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Phase I/II Study of 5-azacitidine in Combination With Vorinostat in Patients With Relapsed or Refractory DLBCL

Phase 1/Phase 2
18 Years
Open (Enrolling)

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Trial Information

Phase I/II Study of 5-azacitidine in Combination With Vorinostat in Patients With Relapsed or Refractory DLBCL

Eligible subjects will have biopsy proven relapsed or refractory DLBCL, have preserved
hematologic and other organ function, and have either progressed following or be
inappropriate candidates for autologous stem cell transplantation.

Patients will be treated with 5-azacitidine via subcutaneous administration and vorinostat
orally at four different dose levels as described below:

- Dose level 1: azacitidine 55 mg/m2 on days 1-5 and oral vorinostat at 300 mg BID on
Days 1-7.

- Dose level 2: azacitidine 75 mg/m2 on days 1-5 and oral vorinostat at 200 mg BID on
Days 1-7.

- Dose level 3: azacitidine 55 mg/m2 on days 1-5 and oral vorinostat at 300 mg BID on
Days 1-14.

- Dose level 4: azacitidine 75 mg/m2 on days 1-5 and oral vorinostat at 200 mg BID on
Days 1-14.

Each cycle will be of 28 days and patients will be treated for up to 6 cycles.

Up to 8 patients will be enrolled at each dose level. If at any time 2 patients in a given
cohort experience DLT, enrollment to that level will be discontinued.

Efficacy will be assessed by standard radiographic and other criteria at baseline and at the
end of treatment to determine ORR. Patients will be followed for 2 years or until disease

Tumor samples will be obtained for correlative studies at baseline through core needle or
surgical biopsy, with an additional biopsy performed on day 15 of cycle 1 as a
pharmacodynamic endpoint.

Inclusion Criteria:

- Patients must have histologically confirmed diffuse large B cell lymphoma, relapsed
after or resistant to prior systemic therapy.

- Subjects must have measurable disease on cross sectional imaging that is at least 1.5
cm in diameter.

- Patients should have relapsed following or be deemed ineligible for autologous stem
cell transplantation. There is no limit to number of prior therapies.

- Age > = 18 years.

- ECOG performance status < = 2.

- Patients must have normal organ and marrow function as defined below:

- ANC > = 1,000/uL

- platelets > = 75,000//uL

- total bilirubin < = 2 X upper limit of normal

- AST(SGOT)/ALT(SGPT) < = 2.5 X upper limit of normal

- Serum creatinine < = 1.5 X upper limit of normal (ULN)

- Women of childbearing potential must have a negative serum pregnancy test prior to

- The effects of these investigational agents on the developing human fetus at the
recommended therapeutic doses are unknown. For this reason, women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier
method of birth control; abstinence) prior to study entry and for the duration of
study participation. Should a woman become pregnant or suspect she is pregnant while
participating in this study, she should inform her treating physician immediately. A
woman who becomes pregnant while participating in the study must withdraw from the
study immediately.

- Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria:

- Prior allogeneic transplant

- Patients may not be receiving any other investigational agents.

- Patients may not have previously received anti-lymphoma therapy with an HDAC
inhibitor (.e.g. Depsipeptide, MS-275, LAQ-824, PXD-101, and valproic acid).
Patients who have received an HDAC inhibitor for another indication such as epilepsy
may enroll after a 30-day washout period

- Patients with known active CNS lymphoma. Subjects with previous CNS lymphoma that
have been treated with chemotherapy, radiotherapy or surgery who have remained
asymptomatic for 90 days (3 months) and demonstrate, no CNS lymphoma, as shown by
lumbar puncture, CT scan or MRI, are eligible..

- Patients with known hypersensitivity to azacytidine, vorinostat or mannitol.

- Patients with a currently active second malignancy.

- Uncontrolled illness including, but not limited to, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,
or psychiatric illness/social situations that would limit compliance with study

- QTc interval > 0.470. Consider discontinuation of medications that prolong QTc
interval to eliminate this exclusion if medically appropriate.

- Pregnant and lactating women are excluded from the study because the risks to an
unborn fetus or potential risks in nursing infants are unknown.

Type of Study:


Study Design:

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

Outcome Measure:

determination of maximum tolerated dose (MTD) of azacitidine and vorinostat when given in combination as treatment for relapsed/refractory DLBCL

Outcome Description:

determine the safety and tolerability of the combination of azacitidine with vorinostat as measured by the occurrence of dose limiting toxicities during the first 28 days of treatment for each patient, and to determine an appropriate dose for further study

Outcome Time Frame:

1 year

Safety Issue:


Principal Investigator

Rebecca Elstrom, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Weill Medical College of Cornell University


United States: Institutional Review Board

Study ID:




Start Date:

September 2010

Completion Date:

Related Keywords:

  • Lymphoma
  • diffuse large b cell lymphoma
  • Lymphoma
  • Lymphoma, B-Cell
  • Lymphoma, Large B-Cell, Diffuse



Weill Cornell Medical College New York, New York  10021