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

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ClinicalTrials.gov Identifier: NCT01998035
Recruitment Status : Terminated (PI left institution)
First Posted : November 28, 2013
Last Update Posted : January 8, 2021
Sponsor:
Collaborator:
Celgene
Information provided by (Responsible Party):
Columbia University

Tracking Information
First Submitted Date  ICMJE November 20, 2013
First Posted Date  ICMJE November 28, 2013
Last Update Posted Date January 8, 2021
Study Start Date  ICMJE November 2013
Actual Primary Completion Date January 6, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 17, 2015)
  • 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 ]
Original Primary Outcome Measures  ICMJE
 (submitted: November 25, 2013)
  • Phase I: Maximum tolerated dose (MTD) of the combination of oral 5-azacitidine & romidepsin [ Time Frame: up to 1.5 years ]
  • Phase I: Dose limiting toxicities (DLTs) of the combination of oral 5-azacitidine & romidepsin [ Time Frame: up to 1 year ]
  • Phase I: Number and type of toxicities experienced by each patient with the combination of oral 5-azacitidine & 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 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 5, 2020)
  • Phase I: Maximum number of cycles received [ Time Frame: Up to 1.5 years ]
    Pending
  • Phase I: Number of dose delays at the maximally tolerated dose (MTD) [ Time Frame: Up to 1.5 years ]
    Pending
  • Phase I: Number of dose reductions at the maximally tolerated dose (MTD) [ Time Frame: Up to 1.5 years ]
    Pending
  • Phase I: Overall response rate (ORR) of the study population [ Time Frame: Up to 1.5 years ]
    Pending
  • Phase I & II: Progression free survival (PFS) of the study population [ Time Frame: Up to 1.5 years ]
    Pending
  • 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 ]
    Data analysis ongoing
  • 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 ]
    Data analysis ongoing
Original Secondary Outcome Measures  ICMJE
 (submitted: November 25, 2013)
  • 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: Overall survival of the patients with T-cell lymphoma on study [ Time Frame: Up to 1.5 years ]
  • Phase II: Potential pre-treatment biomarkers of response to clinical outcome by relating correlative sample data to clinical data on each patient. [ Time Frame: Up to 1.5 years ]
Current Other Pre-specified Outcome Measures
 (submitted: August 17, 2015)
  • 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.
Original Other Pre-specified Outcome Measures
 (submitted: November 25, 2013)
  • Phase I & II: Pharmacodynamic markers of drug effect 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 (pharmacokinetics) for the combination of oral 5-azacitidine & romidepsin at various time intervals 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.
 
Descriptive Information
Brief Title  ICMJE Romidepsin Plus Oral 5-Azacitidine in Relapsed/Refractory Lymphoid Malignancies
Official Title  ICMJE Phase I/IIa Study of the Oral 5-Azacitidine in Combination With the Histone Deacetylase Inhibitor Romidepsin for the Treatment of Patients With Relapsed and Refractory Lymphoid Malignancies
Brief Summary

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.

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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Lymphoid Malignancies
  • Lymphoma
  • Hodgkin Lymphoma
  • Non-hodgkin Lymphoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
  • 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)
    Interventions:
    • Drug: Romidepsin
    • Drug: Oral 5-Azacitidine
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: May 13, 2019)
52
Original Estimated Enrollment  ICMJE
 (submitted: November 25, 2013)
60
Actual Study Completion Date  ICMJE January 6, 2020
Actual Primary Completion Date January 6, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
  • Eastern Cooperative Oncology Group (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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01998035
Other Study ID Numbers  ICMJE AAAM3752
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Columbia University
Study Sponsor  ICMJE Columbia University
Collaborators  ICMJE Celgene
Investigators  ICMJE
Principal Investigator: Owen A. O'Connor, MD, Ph.D. Columbia University
PRS Account Columbia University
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP