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Romidepsin Plus Oral 5-Azacitidine in Relapsed/Refractory Lymphoid Malignancies

This study is currently recruiting participants.
Verified August 2017 by Owen A. O'Connor, Columbia University
Sponsor:
ClinicalTrials.gov Identifier:
NCT01998035
First Posted: November 28, 2013
Last Update Posted: August 28, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Collaborator:
Celgene
Information provided by (Responsible Party):
Owen A. O'Connor, Columbia University
  Purpose

This is an open label, phase I/IIa, 3 x 3 dose escalation study with an initial phase I followed by a disease focused phase II.

The primary objective of the phase I is to determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combinations of oral 5-azacitidine and romidepsin in patients with lymphoma. The safety and toxicity of this combination will be evaluated throughout the entire study.

If the combination of oral 5-azacitidine and romidepsin is found to be feasible and an MTD is established, the phase II part of the study will be initiated.

Phase II will consist of a 2 stage design of the combination of oral 5-azacitidine and romidepsin for patients with relapsed or refractory T-cell lymphomas.


Condition Intervention Phase
Lymphoid Malignancies Lymphoma Hodgkin Lymphoma Non-hodgkin Lymphoma Drug: Romidepsin Drug: Oral 5-Azacitidine Phase 1 Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/IIa Study of the Oral 5-Azacitidine in Combination With the Histone Deacetylase Inhibitor Romidepsin for the Treatment of Patients With Replapsed and Refractory Lymphoid Malignancies

Resource links provided by NLM:


Further study details as provided by Owen A. O'Connor, Columbia University:

Primary Outcome Measures:
  • Phase I: Maximum tolerated dose (MTD) of the combination of oral 5-azacitidine & romidepsin [ Time Frame: up to 1.5 years ]
  • Phase I: Number of dose limiting toxicities (DLTs) of the combination of oral 5-azacitidine & romidepsin [ Time Frame: up to 1 year ]
  • Phase I: Number of toxicities experienced by patients with the combination of oral 5-azacitidine and romidepsin [ Time Frame: Up to 1.5 years ]
  • Phase II: Overall response rate (ORR) (complete + partial response) of the combination of oral 5-azacitidine and romidepsin in patients with relapsed/refractory T-Cell Lymphoma [ Time Frame: Up to 3 years ]

Secondary Outcome Measures:
  • Phase I: Maximum number of cycles received [ Time Frame: Up to 1.5 years ]
  • Phase I: Number of dose delays at the maximally tolerated dose (MTD) [ Time Frame: Up to 1.5 years ]
  • Phase I: Number of dose reductions at the maximally tolerated dose (MTD) [ Time Frame: Up to 1.5 years ]
  • Phase I: Overall response rate (ORR) of the study population [ Time Frame: Up to 1.5 years ]
  • Phase I & II: Progression free survival (PFS) of the study population [ Time Frame: Up to 1.5 years ]
  • Phase I & II: Duration of response (DOR) of the study population [ Time Frame: Up to 1.5 years ]
  • Phase II: Prevalence of overall survival of the patients with T-cell lymphoma on study [ Time Frame: Up to 1.5 years ]
  • Phase II: Positive response to clinical outcome indicating potential pre-treatment biomarkers by relating correlative sample data to clinical data on each patient. [ Time Frame: Up to 1.5 years ]

Other Outcome Measures:
  • Phase I & II: Prevalence of pharmacodynamic markers of drug effect indicated in optional paired tissue biopsies [ Time Frame: Up to 1.5 years ]
    Samples taken from baseline and post treatment timepoints will be compared to try to identify pharmacodynamic markers of drug effect.

  • Phase I: Concentration time curve (AUC) for the combination of oral 5-azacitidine & romidepsin in cycle 1 [ Time Frame: Up to 1.5 hours ]
    Samples will be drawn at various timepoints and run in aggregate during the course of the study.


Estimated Enrollment: 60
Study Start Date: November 2013
Estimated Study Completion Date: February 2019
Estimated Primary Completion Date: December 2017 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: R/O: Level -1
Oral 5-Azacitidine 100 mg (Days 1-14) Romidepsin (10 mg/m2 rounded to 14 mg/m2, Day 8), cycle length (28 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC
Experimental: R/O: Level 1
Oral 5-Azacitidine 100 mg (Days 1-14) Romidepsin (10 mg/m2 rounded to 14 mg/m2, Days 8 and 15), cycle length (28 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC
Experimental: R/O: Level 2
Oral 5-Azacitidine 200 mg (Days 1-14) Romidepsin (10 mg/m2 rounded to 14 mg/m2, Days 8 and 15), cycle length (28 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC
Experimental: R/O: Level 3
Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (10 mg/m2 rounded to 14 mg/m2, Days 8 and 15), cycle length (28 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC
Experimental: R/O: Level 4
Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (14 mg/m2 rounded to 14 mg/m2, Days 8 and 15), cycle length (28 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC
Experimental: R/O: Level 5
Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (14 mg/m2 rounded to 14 mg/m2, Days 8, 15 and 22), cycle length (35 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC
Experimental: R/O: Level 6
Oral 5-Azacitidine 300 mg (Days 1-21) Romidepsin (14 mg/m2 rounded to 14 mg/m2, Days 8, 15 and 22), cycle length (35 days)
Drug: Romidepsin

Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor".

Dose escalation (10, 14 mg/m2)

Other Name: Istodax
Drug: Oral 5-Azacitidine

A pyrimidine nucleoside analogue of cytidine with antineoplastic activity.

Dose escalation (100, 200, 300 mg)

Other Name: 5-AC

Detailed Description:
Subjects will receive oral 5-azacitidine and romidepsin, administered as follows: oral 5-azacitidine from Days 1-14 (Dose cohorts -1 to 5) or Days 1-21 (Dose cohort 6); and romidepsin administered intravenously on Days 8 (Dose cohorts 1-4) of a 28 day cycle, and Day 22 (Dose cohorts 5 and 6) of a 35 day cycle. Cohorts of 3 patients will be enrolled sequentially as outlined in the dose escalation scheme. Once the MTD is reached the Phase II part of the protocol will be initiated in patients with T-Cell Lymphoma.
  Eligibility

Information from the National Library of Medicine

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, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Phase I: Histologically confirmed relapsed or refractory non-Hodgkin lymphoma or Hodgkin lymphoma (WHO criteria), with no accepted curative options.
  • Phase II: Relapsed or refractory T-cell lymphoma, including patients with central nervous system (CNS) involvement or lymphomatous meningitis are allowed on study.
  • Relapsed or refractory disease following frontline chemotherapy. No upper limit for the number of prior therapies. Patients may have relapsed after prior autologous or allogeneic stem cell transplant.
  • Evaluable Disease in the Phase I, and measurable disease for the Phase II.
  • Age > or = 18 years.
  • ECOG performance status < or = 2.
  • Patients must have adequate organ and marrow function.
  • Negative urine or serum pregnancy test for females of childbearing potential.
  • All females of childbearing potential must use an effective barrier method of contraception during the treatment period and for at least 1 month thereafter. Male subjects should use a barrier method of contraception during the treatment period and for at least 3 months thereafter.
  • Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

  • Prior Therapy

    • Exposure to chemotherapy or radiotherapy within 2 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 2 weeks earlier.
    • Systemic steroids that have not been stabilized ( ≥ 5 days) to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs.
    • No other concurrent investigational agents are allowed.
  • History of allergic reactions to Oral 5-azacitidine or Romidepsin.
  • Uncontrolled intercurrent 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.
  • Pregnant women.
  • Nursing women.
  • Active concurrent malignancy (except non-melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy, the patient must be disease-free for ≥ 3 years.
  • Patients known to be Human Immunodeficiency Virus (HIV)-positive.
  • Patients with active hepatitis A, hepatitis B, or hepatitis C infection.
  • Concomitant use of CYP3A4 inhibitors.
  • Any known cardiac abnormalities.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01998035


Contacts
Contact: Celeste Rojas 212-326-5720 cr2393@cumc.columbia.edu

Locations
United States, New York
Columbia University Medical Center Recruiting
New York, New York, United States, 10019
Contact: Celeste Rojas    212-326-5720    cr2393@cumc.columbia.edu   
Principal Investigator: Owen A O'Connor, MD, Ph.D.         
Sponsors and Collaborators
Owen A. O'Connor
Celgene
Investigators
Principal Investigator: Owen A O'Connor, MD, Ph.D. Columbia University
  More Information

Responsible Party: Owen A. O'Connor, Professor of Medicine & Experimental Therapeutics, Director, Center for Lymphoid Malignancies, Co-Director, Program for Lymphoid Development & Malignancies, Herbert Irving Comprehensive Cancer Center, Columbia University
ClinicalTrials.gov Identifier: NCT01998035     History of Changes
Other Study ID Numbers: AAAM3752
First Submitted: November 20, 2013
First Posted: November 28, 2013
Last Update Posted: August 28, 2017
Last Verified: August 2017

Keywords provided by Owen A. O'Connor, Columbia University:
Lymphoid Malignancies
Lymphoma
Hodgkin Lymphoma
Non-hodgkin Lymphoma
Follicular Lymphoma
Diffuse Large B-Cell Lymphoma
Anaplastic Large Cell Lymphoma
Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Mantle Cell Lymphoma
Marginal Zone Lymphoma
Burkitt Lymphoma
Waldenstrom Macroglobulinemia
Peripheral T-cell Lymphoma
Cutaneous T-cell Lymphoma

Additional relevant MeSH terms:
Lymphoma
Neoplasms
Lymphoma, Non-Hodgkin
Hodgkin Disease
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Azacitidine
Romidepsin
Histone Deacetylase Inhibitors
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Antibiotics, Antineoplastic