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)

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.

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

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

3. Age > 18 years old

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

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

6. Frozen tumor or paraffin-embedded sample available.

7. 3-4 core fresh/fresh-frozen biopsy specimens available. Leukapheresis may be done for patients with leukocytosis.

8. 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

2. 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.

3. 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.

4. 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.

5. Investigational drugs < 4 weeks prior to registration.

6. Impaired Cardiac Function per protocol.

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

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

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

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

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

12. Concurrent severe &/or uncontrolled medical conditions

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

14. Active bleeding tendency

15. Positive for HIV.

16. Positive for Hepatitis C virus (HCV).

17. History of non-compliance to medical regimens.