Treatment of PTCL With Aggressive Induction Therapy Followed by Autologous SCT Using Denileukin Diftitox (Ontak)

Study Overview
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Brief Summary
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This study examines the use of denileukin diftitox (Ontak) for patients with peripheral T-cell lymphoma who are candidates for autologous stem cell transplants.

Detailed Description
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This protocol proposes first to increase the proportion of patients who achieve adequate initial disease control and are able to proceed to autologous stem cell transplant (ASCT) in first complete or partial remission. It administers intensive and novel induction therapy. Two cycles of gemcitabine, vinorelbine, Doxil (GND) will be used followed by two cycles of augmented dose Cyclophosphamide (CHOP) plus high-dose methotrexate (MTX). Patients will be restaged after two cycles of GND to assess response to GND alone and again after the second cycle of augmented CHOP/high-dose MTX. Those achieving a remission status will receive intensive consolidation with HiDAC/etoposide followed by stem cell mobilization. A five-day course of denileukin diftitox (Ontak) will be administered at and will serve as an in vivo purge. This will be followed by autologous stem cell transplant. Those not achieving partial remission or better following the four induction courses will receive 2 cycles of denileukin diftitox(Ontak) for 5 days. Those achieving partial remission or better to this regimen will go on to consolidation/mobilization and autologous stem cell transplant. Post-transplant, denileukin diftitox will also be used as an additional module of therapy.

Official Title
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Treatment of Peripheral T-cell Lymphoma With Aggressive Induction Chemotherapy Followed by Autologous Stem Cell Transplant Using Denileukin Diftitox (Ontak) for In-vivo Purging and Post-Transplant Therapy: A Multicenter Phase II Clinical Trial

Conditions
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Peripheral T-Cell Lymphoma

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Navelbine
* Drug: Doxorubicin Hydrochloride Liposome Injection
* Drug: Granulocyte-colony stimulating factor (G-CSF)
* Drug: Pegfilgrastim
* Drug: Cyclophosphamide
* Drug: Vincristine
* Drug: Leucovorin
* Drug: Methotrexate
* Drug: Doxorubicin Hydrochloride
* Drug: Cytarabine
* Drug: Etoposide
* Drug: Carmustine
* Drug: Denileukin diftitox


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologic diagnosis of any of the following: Peripheral T-cell lymphoma not otherwise specified (PTCL-U),(IPI >2) Angioimmunoblastic T-cell lymphoma (AILT) (IPI >2) Non-primary cutaneous Alk-1-negative anaplastic large cell lymphoma Extranodal natural killer (NK)/T lymphoma (Excluding stage I/II nasal disease) Blastic NK cell lymphoma Enteropathy type T-cell lymphoma Cutaneous panniculitis-like T-cell lymphoma Hepatosplenic T-cell lymphoma Measurable or assessable disease is not required. Age ≥ 18 and ≤ 70 years Previously untreated or 1 prior cycle of chemotherapy Creatinine < 2.0 mg/dL Total bilirubin < 2.0 mg/dL, aspartate aminotransferase (AST) < 3x upper limit of normal Patients who test positive for Hepatitis B surface Ag (HepBSAg) or Hepatitis C antibody (HepCAb) are eligible provided all of the following criteria are met: bilirubin ≤ 2 x upper limit of normal; aspartate aminotransferase (AST) ≤ 3 x upper limit of normal; liver biopsy demonstrates ≤ grade 2 fibrosis and no cirrhosis. Hepatitis B surface Ag(+) patients will be treated with lamivudine (3TC) or investigator's preferred antiviral regimen throughout protocol therapy and for 6-12 months thereafter. Neutrophils ≥ 1000/microlitre (uL) platelets > 100,000/uL HIV-negative Left ventricular ejection fraction (LVEF) of ≥ 45% No known hypersensitivity to denileukin diftitox or any of its components: diptheria toxin, interleukin-2, or excipients Non-pregnant, non-nursing: Treatment under this protocol would expose an unborn child to significant risks. Women and men of reproductive potential should agree to use an effective means of birth control. Patients with a currently active second malignancy, other than non-melanoma skin cancers are not eligible. (This includes Waldenstrom's Macroglobulinemia, since such patents have experienced transient increases inImmunoglobulin M (IgM) following initiation of rituximab, with the potential for hyperviscosity syndrome requiring plasmapheresis). Patients are not considered to have a currently active malignancy if they have completed anti-cancer therapy, and are considered by their physician to be at less than 30% risk of relapse. Exclusion Criteria: PTCL-U / AILT with IPI 0 or 1 Extranodal NK/T nasal stage I/II T-lymphoblastic lymphoma Adult T-cell leukemia/lymphoma Adult T-cell leukemia/lymphoma

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Plan<br>(1) Induction Chemo A; Two 21-day cycles of Gemcitabine 1000 mg/m2 days (D) 1, 8, Navelbine 20 mg/m2 D1, D8; Doxil 15 mg/m2 Days 1 and 8, G-CSF Days 4-6 and 10-15 (2) Induction Chemo B: Two 21-day cycles of Cyclophosphamide 2000 mg/m2 day 1; Doxorubicin 50 mg/m2 day 1; Vincristine 1.4 mg/m2 day 1; Prednisone 100 mg/m2 days 1-5; Methotrexate 3000 mg/m2 IV over 4h day 15; Leucovorin rescue (3) Disease Evaluation (4) High-dose Consolidation Chemo, high dose Ara-C, Denileukin diftitox (Ontak) and Stem Cell Collection (5) Consolidation Cytarabine 2000 mg/m2 IV over 2 h q 12h days 1-4, Etoposide 40 mg/m2 continuous intravenous infusion (CIVI), days 1-4, Denileukin Diftitox (Ontak) 9 mcg/kg/day days 6-10, G-CSF 10 mcg/kg/day day 14+, Stem cell collection day 22 (6) Autologous Stem Cell Transplant Carmustine 550 mg/m2 day -6, Etoposide 60 mg/kg IV over 4h day -4, Cyclophosphamide 100 mg/kg day -2, Stem cell infusion D0 (7) Post-transplant: Denileukin Diftitox (Ontak) 18 mcg/kg/day days 1- 5 | Drug: Gemcitabine<br>* Chemotherapy medication used to treat a number of types of cancer<br>* Other names: Gemzar;Drug: Navelbine<br>* Navelbine is an chemotherapy medication used to treat a number of types of cancer<br>* Other names: Vinorelbine;Drug: Doxorubicin Hydrochloride Liposome Injection<br>* Doxorubicin Hydrochloride Liposome Injection is an anti-cancer chemotherapy drug<br>* Other names: Doxil;Drug: Granulocyte-colony stimulating factor (G-CSF)<br>* G-CSF is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.<br>* Other names: G-CSF;Drug: Pegfilgrastim<br>* Colony-stimulating factor 3 (CSF 3) and, is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream. May be used instead of G-CSF<br>* Other names: Neulasta;Drug: Cyclophosphamide<br>* Cancer medication that interferes with the growth and spread of cancer cells in the body<br>* Other names: Cytoxan;Drug: Vincristine<br>* Vincristine is a chemotherapy medication used to treat cancer. Vincristine works by stopping the cancer cells from separating into 2 new cells to stops the growth of the cancer<br>* Other names: Oncovin;Drug: Leucovorin<br>* Leucovorin is used to prevent harmful effects of methotrexate when methotrexate is used to treat certain types of cancer.<br>* Other names: Wellcovorin;Drug: Methotrexate<br>* Methotrexate is a chemotherapy medication used to treat cancer<br>* Other names: Trexall;Drug: Doxorubicin Hydrochloride<br>* Doxorubicin Hydrochloride is a chemotherapy medication used to treat cancer<br>* Other names: Adriamycin;Drug: Cytarabine<br>* Medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), and non-Hodgkin's lymphoma<br>* Other names: HiDAC;Drug: Etoposide<br>* Etoposide is a is a chemotherapy medication used to treat cancer<br>* Other names: Etopophos;Drug: Carmustine<br>* Carmustine is a chemotherapy medication used to treat cancer<br>* Other names: BCNU;Drug: Denileukin diftitox<br>* Denileukin diftitox is an antineoplastic agent, an engineered protein combining Interleukin-2 and Diphtheria toxin. Denileukin diftitox could bind to Interleukin-2 receptors and introduce the diphtheria toxin into cells that express those receptors, killing the cells<br>* Other names: Ontak;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression-Free Survival will be defined the percentage of participants alive and progression-free at median follow up of 25 months. Patients will be routinely followed for disease progression and those who die without a reported prior progression will be considered to have progressed on the day of their death. Patients who did not progress or die will be censored at the day of their last treatment assessment. Patients who have not received study regimen or did not have on-study treatment assessments will be censored on the day they entered the trial. Patients who receive chemotherapy for reasons other than documented progression of disease or clinical progression without documented progression will be censored on the earliest date of subsequent therapy | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Rate | Overall Survival will be defined the percentage of participants alive at median follow up of 25 months. If the patient is lost to follow-up, survival will be censored on the last date the patient was known to be alive. The analysis is expected to occur up to 60 months after the first patient is entered the trial. | Up to 5 years | 
| Complete Response Rate | The complete response rate will be defined as the total number of patients who have defined complete response using study regimen (intensive induction therapy/progressive chemotherapy/stem cell rescue), divided by the number of patients entered in the trial using response-evaluable patients. | Up to 3 years | 
| Median Time to Response | The time to response is measured from the time measurement criteria are met for complete response or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started) in months. | Up to 2 years |