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

Phase 2

Terminated

Conditions: Diffuse Large B-cell Lymphoma

Interventions: Drug: RAD001
Drug: Doublet (RAD001 and LBH589)
Drug: LBH589

Registration Number: NCT00978432

Lead Sponsor: Anne Beaven, MD

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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 50

Inclusion Criteria

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
Refractory or relapsed disease to >/= 1 prior treatment regimen: should include autologous stem cell transplant unless patient refused or ineligible.
Age > 18 years old
Eastern Cooperative Oncology Group (ECOG) performance status <2.
Measurable or evaluable disease by physical exam, radiographs or bone marrow involvement
Frozen tumor or paraffin-embedded sample available.
3-4 core fresh/fresh-frozen biopsy specimens available. Leukapheresis may be done for patients with leukocytosis.
Laboratory Values per protocol.

Exclusion Criteria

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
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.
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.
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.
Investigational drugs < 4 weeks prior to registration.
Impaired Cardiac Function per protocol.
Pregnant or breastfeeding females or adults of reproductive potential not using effective birth control
Diffusing capacity or transfer factor of the lung for carbon monoxide (DLCO) < 40% if tested (per protocol).
Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse Oximetry.
Immunization with live attenuated vaccines < 1 week of study entry
Impaired GI function or GI disease that may alter absorption of RAD001 or LBH589
Concurrent severe &/or uncontrolled medical conditions
Medications with risk of prolonging QT interval or inducing torsade de pointes or interacting with LBH589 and RAD001 may be used per the protocol.
Active bleeding tendency
Positive for HIV.
Positive for Hepatitis C virus (HCV).
History of non-compliance to medical regimens.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 1b (LBH589 followed by RAD001)	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.
Arm 1a (RAD001 followed by LBH589)	RAD001	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.
Arm 1a (RAD001 followed by LBH589)	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.
Arm 1b (LBH589 followed by RAD001)	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.
Doublet (Combination RAD001 and LBH589)	Doublet (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.

Primary Outcome Measures

Name	Time	Method
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
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

Name	Time	Method
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.
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.
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.