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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Lymphoid Malignancies, Lymphoma, Hodgkin Lymphoma, Non-hodgkin Lymphoma

Intervention / Treatment
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* Drug: Romidepsin
* Drug: Oral 5-Azacitidine


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: R/O: Level -1<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|
| Experimental: R/O: Level 1<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|
| Experimental: R/O: Level 2<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|
| Experimental: R/O: Level 3<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|
| Experimental: R/O: Level 4<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|
| Experimental: R/O: Level 5<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|
| Experimental: R/O: Level 6<br>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<br>* Romidepsin is an anti-cancer (antineoplastic or cytotoxic) chemotherapy drug. Romidepsin is classified as a Histone Deacetylase Inhibitor. Dose escalation (10, 14 mg/m2)<br>* Other names: Istodax;Drug: Oral 5-Azacitidine<br>* A pyrimidine nucleoside analogue of cytidine with antineoplastic activity. Dose escalation (100, 200, 300 mg)<br>* Other names: 5-AC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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

| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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