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

Lymphoma Clinical Trial

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 Relapsed and Refractory Lymphoid Malignancies

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01998035
• Other study ID #: AAAM3752
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: November 2013
• Est. completion date: January 6, 2020

Study information

• Verified date: January 2021
• Source: Columbia University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 52
• Est. completion date: January 6, 2020
• Est. primary completion date: January 6, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Hodgkin Disease
• Hodgkin Lymphoma
• Lymphoid Malignancies
• Lymphoma
• Lymphoma, Non-Hodgkin
• Neoplasms
• Non-hodgkin Lymphoma

Intervention

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)
• Oral 5-Azacitidine
A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)

Locations

Country	Name	City	State
United States	Columbia University Medical Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Columbia University	Celgene

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	Phase I: Maximum tolerated dose (MTD) of the combination of oral 5-azacitidine & romidepsin		up to 1.5 years
Primary	Phase I: Number of dose limiting toxicities (DLTs) of the combination of oral 5-azacitidine & romidepsin		up to 1 year
Primary	Phase I: Number of toxicities experienced by patients with the combination of oral 5-azacitidine and romidepsin		Up to 1.5 years
Primary	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		Up to 3 years
Secondary	Phase I: Maximum number of cycles received	Pending	Up to 1.5 years
Secondary	Phase I: Number of dose delays at the maximally tolerated dose (MTD)	Pending	Up to 1.5 years
Secondary	Phase I: Number of dose reductions at the maximally tolerated dose (MTD)	Pending	Up to 1.5 years
Secondary	Phase I: Overall response rate (ORR) of the study population	Pending	Up to 1.5 years
Secondary	Phase I & II: Progression free survival (PFS) of the study population	Pending	Up to 1.5 years
Secondary	Phase I & II: Duration of response (DOR) of the study population		Up to 1.5 years
Secondary	Phase II: Prevalence of overall survival of the patients with T-cell lymphoma on study	Data analysis ongoing	Up to 1.5 years
Secondary	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