Clinical trial NCT01998035: Romidepsin Plus Oral 5-Azacitidine in Relapsed/Refractory Lymphoid Malignancies
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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Lymphoid Malignancies
Lymphoma
Hodgkin Lymphoma
Non-hodgkin Lymphoma
Keywords: 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
Lead sponsor: Columbia University
Sponsor class: OTHER
Collaborators: name: Celgene
First posted: 2013-11-28
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility 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.
* 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.

Primary outcomes:
measure: Phase I: Maximum Tolerated Dose (MTD) of the Combination of Oral 5-azacitidine in Combination With Romidepsin
timeFrame: up to 1.5 years
measure: Phase I: Maximum Tolerated Dose (MTD) of Romidepsin in Combination With Oral 5-azacytidine
timeFrame: up to 1.5 years
measure: Percentage of Patients Who Experienced Significant Toxicities in Phase 1
timeFrame: Up to 1.5 years
measure: 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
timeFrame: Up to 3 years
Secondary outcomes:
Other outcomes:
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
Study officials:
affiliation: Columbia University
name: Owen A. O'Connor, MD, Ph.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.