Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
Condition: Diffuse Large B-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: RAD001; LBH589; Doublet (RAD001 and LBH589)
Intervention description: 10 mg/day for Part 1 of the trial; 40 mg on Monday, Wednesday and Friday weekly for Part 1 of the trial; RAD001 7.5 mg by mouth daily and LBH589 15 mg by mouth on Monday/Wednesday/Friday during Part 2.
Intervention MeSH terms: Everolimus; Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 50.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: NHL; DLBCL; recurrent; refractory; de novo

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.
    

Eligibility criteria:

        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.