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A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

Phase 2
18 Years
Open (Enrolling)
Diffuse Large B-cell Lymphoma

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Trial Information

A Phase 2 Study to Evaluate the Efficacy of Epigenetic Modulation in Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)

This will be a prospective, non-randomized, un-blinded phase 2 efficacy trial using an mTOR
inhibitor and a histone deacetylase (HDAC) inhibitor for epigenetic targeted therapies.

Subjects will receive RAD001 and LBH589 given in four to thirteen, 28-day cycles. Subjects
with progressive disease will stop after 4 cycles. Subjects with stable disease or better
after 4 cycles may receive up to 13 cycles. LBH will start at 20mg po on days M/W/F and
RAD001 will start at 10mg po daily.

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. 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
Burkitt lymphoma,

- 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
marrow involvement

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.

Exclusion Criteria:

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
adequately controlled

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
the study.

- 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
this trial.

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

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Overall response rate

Outcome 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 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

Outcome Time Frame:

From the start of combination therapy until a maximum of 2 years after completion of therapy

Safety Issue:


Principal Investigator

Anne W. Beaven, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Duke University


United States: Food and Drug Administration

Study ID:




Start Date:

February 2012

Completion Date:

June 2018

Related Keywords:

  • Diffuse Large B-Cell Lymphoma
  • NHL
  • recurrent
  • refractory
  • de novo
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse



Duke University Medical Center Durham, North Carolina  27710