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Study of 5-azacitidine in Combination With Vorinostat in Patients With Relapsed or Refractory Diffuse Large b Cell Lymphoma (DLBCL)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified October 2010 by Weill Medical College of Cornell University.
Recruitment status was  Recruiting
Sponsor:
Collaborators:
Celgene Corporation
Merck Sharp & Dohme Corp.
Information provided by:
Weill Medical College of Cornell University
ClinicalTrials.gov Identifier:
NCT01120834
First received: April 19, 2010
Last updated: October 27, 2010
Last verified: October 2010
  Purpose

This will be a phase I/II study of 5-azacitidine in combination with vorinostat in patients with relapsed or refractory DLBCL. Combination therapy with methyltransferase inhibitors and histone deacetylase inhibitors is highly synergistic in DLBCL cells, and both classes of drugs can also synergize powerfully with standard anti-lymphoma chemotheraputics such as doxorubicin in pre-clinical studies. We hypothesize that azacytidine + vorinostat combination therapy will be safe and effective in selected patients with relapsed or refractory DLBCL. We also hypothesize that patients demonstrating objective responses to this combination therapy display specific epigenetic signatures, and that a biomarker or gene classifier can be generated which will identify those patients likely to respond.


Condition Intervention Phase
Lymphoma
Drug: azacytidine
Drug: vorinostat
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Study of 5-azacitidine in Combination With Vorinostat in Patients With Relapsed or Refractory DLBCL

Resource links provided by NLM:


Further study details as provided by Weill Medical College of Cornell University:

Primary Outcome Measures:
  • determination of maximum tolerated dose (MTD) of azacitidine and vorinostat when given in combination as treatment for relapsed/refractory DLBCL [ Time Frame: 1 year ] [ Designated as safety issue: Yes ]
    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


Secondary Outcome Measures:
  • overall response rate [ Time Frame: at end of treatment (6 months) and for up to 2 years ] [ Designated as safety issue: No ]
    determine efficacy of the combination of 5-azacitidine with vorinostat in patients with relapsed and refractory DLBCL, as measured by overall response rate (ORR)


Estimated Enrollment: 32
Study Start Date: September 2010
Estimated Primary Completion Date: April 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: all subjects Drug: azacytidine
  • Dose level 1: azacitidine 55 mg/m2 on days 1-5
  • Dose level 2: azacitidine 75 mg/m2 on days 1-5
  • Dose level 3: azacitidine 55 mg/m2 on days 1-5
  • Dose level 4: azacitidine 75 mg/m2 on days 1-5

Each cycle = 28 days. Subjects may receive up to 6 cycles.

Drug: vorinostat
  • Dose level 1: oral vorinostat at 300 mg BID on Days 1-7.
  • Dose level 2: oral vorinostat at 200 mg BID on Days 1-7.
  • Dose level 3: oral vorinostat at 300 mg BID on Days 1-14.
  • Dose level 4: oral vorinostat at 200 mg BID on Days 1-14.

Each cycle = 28 days. Subjects receive up to 6 cycles.


Detailed Description:

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 progression.

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 treatment
  • 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 document.

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 requirements.
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01120834

Contacts
Contact: Rebecca Elstrom Elstrom, MD 646-962-2064 ree2001@med.cornell.edu

Locations
United States, New York
Weill Cornell Medical College Recruiting
New York, New York, United States, 10065
Contact: Rebecca Elstrom, MD    646-962-2064    ree2001@med.cornell.edu   
Principal Investigator: Rebecca Elstrom, MD         
Sponsors and Collaborators
Weill Medical College of Cornell University
Celgene Corporation
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Rebecca Elstrom, MD Weill Medical College of Cornell University
  More Information

Additional Information:
No publications provided

Responsible Party: Dr. Rebecca Elstrom, Weill Cornell Medical College
ClinicalTrials.gov Identifier: NCT01120834     History of Changes
Other Study ID Numbers: 0912010795
Study First Received: April 19, 2010
Last Updated: October 27, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by Weill Medical College of Cornell University:
diffuse large b cell lymphoma

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Large B-Cell, Diffuse
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoma, B-Cell
Lymphoma, Non-Hodgkin
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
Azacitidine
Vorinostat
Antimetabolites
Antimetabolites, Antineoplastic
Antineoplastic Agents
Enzyme Inhibitors
Histone Deacetylase Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on November 25, 2014