mg/day for Part 1 of the trial; Other Names: Everolimus ; Drug: LBH589; 40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial; Other Names: panobinostat
Experimental: Doublet (Combination RAD001 and LBH589) 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.	Drug: Doublet (RAD001 and LBH589); RAD001 7.5 mg by mouth daily and LBH589 15 mg by mouth on Monday/Wednesday/Friday during Part 2.

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate [after 2 cycles of each study drug or after 2 cycles of doublet, up to 24 weeks]

   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

2. Assessment of Association Between Observed Response to RAD001 and LBH589 and the Response Predicted by Molecular Signatures Developed in Our Pre-clinical Model [From the start of combination therapy until a maximum of 2 years after completion of therapy]

   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.

Secondary Outcome Measures

1. Summary of Adverse Events (AEs) [From the time of first dose of study drug until 4 weeks after participant has stopped study drug; up to 1 year]

   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.

2. 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. [after 2 cycles of study therapy; up to 8 weeks]

   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.

3. 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. [up to 13 cycles of therapy; approximately 1 year]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. de novo or transformed Diffuse large B cell non-Hodgkin lymphoma (DLBCL). DLBCL-like lymphomas allowed:

• Epstei-Barr virus (EBV)+ DLBCL in elderly,

• DLBCL with chronic inflammation,

• Primary cutaneous DLBCL, leg type,

• B cell lymphoma unclassifiable - between DLBCL and Burkitt lymphoma,

• B cell lymphoma unclassifiable - between large B cell lymphoma and classical Hodgkin lymphoma,

• Anaplastic lymphoma kinase (ALK)+ large B cell lymphoma,

• T cell histiocyte rich large B cell lymphoma

• Primary mediastinal B cell lymphoma

• Follicular grade 3 B cell lymphoma

1. Refractory or relapsed disease to >/= 1 prior treatment regimen: should include autologous stem cell transplant unless patient refused or ineligible.

2. Age > 18 years old

3. Eastern Cooperative Oncology Group (ECOG) performance status <2.

4. Measurable or evaluable disease by physical exam, radiographs or bone marrow involvement

5. Frozen tumor or paraffin-embedded sample available.

6. 3-4 core fresh/fresh-frozen biopsy specimens available. Leukapheresis may be done for patients with leukocytosis.

7. Laboratory Values per protocol.

Exclusion Criteria:

1. Laboratory Values

• Grade 3 hyperlipidemia (Serum cholesterol >400mg/dl or serum triglycerides >5 x ULN)

• Serum Glucose > 250mg/dl on >/= 2 checks on 2 separate days

• Diabetics accepted if sugars controlled

1. Unlimited prior chemotherapy regimens, however:

• No prior exposure to RAD001 or LBH589 or drugs that target mTOR (sirolimus, temsirolimus, etc) or HDAC (vorinostat)

• No valproic acid during study or 5 days preceding start of first drug

• No chemotherapy, biologics or immunotherapy < 2 weeks before registration (6 weeks if last received bis-chloroethylnitrosourea (BCNU) or mitomycin C). Subjects must be recovered from therapy-related non-hematological toxicities to < grade 1 or baseline if started with > grade 1 toxicity.

• No time limit for radiation prior to registration.

• No radioimmunotherapy < 2 months prior to registration. Subjects must be recovered from therapy-related toxicities to < grade 1 or baseline if started with > grade 1 toxicity.

• No prior allogeneic stem cell transplantation unless allogeneic engraftment is <2%.

• Subjects receiving chronic, systemic treatment with corticosteroids = to >20mg of prednisone per day.

• Subjects receiving replacement for adrenal insufficiency allowed.

• Topical or inhaled corticosteroids allowed.

1. History of other primary malignancy < 3 years ago, except inactive basal, squamous cell carcinoma of the skin or superficial melanoma only requiring excision, prostate cancer with a prostate specific antigen (PSA) stable for >/=3 months, carcinoma in situ of cervix.

2. Major surgery < 4 weeks before or Minor surgery < 2 weeks before registration. Subjects must be recovered from toxicities to < grade 1 or baseline if started with > grade 1 toxicity.

3. Investigational drugs < 4 weeks prior to registration.

4. Impaired Cardiac Function per protocol.

5. Pregnant or breastfeeding females or adults of reproductive potential not using effective birth control

6. Diffusing capacity or transfer factor of the lung for carbon monoxide (DLCO) < 40% if tested (per protocol).

7. Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse Oximetry.

8. Immunization with live attenuated vaccines < 1 week of study entry

9. Impaired GI function or GI disease that may alter absorption of RAD001 or LBH589

10. Concurrent severe &/or uncontrolled medical conditions

11. Medications with risk of prolonging QT interval or inducing torsade de pointes or interacting with LBH589 and RAD001 may be used per the protocol.

12. Active bleeding tendency

13. Positive for HIV.

14. Positive for Hepatitis C virus (HCV).

15. History of non-compliance to medical regimens.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Duke University Medical Center	Durham	North Carolina	United States	27710

Sponsors and Collaborators

• Anne Beaven, MD
• Novartis

Investigators

• Principal Investigator: Anne W. Beaven, MD, Duke University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Anne Beaven, MD, Assistant Professor of Medicine, Duke University
• ClinicalTrials.gov Identifier: NCT00978432
• Other Study ID Numbers: Pro00012947
• First Posted: Sep 17, 2009
• Last Update Posted: Nov 25, 2016
• Last Verified: Oct 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Anne Beaven, MD, Assistant Professor of Medicine, Duke University: NHL; DLBCL; recurrent; refractory; de novo
• Additional relevant MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Everolimus; Panobinostat

Study Results

Participant Flow

Recruitment Details	The study opened to enrollment in October, 2009. 50 subjects were consented until enrollment closure in April 2015. Patients were recruited at the Duke Cancer Center Hematology clinic.
Pre-assignment Detail	Fifty (50) participants signed consent. Eleven subjects were screen failures. The PI removed three subjects prior to treatment to receive alternate therapy. Three subjects chose to withdraw from the study prior to treatment.

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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	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	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.
Period Title: Overall Study
STARTED	10	5	18
COMPLETED	7	4	13
NOT COMPLETED	3	1	5

Baseline Characteristics

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)	Total
Arm/Group Description	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	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	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.	Total of all reporting groups
Overall Participants	10	5	18	33
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	5 50%	2 40%	9 50%	16 48.5%
>=65 years	5 50%	3 60%	9 50%	17 51.5%
Sex: Female, Male (Count of Participants)
Female	6 60%	1 20%	3 16.7%	10 30.3%
Male	4 40%	4 80%	15 83.3%	23 69.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%	0 0%	0 0%	0 0%
Not Hispanic or Latino	10 100%	5 100%	18 100%	33 100%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	1 10%	0 0%	1 5.6%	2 6.1%
White	9 90%	5 100%	17 94.4%	31 93.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	10 100%	5 100%	18 100%	33 100%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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	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	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.
Measure Participants	10	5	18
Number [participants]	1 10%	0 0%	4 22.2%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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	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	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.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Summary of Adverse Events (AEs)
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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	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	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.
Measure Participants	10	5	18
Blood and lymphatic AEs	18	6	42
Gastrointestinal AEs	30	10	39
General Disorder AEs	6	5	19
Investigation (Lab) AEs	6	3	23
Metabolism and Nutrition AEs	5	2	45
Musculoskeletal and Connective Tissue AEs	4	1	2
Nervous System AEs	13	3	5
Renal and Urinary AEs	0	1	4
Reproductive System AEs	0	1	1
Respiratory, thoracic and mediastinal AEs	10	4	15
Skin and Subcutaneous Tissue AEs	8	2	3
Vascular AEs	2	1	1

4. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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	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	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.
Measure Participants	0	0	0

5. Secondary Outcome

Title	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.
Description	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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)	Arm 1b (LBH589 Followed by RAD001)	Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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	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	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.
Measure Participants	0	0	0

Adverse Events

Time Frame	From the time of consent until 4 weeks after the last dose of study drug; approximately 1 year.
Arm/Group Title	Arm 1a (RAD001 Followed by LBH589)		Arm 1b (LBH589 Followed by RAD001)		Doublet (Combination RAD001 and LBH589)
Arm/Group Description	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		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		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.
All Cause Mortality
	Arm 1a (RAD001 Followed by LBH589)		Arm 1b (LBH589 Followed by RAD001)		Doublet (Combination RAD001 and LBH589)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm 1a (RAD001 Followed by LBH589)		Arm 1b (LBH589 Followed by RAD001)		Doublet (Combination RAD001 and LBH589)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/10 (10%)		1/5 (20%)		6/18 (33.3%)
Cardiac disorders
Atrial flutter	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Pericardial effusion	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Gastrointestinal disorders
Diarrhea	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Colitis	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Ascites	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
General disorders
Fever	0/10 (0%)	0	0/5 (0%)	0	2/18 (11.1%)	2
Fatigue	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Metabolism and nutrition disorders
Dehydration	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Anorexia	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Cognitive disturbance	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Respiratory, thoracic and mediastinal disorders
Hypoxia	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Other (Not Including Serious) Adverse Events
	Arm 1a (RAD001 Followed by LBH589)		Arm 1b (LBH589 Followed by RAD001)		Doublet (Combination RAD001 and LBH589)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		5/5 (100%)		18/18 (100%)
Blood and lymphatic system disorders
Anemia	4/10 (40%)	6	0/5 (0%)	0	7/18 (38.9%)	7
Leukocytosis	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Neutropenia	3/10 (30%)	5	2/5 (40%)	2	9/18 (50%)	13
Thrombocytopenia	5/10 (50%)	7	4/5 (80%)	4	15/18 (83.3%)	21
Cardiac disorders
Pericardial effusion	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Eye disorders
Blurred vision	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Gastrointestinal disorders
Abdominal pain	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Bloating	0/10 (0%)	0	0/5 (0%)	0	2/18 (11.1%)	2
Constipation	1/10 (10%)	1	2/5 (40%)	2	2/18 (11.1%)	3
Diarrhea	5/10 (50%)	8	2/5 (40%)	2	12/18 (66.7%)	16
Dry mouth	1/10 (10%)	2	0/5 (0%)	0	2/18 (11.1%)	2
Dyspepsia	3/10 (30%)	3	0/5 (0%)	0	0/18 (0%)	0
Flatulence	2/10 (20%)	2	0/5 (0%)	0	0/18 (0%)	0
Gastrointestinal - Other (Burping)	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Gastrointestinal - Other (Gas)	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Gastroparesis	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Mucositis Oral	0/10 (0%)	0	1/5 (20%)	1	7/18 (38.9%)	7
Nausea	7/10 (70%)	8	1/5 (20%)	1	4/18 (22.2%)	5
Stomach pain	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Vomiting	4/5 (80%)	5	1/5 (20%)	1	3/18 (16.7%)	3
General disorders
Edema face	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Edema limbs	0/10 (0%)	0	1/5 (20%)	1	3/18 (16.7%)	4
Fatigue	4/10 (40%)	4	3/5 (60%)	3	12/18 (66.7%)	14
Non-cardiac Chest pain	1/10 (10%)	1	1/5 (20%)	1	1/18 (5.6%)	1
Infections and infestations
Infections and Infestations - Other (cellulitis)	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Investigations
Alkaline phosphatase increased	0/10 (0%)	0	0/5 (0%)	0	6/18 (33.3%)	6
Aspartate aminotransferase increased	0/10 (0%)	0	0/5 (0%)	0	3/18 (16.7%)	3
Cholesterol high	2/10 (20%)	2	0/5 (0%)	0	3/18 (16.7%)	3
Creatinine increased	2/10 (20%)	3	2/5 (40%)	2	5/18 (27.8%)	7
Weight loss	1/10 (10%)	1	1/5 (20%)	1	4/18 (22.2%)	4
Metabolism and nutrition disorders
Acidosis	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Anorexia	2/10 (20%)	2	2/5 (40%)	2	7/18 (38.9%)	7
Hyperglycemia	1/10 (10%)	2	0/5 (0%)	0	3/18 (16.7%)	5
Hyperkalemia	0/10 (0%)	0	0/5 (0%)	0	3/18 (16.7%)	6
Hypernatremia	0/10 (0%)	0	0/5 (0%)	0	5/18 (27.8%)	5
Hypertriglyceridemia	0/10 (0%)	0	0/5 (0%)	0	4/18 (22.2%)	5
Hypoalbuminemia	0/10 (0%)	0	0/5 (0%)	0	9/18 (50%)	11
Hypocalcemia	1/10 (10%)	1	0/5 (0%)	0	1/18 (5.6%)	2
Hypomagnesemia	0/10 (0%)	0	0/5 (0%)	0	3/18 (16.7%)	3
Musculoskeletal and connective tissue disorders
Athralgia	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Back pain	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Flank pain	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Generalized muscle weakness	1/10 (10%)	1	1/5 (20%)	1	1/18 (5.6%)	1
Pain in Extremity	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Nervous system disorders
Agitation	2/10 (20%)	2	0/5 (0%)	0	0/18 (0%)	0
Depression	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Dizziness	2/10 (20%)	2	1/5 (20%)	1	0/18 (0%)	0
Dysgeusia	4/10 (40%)	5	1/5 (20%)	1	3/18 (16.7%)	3
Dysphagia	1/10 (10%)	1	0/5 (0%)	0	1/18 (5.6%)	1
Headache	1/10 (10%)	2	0/5 (0%)	0	0/18 (0%)	0
Paresthesia	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Peripheral sensory neuropathy	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Psychiatric disorders
Insomnia	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Insomnia	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Renal and urinary disorders
Cystitis noninfective	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Hematuria	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	2
Urinary frequency	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Urinary incontinence	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Reproductive system and breast disorders
Genital edema	0/10 (0%)	0	1/5 (20%)	1	1/18 (5.6%)	1
Respiratory, thoracic and mediastinal disorders
Cough	2/10 (20%)	2	1/5 (20%)	1	5/18 (27.8%)	5
Dyspnea	3/10 (30%)	3	2/5 (40%)	2	3/18 (16.7%)	3
Epistaxis	0/10 (0%)	0	1/5 (20%)	1	2/18 (11.1%)	3
Nasal congestion	1/10 (10%)	1	0/5 (0%)	0	1/18 (5.6%)	1
Pneumonitis	3/10 (30%)	3	0/5 (0%)	0	3/18 (16.7%)	3
Respiratory, thoracic and mediastinal disorders - Other (Dry Throat)	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Skin and subcutaneous tissue disorders
Alopecia	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Bullous dermatitis	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Dermatitis radiation	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Dry Skin	2/10 (20%)	2	0/5 (0%)	0	0/18 (0%)	0
Pruritus	2/10 (20%)	2	1/5 (20%)	1	0/18 (0%)	0
Purpura	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1
Skin and subcutaneous tissue disorders - Other (Rash, NOS)	2/10 (20%)	3	0/5 (0%)	0	0/18 (0%)	0
Urticaria	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Vascular disorders
Flushing	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Hot flashes	0/10 (0%)	0	1/5 (20%)	1	0/18 (0%)	0
Hypertension	1/10 (10%)	1	0/5 (0%)	0	0/18 (0%)	0
Hypotension	0/10 (0%)	0	0/5 (0%)	0	1/18 (5.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.