Pralatrexate + Romidepsin in Relapsed/Refractory Lymphoid Malignancies

Study Overview
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Brief Summary
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This is a study to test how safe the combination of the drugs Romidepsin and Pralatrexate are in patients with lymphoid malignancies and to determine the dose of the combination of drugs that is safest. If the combination is determined to be safe, the study will continue accrual patients with peripheral T-Cell lymphoma (PTCL).

Detailed Description
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The non- Hodgkin lymphomas (NHL) represent a heterogeneous group of malignancies. Under the rubric of lymphoma exist some of the fastest growing cancers known to science, (Burkett's lymphoma, lymphoblastic lymphoma/leukemia), as well as some of the most indolent (small lymphocytic lymphoma, follicular lymphoma, and marginal zone lymphoma). This remarkable diversity of biology imposes significant challenges. Researchers are seeking to understand the cell of origin and differentiate what are sometimes subtle differences between the related sub-types of disease; and to identify the best treatments for these subtypes, with the ever-increasing likelihood that new understanding of the molecular pathogenesis of these diseases will result in an increase in new drugs for specific target populations.

Official Title
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Phase I/IIA Study of the Novel Antifolate Agent Pralatrexate in Combination With the Histone Deacetylase Inhibitor Romidepsin for the Treatment of Patients With Peripheral T-cell Lymphoma

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

Intervention / Treatment
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* Drug: Pralatrexate
* Drug: Romidepsin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase I: Patients must have histologically confirmed relapsed or refractory Non-Hodgkin's lymphoma, Hodgkin's Disease or multiple myeloma (defined by World Health Organization (WHO) criteria). Phase II: Patients must have histologically confirmed relapsed or refractory T-Cell Lymphoma (as defined by WHO criteria). Must have received first line chemotherapy. No upper limit for the number of prior therapies Evaluable Disease Age ≥18 years Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Patients must have adequate organ and marrow function as defined in the protocol Adequate Contraception Ability to understand and the willingness to sign a written informed consent document Inclusion Criteria for Multiple Myeloma patients specified in the protocol Exclusion Criteria: Prior Therapy Exposure to chemotherapy or radiotherapy within 2 weeks (6 weeks for nitrosureas or mitomycin C) 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 to the equivalent of ≤10 mg/day prednisone prior to the start of the study drugs No other investigational agents are allowed Central nervous system metastases, including lymphomatous meningitis History of allergic reactions to Pralatrexate or Romidepsin Uncontrolled intercurrent illness Pregnant women Nursing women Current malignancy or history of a prior malignancy, as outlined in the protocol Patient known to be Human Immunodeficiency Virus (HIV)-positive Active Hepatitis A, Hepatitis B, or Hepatitis C infection

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I: Schedule A<br>Subjects will receive dose escalation of pralatrexate and romidepsin, receiving both infusions on days 1 and 8 of each 21 day cycle | Drug: Pralatrexate<br>* Phase I - Schedule A: Intravenous drug given on days 1 and 8 of each 21 day cycle Schedule B: Intravenous drug given on days 1 and 15 of each 28 day cycle Dose escalation from 10 mg/m2 to 25 mg/m2 Phase II - 25 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle.<br>* Other names: Folotyn;Drug: Romidepsin<br>* Phase I - Schedule A: Intravenous drug given on days 1 and 8 of each 21 day cycle Schedule B: Intravenous drug given on days 1 and 15 of each 28 day cycle Dose escalation from 12 mg/m2 to 14 mg/m2. Phase II - 12 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle.<br>* Other names: Istodax;|
| Experimental: Phase I: Schedule B<br>Subjects will receive dose escalation of pralatrexate and romidepsin, receiving both infusions on days 1 and 15 of each 28 day cycle | Drug: Pralatrexate<br>* Phase I - Schedule A: Intravenous drug given on days 1 and 8 of each 21 day cycle Schedule B: Intravenous drug given on days 1 and 15 of each 28 day cycle Dose escalation from 10 mg/m2 to 25 mg/m2 Phase II - 25 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle.<br>* Other names: Folotyn;Drug: Romidepsin<br>* Phase I - Schedule A: Intravenous drug given on days 1 and 8 of each 21 day cycle Schedule B: Intravenous drug given on days 1 and 15 of each 28 day cycle Dose escalation from 12 mg/m2 to 14 mg/m2. Phase II - 12 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle.<br>* Other names: Istodax;|
| Experimental: Phase II<br>Subjects will receive Pralatrexate 25 mg/m2 and Romidepsin 12 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle | Drug: Pralatrexate<br>* Phase I - Schedule A: Intravenous drug given on days 1 and 8 of each 21 day cycle Schedule B: Intravenous drug given on days 1 and 15 of each 28 day cycle Dose escalation from 10 mg/m2 to 25 mg/m2 Phase II - 25 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle.<br>* Other names: Folotyn;Drug: Romidepsin<br>* Phase I - Schedule A: Intravenous drug given on days 1 and 8 of each 21 day cycle Schedule B: Intravenous drug given on days 1 and 15 of each 28 day cycle Dose escalation from 12 mg/m2 to 14 mg/m2. Phase II - 12 mg/m2 will be given intravenously once weekly on days 1 and 15 on a 28 day cycle.<br>* Other names: Istodax;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose (MTD) of the combination of pralatrexate and romidepsin | For Phase I | Up to 1.5 years | 
| Overall response rate (ORR) (complete + partial response) of the combination of pralatrexate and romidepsin in patients with relapsed/refractory T-Cell Lymphoma | For Phase II | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum number of cycles received | For Phase II | Up to 1.5 years | 
| Number of dose delays at the MTD | For Phase I | Up to 1.5 years | 
| Overall response rate (ORR) of the study population | For Phase I | Up to 1.5 years | 
| Duration of response (DOR) of the combination in patients with T-Cell Lymphoma | For Phase II | Up to 3 years | 
| Overall survival (OS) of patients with T-Cell Lymphoma on study | For Phase II | Up to 3 years | 
| Progression free survival (PFS) of the combination in patients with T-Cell Lymphoma | For Phase II | Up to 3 years | 
| Number of dose reductions at the MTD | For Phase I | Up to 1.5 years | 
| Progression free survival (PFS) of the study population | For Phase I | Up to 1.5 years | 
| Duration of response (DOR) of the study population. | For Phase I | 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, Multiple Myeloma, 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