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

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

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.

Study Overview

• Status: Terminated
• Conditions: Lymphoma; Hodgkin Lymphoma; Lymphoid Malignancies; Non-hodgkin Lymphoma
• Intervention / Treatment: Drug: RomiDEPsin 10 MG/M2; Drug: Oral 5-Azacitidine 100 MG; Drug: Oral 5-Azacitidine 200 MG; Drug: Oral 5-Azacitidine 300 MG; Drug: Romidepsin 14 MG/M2

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: Interventional
• Enrollment (Actual): 58
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10019
      • Columbia University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: R/O: Level -1; Oral 5-Azacitidine 100 mg (Days 1-14) Romidepsin (10 mg/m2, Day 8), cycle length (28 days)	Drug: RomiDEPsin 10 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (10 mg/m2); Other Names: Istodax; Drug: Oral 5-Azacitidine 100 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100 mg); Other Names: 5-AC
Experimental: R/O: Level 1; Oral 5-Azacitidine 100 mg (Days 1-14) Romidepsin (10 mg/m2, Days 8 and 15), cycle length (28 days)	Drug: RomiDEPsin 10 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (10 mg/m2); Other Names: Istodax; Drug: Oral 5-Azacitidine 100 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100 mg); Other Names: 5-AC
Experimental: R/O: Level 2; Oral 5-Azacitidine 200 mg (Days 1-14) Romidepsin (10 mg/m2, Days 8 and 15), cycle length (28 days)	Drug: RomiDEPsin 10 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (10 mg/m2); Other Names: Istodax; Drug: Oral 5-Azacitidine 200 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (200 mg); Other Names: 5-AC
Experimental: R/O: Level 3; Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (10 mg/m2, Days 8 and 15), cycle length (28 days)	Drug: RomiDEPsin 10 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (10 mg/m2); Other Names: Istodax; Drug: Oral 5-Azacitidine 300 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (300 mg); Other Names: 5-AC
Experimental: R/O: Level 4; Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (14 mg/m2, Days 8 and 15), cycle length (28 days)	Drug: Oral 5-Azacitidine 300 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (300 mg); Other Names: 5-AC; Drug: Romidepsin 14 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (14 mg/m2); Other Names: Istodax
Experimental: R/O: Level 5; Oral 5-Azacitidine 300 mg (Days 1-14) Romidepsin (14 mg/m2, Days 8, 15 and 22), cycle length (35 days)	Drug: Oral 5-Azacitidine 300 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (300 mg); Other Names: 5-AC; Drug: Romidepsin 14 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (14 mg/m2); Other Names: Istodax
Experimental: R/O: Level 6; Oral 5-Azacitidine 300 mg (Days 1-21) Romidepsin (14 mg/m2, Days 8, 15 and 22), cycle length (35 days)	Drug: Oral 5-Azacitidine 300 MG; A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (300 mg); Other Names: 5-AC; Drug: Romidepsin 14 MG/M2; Romidepsin is an anti-cancer ("antineoplastic" or "cytotoxic") chemotherapy drug. Romidepsin is classified as a "Histone Deacetylase Inhibitor". Dose escalation (14 mg/m2); Other Names: Istodax

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum Tolerated Dose (MTD) of the Combination of Oral 5-azacitidine in Combination With Romidepsin	The highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.	up to 1.5 years
Phase I: Maximum Tolerated Dose (MTD) of Romidepsin in Combination With Oral 5-azacytidine	The highest dose of a drug or treatment that does not cause unacceptable side effects. The MTD is determined in clinical trials by testing increasing doses on different groups of people until the highest dose with acceptable side effects is found.	up to 1.5 years
Percentage of Patients Who Experienced Significant Toxicities in Phase 1	Patients receiving the combination of oral 5-azacitidine and romidepsin and experiencing grades 1-4 toxicities will be tallied based on events observed and assessed by a qualified investigator. This Outcome Measure is specifically for Phase 1 of the study.	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	The percentage of people in a study or treatment group who have a partial response or complete response to the treatment within a certain period of time. A partial response is a decrease in the size of a tumor or in the amount of cancer in the body, and a complete response is the disappearance of all signs of cancer in the body. In a clinical trial, measuring the ORR is one way to see how well a new treatment works.	Up to 3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I: Maximum number of cycles received	Pending	Up to 1.5 years
Phase I: Number of dose delays at the maximally tolerated dose (MTD)	Pending	Up to 1.5 years
Phase I: Number of dose reductions at the maximally tolerated dose (MTD)	Pending	Up to 1.5 years
Phase I: Overall response rate (ORR) of the study population	Pending	Up to 1.5 years
Phase I & II: Progression free survival (PFS) of the study population	Pending	Up to 1.5 years
Phase I & II: Duration of response (DOR) of the study population		Up to 1.5 years
Phase II: Prevalence of overall survival of the patients with T-cell lymphoma on study	Data analysis ongoing	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.	Data analysis ongoing	Up to 1.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase I & II: Prevalence of pharmacodynamic markers of drug effect indicated in optional paired tissue biopsies	Samples taken from baseline and post treatment timepoints will be compared to try to identify pharmacodynamic markers of drug effect.	Up to 1.5 years
Phase I: Concentration time curve (AUC) for the combination of oral 5-azacitidine & romidepsin in cycle 1	Samples will be drawn at various timepoints and run in aggregate during the course of the study.	Up to 1.5 hours

Collaborators and Investigators

• Sponsor: Columbia University
• Collaborators: Celgene
• Investigators: Principal Investigator: Owen A. O'Connor, MD, Ph.D., Columbia University

Publications and helpful links

General Publications

• O'Connor OA, Falchi L, Lue JK, Marchi E, Kinahan C, Sawas A, Deng C, Montanari F, Amengual JE, Kim HA, Rada AM, Khan K, Jacob AT, Malanga M, Francescone MM, Nandakumar R, Soderquist CR, Park DC, Bhagat G, Cheng B, Risueno A, Menezes D, Shustov AR, Sokol L, Scotto L. Oral 5-azacytidine and romidepsin exhibit marked activity in patients with PTCL: a multicenter phase 1 study. Blood. 2019 Oct 24;134(17):1395-1405. doi: 10.1182/blood.2019001285.
• Falchi L, Ma H, Klein S, Lue JK, Montanari F, Marchi E, Deng C, Kim HA, Rada A, Jacob AT, Kinahan C, Francescone MM, Soderquist CR, Park DC, Bhagat G, Nandakumar R, Menezes D, Scotto L, Sokol L, Shustov AR, O'Connor OA. Combined oral 5-azacytidine and romidepsin are highly effective in patients with PTCL: a multicenter phase 2 study. Blood. 2021 Apr 22;137(16):2161-2170. doi: 10.1182/blood.2020009004. Erratum In: Blood. 2022 Mar 10;139(10):1600. doi: 10.1182/blood.2021012550.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2013
• Primary Completion (Actual): January 6, 2020
• Study Completion (Actual): January 6, 2020

Study Registration Dates

• First Submitted: November 20, 2013
• First Submitted That Met QC Criteria: November 25, 2013
• First Posted (Estimated): November 28, 2013

Study Record Updates

• Last Update Posted (Actual): August 22, 2024
• Last Update Submitted That Met QC Criteria: August 16, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Lymphoma; Follicular Lymphoma; Marginal Zone Lymphoma; Chronic Lymphocytic Leukemia; Waldenstrom Macroglobulinemia; Mantle Cell Lymphoma; Burkitt Lymphoma; Diffuse Large B-Cell Lymphoma; Peripheral T-cell Lymphoma; Anaplastic Large Cell Lymphoma; Small Lymphocytic Lymphoma; Cutaneous T-cell Lymphoma; Hodgkin Lymphoma; Lymphoid Malignancies; Non-hodgkin Lymphoma
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Neoplasms; Lymphoma; Hodgkin Disease; Lymphoma, Non-Hodgkin; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Antibiotics, Antineoplastic; Histone Deacetylase Inhibitors; Azacitidine; Romidepsin
• Other Study ID Numbers: AAAM3752

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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