Study of Pralatrexate & Gemcitabine With B12 & Folic Acid to Treat Relapsed/Refractory Lymphoproliferative Malignancies

Study Overview
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Brief Summary
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This study is for patients with lymphoproliferative malignancies that have progressed after receiving a previous treatment (relapsed) or are no longer responding to treatment (refractory). To be in this study, patients must have certain types of Hodgkin's lymphoma (HL), peripheral T-cell lymphoma (PTCL), or B-cell lymphoma, including Waldenstrom's macroglobulinemia. This study is being done to find doses of the combination of pralatrexate and gemcitabine with vitamin B12 and folic acid that can be safely given to patients with these types of lymphoma and explore the effectiveness of the treatment.

Official Title
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A Phase 1/2a Open-label Study of Pralatrexate and Gemcitabine With Vitamin B12 and Folic Acid Supplementation in Patients With Relapsed or Refractory Lymphoproliferative Malignancies

Conditions
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Relapsed or Refractory Lymphoproliferative Malignancies, Hodgkin's Lymphoma, Peripheral T-cell Lymphoma, B-cell Lymphoma, Waldenstrom's Macroglobulinemia

Intervention / Treatment
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* Drug: Pralatrexate Injection
* Drug: Gemcitabine Hydrochloride
* Dietary Supplement: Vitamin B12
* Dietary Supplement: Folic Acid


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1: Histologically/cytologically confirmed lymphoproliferative malignancy. Patients with Hodgkin lymphoma (HL) or non-HL are eligible, with exceptions per exclusion criteria. Phase 2a: Histologically/cytologically confirmed HL, peripheral T-cell lymphoma (PTCL), or B-cell lymphoma including Waldenström's macroglobulinemia, with exceptions per exclusion criteria. Progression of disease (PD) after at least 1 prior treatment (any number of prior therapies allowed). PD after last prior treatment and recovered from toxic effects of prior therapy. Patients treated with an FDA-approved monoclonal antibody therapy may be enrolled at any time after the therapy if they have PD. PTCL patients must have received single-agent pralatrexate as a prior therapy. Eastern Cooperative Oncology Group performance status ≤ 2. Adequate blood, liver and kidney function per laboratory tests. Has taken 1 mg daily oral folic acid for at least 7 days prior to planned start of pralatrexate and received 1 mg vitamin B12 intramuscularly within 10 weeks of the planned start of pralatrexate. Females of childbearing potential must practice a medically acceptable contraceptive regimen from first dose until at least 30 days after last dose of pralatrexate and have a negative serum pregnancy test within 14 days prior to the first day of study treatment. Postmenopausal (defined as greater than 12 months since last menses) and surgically sterilized females do not require this test. Males who are not surgically sterile must practice a medically acceptable contraceptive regimen from first dose until at least 90 days after last dose of pralatrexate. Give written informed consent. Exclusion Criteria: Phase 1 1. B-cell: lymphoplasmacytic lymphoma (± Waldenström's macroglobulinemia); plasma cell myeloma/plasmacytoma; hairy cell leukemia. Phase 2a PTCL: precursor T/Natural Killer (NK) neoplasms, with the exception of blastic NK lymphoma; T-cell prolymphocytic leukemia; T-cell large granular lymphocytic leukemia; mycosis fungoides (MF), except transformed MF; Sézary syndrome; primary cutaneous CD30+ disorders: Anaplastic large cell lymphoma and lymphomatoid papulosis. B-cell: plasma cell myeloma/plasmacytoma; hairy cell leukemia. Relapsed HL or diffuse large B-cell lymphoma patients who are candidates for high dose therapy and autologous stem cell transplantation (SCT) and for whom it is a standard curative option. Active concurrent malignancy (except non melanoma skin cancer or carcinoma in situ of the cervix). If there is a history of prior malignancy, must be disease free for at least 5 years. Congestive heart failure Class III/IV. Uncontrolled hypertension. Human immunodeficiency virus (HIV)- positive diagnosis with CD4 less than 100 or detectable viral load within past 3 months and receiving anti-retroviral therapy. Hepatitis B or C virus with detectable viral load or immunological evidence of chronic active disease or receiving/requiring antiviral therapy. Central nervous system disease. Undergone an allogeneic SCT. Patients with disease refractory to peripheral blood SCT, or who have relapsed less than 100 days since an autologous or peripheral blood SCT. Active uncontrolled infection, underlying medical condition including unstable heart disease, or other serious illness impairing the ability to receive protocol treatment. Major surgery within 2 weeks of planned start of treatment. Receipt of any conventional chemotherapy or radiation therapy (encompassing greater than 10% of bone marrow) within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study treatment or planned use during the study. Receipt of systemic corticosteroids within 7 days of study treatment, unless on a continuous dose of no more than 10 mg/day of prednisone for at least 1 month. Use of investigational drugs, biologics, or devices within 4 weeks prior to study treatment or planned use during the study. Received a monoclonal antibody within 3 months without evidence of PD. Previous exposure to pralatrexate and/or gemcitabine if discontinued due to treatment-related toxicity.

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: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pralatrexate & Gemcitabine - Sequential Days<br> | Drug: Pralatrexate Injection<br>* Intravenous (IV) push administration over 30 seconds to 5 minutes into a patent IV line containing normal saline (0.9% sodium chloride). Sequential Dosing: 10 mg/m2 every 2 weeks (days 1 and 15) of a 4-week cycle until criteria for discontinuation per the protocol are met. Same Day Dosing: 15 mg/m2 every 2 weeks (days 1 and 15) of a 4-week cycle until criteria for discontinuation per the protocol are met.<br>* Other names: (RS)-10-propargyl-10-deazaaminopterin;Drug: Gemcitabine Hydrochloride<br>* Gemcitabine will be prepared and administered as an IV infusion as per manufacturer instructions. Sequential Dosing: 400 mg/m2 every 2 weeks (days 2 and 16) of a 4-week cycle until criteria for discontinuation per the protocol are met. Same Day Dosing: 600 mg/m2 every 2 weeks (days 1 and 15) of a 4-week cycle until criteria for discontinuation per the protocol are met.<br>* Other names: Gemcitabine Hydrochloride (HCl) for Injection;Dietary Supplement: Vitamin B12<br>* 1 mg intramuscular injection Administered within 10 weeks of enrollment, every 8-10 weeks throughout the study and for at least 30 days after last dose of pralatrexate.<br>* Other names: Cyanocobalamin;Dietary Supplement: Folic Acid<br>* 1 mg orally Administered daily for at least 7 days prior to start of pralatrexate, throughout the study and for at least 30 days after last dose of pralatrexate.<br>* Other names: Folacin;|
| Experimental: Pralatrexate & Gemcitabine - Same Day<br> | Drug: Pralatrexate Injection<br>* Intravenous (IV) push administration over 30 seconds to 5 minutes into a patent IV line containing normal saline (0.9% sodium chloride). Sequential Dosing: 10 mg/m2 every 2 weeks (days 1 and 15) of a 4-week cycle until criteria for discontinuation per the protocol are met. Same Day Dosing: 15 mg/m2 every 2 weeks (days 1 and 15) of a 4-week cycle until criteria for discontinuation per the protocol are met.<br>* Other names: (RS)-10-propargyl-10-deazaaminopterin;Drug: Gemcitabine Hydrochloride<br>* Gemcitabine will be prepared and administered as an IV infusion as per manufacturer instructions. Sequential Dosing: 400 mg/m2 every 2 weeks (days 2 and 16) of a 4-week cycle until criteria for discontinuation per the protocol are met. Same Day Dosing: 600 mg/m2 every 2 weeks (days 1 and 15) of a 4-week cycle until criteria for discontinuation per the protocol are met.<br>* Other names: Gemcitabine Hydrochloride (HCl) for Injection;Dietary Supplement: Vitamin B12<br>* 1 mg intramuscular injection Administered within 10 weeks of enrollment, every 8-10 weeks throughout the study and for at least 30 days after last dose of pralatrexate.<br>* Other names: Cyanocobalamin;Dietary Supplement: Folic Acid<br>* 1 mg orally Administered daily for at least 7 days prior to start of pralatrexate, throughout the study and for at least 30 days after last dose of pralatrexate.<br>* Other names: Folacin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Responses Assessed by International Workshop Criteria (IWC) | Number of participants who achieved an objective response. Objective response was defined as a tumor response assessment of either complete response (CR) or partial response (PR) and was determined only for patients with measurable disease at baseline. A tumor response assessment reported by IWC without PET was used for any analyses in cases where an IWC+PET evaluation was not done. | Assessed every 8 weeks (+/- 1 week) for Phase II and no less than every 3 cycles for Phase I | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of Response | Duration of response was defined as the number of days between the date of first tumor response assessment of objective response to the time of the first tumor response assessment of progressive disease (PD) or death due to any cause (date of first PD assessment or death - date of first objective response assessment + 1) | Response assessments were performed no less than every 3 cycles in the Phase 1 part of the study and every 8 weeks (± 1 week) in the Phase 2a part of the study | 
| Progression-free Survival (PFS) Time | PFS time was calculated as the number of days from study day 1 to the date of PD or death, regardless of cause (date of PD or death - study day 1 + 1). | Response assessments were performed no less than every 3 cycles in the Phase 1 part of the study and every 8 weeks (± 1 week) in the Phase 2a part of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PDX, Lymphoproliferative malignancies, Lymphoma, Hodgkin's lymphoma (HL), Non-Hodgkin's lymphoma (NHL), PTCL, T/NK-cell leukemia/lymphoma, T-cell lymphoma/leukemia (HTLV 1+), Angioimmunoblastic T-cell lymphoma, Blastic NK lymphoma, Anaplastic large cell lymphoma, T/NK-cell lymphoma, Enteropathy-type intestinal lymphoma, Hepatosplenic T-cell lymphoma, Extranodal peripheral T/NK-cell lymphoma, Subcutaneous panniculitis T-cell lymphoma, Transformed mycosis fungoides, Pralatrexate, Gemcitabine, Gemzar, Vitamin B12, Folic acid