Combination Chemotherapy and Pralatrexate as First-Line Therapy in Treating Patients With Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To evaluate in a Phase II study a preliminary estimate of the complete response (CR) rate of a new chemotherapy regimen involving Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) alternating with Pralatrexate (P) as front line therapy for patients with Stage II, III and IV Peripheral T-Cell NHL not otherwise specified (NOS), Anaplastic large cell lymphoma (ALK negative), Angioimmunoblastic T-cell lymphoma, Enteropathy associated T-cell lymphoma, Hepatosplenic gamma delta T-cell lymphoma followed by an optional stem cell transplant with high dose chemotherapy and Autologous stem cell transplant.

SECONDARY OBJECTIVES:

I. To evaluate partial response (PR). II. To evaluate overall response (CR+PR). III. To evaluate the safety and tolerability of the regimen IV. To assess the 2 year event free survival (EFS) and overall survival (OS) using this regimen.

V. To assess the percentage of patients who proceeded with transplant. VI. To evaluate the ability to collect peripheral blood stem cells after this regimen.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) and vincristine IV on day 1, etoposide IV on days 1-3 or orally (PO) once daily (QD) on days 2-3, and prednisone PO QD on days 1-5 (CEOP administration). Patients also receive pralatrexate IV over 3-5 minutes on days 15, 22, and 29 (P administration). Treatment repeats every 42 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Patients with Complete Response (CR) or Partial Response (PR), per investigators discretion, may then undergo hematopoietic stem cell collection and administration of standard preparative regimen followed by hematopoietic stem cell transplantation.

After completion of study treatment, patients are followed up for 2 years (transplant patients) or periodically.

• prednisone (Drug), also known as DeCortin, Deltra: Given PO
• cyclophosphamide (Drug), also known as CPM, CTX, Cytoxan, Endoxan, Endoxana: Given IV
• etoposide (Drug), also known as EPEG, VP-16, VP-16-213: Given PO or IV
• Vincristine (Drug), also known as leurocristine sulfate, VCR, Vincasar PFS: Given IV
• pralatrexate (Drug), also known as FOLOTYN, PDX: Given IV
• laboratory biomarker analysis (Other): Correlative studies
• comparative genomic hybridization (Genetic), also known as comparative genomic analysis: Correlative studies
• gene expression analysis (Genetic): Correlative studies
• nucleic acid sequencing (Genetic), also known as Gene Sequencing, Molecular Biology, Nucleic Acid Sequencing: Correlative studies
• mutation analysis (Genetic): Correlative studies
• immunohistochemistry staining method (Other), also known as immunohistochemistry: Correlative studies
• microarray analysis (Genetic), also known as gene expression profiling: Correlative studies
• RNA analysis (Genetic): Correlative studies

Primary outcomes

• Complete Response Rate of Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) and Pralatrexate (P) Treatment [168 days - 252 days (4-6 courses; 42 days per course)]: Complete Response Rate (CR) was reported at the end of the CEOP-P (6 courses for patients not receiving transplant and 4-6 courses for patients receiving transplant). Response assessment was performed by computerized tomography (CT) or positron emission tomography (PET)/CT based on the investigator's preference after cycles 2, 4 and 6. Response was assessed by the treating physician according to the Cheson Revised response criteria (Cheson et al,, 2007) or International Harmonization Project criteria (Cheson, 2007), based on imaging modality used. Complete Response Definition: Disappearance of all evidence of disease Nodal Masses: (a) \[18F\]fluorodeoxyglucose(FDG)-avid or PET positive prior to therapy; mass of any size permitted if PETnegative (b) Variably FDG-avid or PET negative; regression to normal size on CT Spleen, Liver: Not palpable, nodules disappeared Bone Marrow: Infiltrate cleared on repeat biopsy; if indeterminate by morphology, immunohistochemistry should be negative

Secondary outcomes

• Overall Response Rates (ORR)= (Complete Response Rates (CR) + Partial Response Rates (PR)) [2 years]: Every patient who fulfills all aspects of patient eligibility who receives at least 2 complete courses of chemotherapy will be evaluable for the response endpoint. Response rates will be descriptively summarized using percentages and 95% confidence intervals. Complete Response Definition: Defined in Primary Objective Partial Response Definition: Regression of measurable disease and no new sites, Nodal Masses: > 50% decrease in sum of the product of the diameters (SPD) of up to 6 largest dominant masses; no increase in size of other nodes 1. FDG-avid or PET positive prior to therapy; one or more PET positive at previously involved site 2. Variably FDG-avid or PET negative; regression on CT Spleen, Liver:> 50% decrease in SPD of nodules (for single nodule in greatest transverse diameter); no increase in size of liver or spleen Bone Marrow: Irrelevant if positive prior to therapy; cell type should be specified
• Event Free Survival (EFS) [2 years]: Estimated 2-year Event Free Survival (EFS), as well as plots of EFS, will be produced using the method of Kaplan-Meier, along with 95% confidence intervals for EFS. Event-free survival is defined as time from therapy until relapse, progression, or death from any cause.
• Overall Survival (OS) [2 years]: Estimated 2-year Overall Survival (OS), as well as plots of OS, will be produced using the method of Kaplan-Meier, along with 95% confidence intervals for OS. Overall survival is defined as time from the first chemotherapy administered on trial until death from any cause.
• To Evaluate the Safety and Tolerability of the Regimen by the Percent of Participants With Indicated Adverse Events [22 months]: Adverse events will be summarized using patient level incidence rates so that a patient contributes once to any adverse event. The number and percentage of patients with any adverse event will be summarized for each course. Serious adverse events will be analyzed similarly.
• Percent of Patients Who Proceeded With Transplant [168-252 days (4 courses up to 6 courses of treatment)]: Percentage of patients who received consolidation with high dose therapy and autologous stem cell rescue (HDT/SCR).

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Histologically confirmed new diagnosis of Stage II, III and IV peripheral T-cell NHL not otherwise specified (NOS), anaplastic large cell lymphoma (ALK negative) (ALK positive if international prognostic index \[IPI\] 3, 4, or 5), angioimmunoblastic T-cell lymphoma, enteropathy associated T-cell lymphoma, hepatosplenic gamma delta T-cell lymphoma
* Pathology material (hematoxylin and eosin \[H\&E\] stain, immunohistochemistry \[IHC\] and pathology report from initial diagnosis, if slides are not available, then 8 unstained slides of 4 micron thickness or a representative block should be sent) will be reviewed, and the diagnosis confirmed by University Nebraska Medical Center (UNMC) pathology department (retrospective diagnostic review: treatment may commence prior to the UNMC review)
* No prior therapy with the exception of prior radiation therapy and 1 cycle of chemotherapy based on current diagnosis and clinical condition
* Age 19 years or older (the age of consent in Nebraska); age 18 years or older (applicable to states where the age of majority is 18)
* Expected survival duration of >= six months
* Karnofsky Performance Status >= 70
* Absolute neutrophil count (ANC) >= 1000 cells/mm\^3, unless due to lymphoma involvement of the bone marrow
* Platelet Count >= 100 mm\^3, unless due to lymphoma involvement of the bone marrow
* Total bilirubin =< 1.5 x upper normal limit (ULN), or =< 3 x ULN if documented hepatic involvement with lymphoma, or =< 5 x ULN if history of Gilbert's Disease
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN (=< 5 x ULN if documented hepatic involvement with lymphoma)
* Serum potassium within normal range
* Serum creatinine < 2.0 mg/dL or calculated creatinine clearance (CrCl) > 45 mL/min
* Prothrombin time (PT) or international normalized ratio (INR), and partial thromboplastin time (PTT) =< 1.5 x ULN unless patient is receiving anticoagulants; if patient is on anticoagulation therapy, levels should be within therapeutic range
* Patients with measurable disease; patients with non-measurable but evaluable disease may be eligible after discussion with the principal investigator (PI); baseline measurements and evaluations must be obtained within 6 weeks of registration to the study; abnormal positron emission tomography (PET) scans will not constitute evaluable disease, unless verified by computed tomography (CT) scan or other appropriate imaging
* Patients with measurable disease must have at least one objective measurable disease parameter; a clearly defined, bidimensionally measurable defect or mass measuring at least 2 cm in diameter on a CT scan will constitute measurable disease; proof of lymphoma in the liver is required by a confirmation biopsy
* Women must not be pregnant or breast-feeding due to teratogenic effects of chemotherapy

  * All females of childbearing potential must have a blood test within 2 weeks prior to registration to rule out pregnancy
  * Pregnancy testing is not required for post-menopausal or surgically sterilized women
* Male and female patients of reproductive potential must agree follow accepted birth control measures
* Patient must be able to adhere to the study visit schedule and other protocol requirements
* Patients must be willing to give written informed consent, and sign an institutionally approved consent form before performance of any study-related procedure not part of normal medical care; with the exception of 1 cycle of chemotherapy based on current diagnosis and clinical condition, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care
* No serious disease or condition that, in the opinion of the investigator, would compromise the patient's ability to participate in the study

Exclusion Criteria:

* Pregnant or breast feeding females
* Known positive for human immunodeficiency virus (HIV), human T-lymphotropic virus type 1 (HTLV-1), or infectious hepatitis, type A, B or C or active hepatitis
* Major surgery within 2 weeks of study drug administration
* Prior malignancies within the past 3 years with exception of adequately treated basal cell, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Grade 6 or less with stable prostate-specific antigen (PSA) levels
* Patients with a diagnosis of other peripheral T-cell lymphoma (PTCL) histologies other than those specified in the inclusion criteria
* Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment
* Any other clinically significant medical disease or condition laboratory abnormality or psychiatric illness that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent
* Concomitant administration of nonsteroidal anti-inflammatory drugs (NSAIDs) and trimethoprim/sulfamethoxazole will not be allowed, since these may result in delayed clearance of pralatrexate

Participant flow

Outcome results

• Complete Response Rate of Cyclophosphamide, Etoposide, Vincristine and Prednisone (CEOP) and Pralatrexate (P) Treatment (Primary), Number, percentage of participants analyzed: Treatment (Chemotherapy and Enzyme Inhibitor Therapy) 52
• Overall Response Rates (ORR)= (Complete Response Rates (CR) + Partial Response Rates (PR)) (Secondary), Number, percentage of participants analyzed: Treatment (Chemotherapy and Enzyme Inhibitor Therapy) 70
• Event Free Survival (EFS) (Secondary), Number, percentage of participants analyzed: Treatment (Chemotherapy and Enzyme Inhibitor Therapy) 39 (21 to 57)
• Overall Survival (OS) (Secondary), Number, percentage of participants analyzed: Treatment (Chemotherapy and Enzyme Inhibitor Therapy) 60 (39 to 76)
• To Evaluate the Safety and Tolerability of the Regimen by the Percent of Participants With Indicated Adverse Events (Secondary), Number, percentage of participants: Treatment (Chemotherapy and Enzyme Inhibitor Therapy) 27
• Percent of Patients Who Proceeded With Transplant (Secondary), Count of participants, Participants: Treatment 15

Adverse events

Time frame: 20 months

Serious adverse events by term

Other adverse events by term

• Advani RH, Ansell SM, Lechowicz MJ, Beaven AW, Loberiza F, Carson KR, Evens AM, Foss F, Horwitz S, Pro B, Pinter-Brown LC, Smith SM, Shustov AR, Savage KJ, Vose JM. A phase II study of cyclophosphamide, etoposide, vincristine and prednisone (CEOP) Alternating with Pralatrexate (P) as front line therapy for patients with peripheral T-cell lymphoma (PTCL): final results from the T- cell consortium trial. Br J Haematol. 2016 Feb;172(4):535-44. doi: 10.1111/bjh.13855. Epub 2015 Dec 2. PMID 26627450

• Julie M Vose, Principal investigator, University of Nebraska

NIH grants: P30CA036727