A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
1. Histologically or cytologically confirmed diffuse large B cell non-Hodgkin lymphoma
(DLBCL) that is de novo or transformed. Based on the revised 2008 WHO criteria
subjects with DLBCL-like lymphomas will also be allowed including the list below,
although this list is not all-inclusive.
- EBV+ DLBCL in elderly,
- DLBCL associated with chronic inflammation,
- Primary cutaneous DLBCL, leg type,
- B cell lymphoma unclassifiable with features intermediate between DLBCL and
- B cell lymphoma unclassifiable with features intermediate between large B cell
lymphoma and classical Hodgkin lymphoma,
- 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 at least one prior treatment regimen, which should
include autologous stem cell transplant unless the patient refused or was ineligible
for transplant for any reason.
3. Age > 18 years old
4. ECOG performance status of <2.
5. Measurable or evaluable disease based on physical exam and/or radiographs or bone
6. Have a frozen tumor or paraffin-embedded sample available for for gene expression
using a previously collected sample unless a new biopsy is needed for clinical
management of the patient.
7. At least 3-4 core biopsy specimens using at least a 18 gauge needle. An equivalent
amount of biopsy material from previously performed procedures, as long as it was
fresh frozen, can be used in lieu of freshly obtained tissue. FNA is not acceptable
for this initial specimen. Leukapheresis sample may be obtained instead of core
biopsy for patients with leukocytosis.
8. Laboratory Values as per protocol.
1. Laboratory Values
- Grade 3 hyperlipidemia (Serum cholesterol >400mg/dl or serum triglycerides >5 x
ULN) despite optimal supportive medical therapy
- Serum Glucose > 250mg/dl on at least two checks on two separate days despite
optimal medical management
- Patients with diabetes may be enrolled on the trial as long as their sugars are
2. No limit to the number of prior chemotherapy regimens, however:
- No prior exposure to RAD001 or LBH589 or to any drugs that mainly target mTOR
(everolimus, sirolimus, temsirolimus etc) or HDAC (vorinostat)
- Valproic acid is a mild HDAC inhibitor so patients may not receive valproic
acid at any time during the study or for the 5 days preceding starting the
first study drug.
- No chemotherapy, biologics or immunotherapy within 2 weeks prior to registration
(6 weeks if last received BCNU or mitomycin C). Subjects must have recovered
from all therapy-related non-hematological toxicities to < grade 1 or to
baseline if patient started with > grade 1 toxicity.
- No time limit with regards to radiation prior to registration.
- No radioimmunotherapy within 2 months prior to registration. Subjects must have
recovered from all therapy-related toxicities to < grade 1 or to baseline if
patient started with > grade 1 toxicity.
- No prior allogeneic stem cell transplantation unless allogeneic engraftment is
- Subjects receiving chronic, systemic treatment with corticosteroids equivalent
to >20mg of prednisone per day.
- Subjects receiving replacement for adrenal insufficiency will be allowed on
- Topical or inhaled corticosteroids are allowed.
3. Subjects with a history of another primary malignancy < 3 years ago, with the
exception of inactive basal, squamous cell carcinoma of the skin or superficial
melanoma only requiring excision, prostate cancer with a PSA that has not increased
for at least 3 months, carcinoma in situ of the cervix.
4. Major surgery < 4 weeks prior to registration. Minor surgery < 2 weeks prior to
registration. Subjects must have recovered from all surgery related toxicities to <
grade 1 or to baseline if subject started with > grade 1 toxicity.
5. Subjects who have received investigational drugs < 4 weeks prior to registration.
6. Impaired Cardiac Function as per protocol.
7. Female patients who are pregnant or breast feeding, or adults of reproductive
potential not employing an effective method of birth control will be excluded from
8. DLCO < 40%
9. Impaired lung function: O2 saturation 88% or less at rest on room air by Pulse
10. Immunization with live attenuated vaccines within 1 week of study entry
11. Impairment of GI function or GI disease that may alter absorption of RAD001 or LBH589
12. Concurrent severe &/or uncontrolled medical conditions
13. Using meds that have a relative risk of prolonging QT interval or inducing torsade de
14. Active bleeding tendency
15. Known positivity for HIV or HCV. Baseline testing is required if patient has risk
factors for HCV
16. History of non-compliance to medical regimens