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

Sponsor

Columbia University (Other)

Overall Status

Terminated

CT.gov ID

NCT01998035

Collaborator

Celgene (Industry)

Enrollment

Location

Arms

74.2

Duration (Months)

0.7

Patients Per Site Per Month

Study Details

Study Description

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.

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

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 Design

Study Type:

Interventional

Actual Enrollment :

52 participants

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 Relapsed and Refractory Lymphoid Malignancies

Study Start Date :

Nov 1, 2013

Actual Primary Completion Date :

Jan 6, 2020

Actual Study Completion Date :

Jan 6, 2020

Arms and Interventions

Arm	Intervention/Treatment
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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 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 Names: Istodax Drug: Oral 5-Azacitidine A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg) Other Names: 5-AC

Outcome Measures

Primary Outcome Measures

Phase I: Maximum tolerated dose (MTD) of the combination of oral 5-azacitidine & romidepsin [up to 1.5 years]
Phase I: Number of dose limiting toxicities (DLTs) of the combination of oral 5-azacitidine & romidepsin [up to 1 year]
Phase I: Number of toxicities experienced by patients with the combination of oral 5-azacitidine and romidepsin [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 [Up to 3 years]

Secondary Outcome Measures

Phase I: Maximum number of cycles received [Up to 1.5 years]
Pending
Phase I: Number of dose delays at the maximally tolerated dose (MTD) [Up to 1.5 years]
Pending
Phase I: Number of dose reductions at the maximally tolerated dose (MTD) [Up to 1.5 years]
Pending
Phase I: Overall response rate (ORR) of the study population [Up to 1.5 years]
Pending
Phase I & II: Progression free survival (PFS) of the study population [Up to 1.5 years]
Pending
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 [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. [Up to 1.5 years]
Data analysis ongoing

Other Outcome Measures

Phase I & II: Prevalence of pharmacodynamic markers of drug effect indicated in optional paired tissue biopsies [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 [Up to 1.5 hours]
Samples will be drawn at various timepoints and run in aggregate during the course of the study.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.