Yttrium Y 90 Basiliximab and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With Mature T-cell Non-Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase I trial studies the side effects and best dose of yttrium Y 90 basiliximab when given together with standard combination chemotherapy before a stem cell transplant in treating patients with mature T-cell non-Hodgkin lymphoma. Radioactive substances linked to monoclonal antibodies, such as yttrium Y 90 basiliximab, can bind to cancer cells and give off radiation which may help kill cancer cells. Drugs used in chemotherapy, such as carmustine, cytarabine, etoposide, and melphalan (BEAM), work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving yttrium Y 90 basiliximab and chemotherapy before a stem cell transplant may help kill any cancer cells that are in the body and help make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. Stem cells that were collected from the patient's blood and stored before treatment are later returned to the patient to replace the blood-forming cells that were destroyed.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine if administration of 90Y-basiliximab/DOTA (yttrium Y 90 basiliximab), when given in combination with standard dose BEAM, as conditioning for autologous hematopoietic cell transplant (AHCT), is safe, by evaluation of toxicities, including type, frequency, severity, attribution, time course and duration. II. To determine the maximum tolerated dose (MTD) of 90Y-basiliximab/DOTA when given in combination with standard dose BEAM, in patients with T-cell non-Hodgkin lymphoma (T-NHL) as part of conditioning for AHCT. SECONDARY OBJECTIVES: I. To characterize and evaluate hematologic recovery in terms of neutrophil and platelet engraftment time. II. To estimate radiation doses to the whole body and normal organs through serial imaging studies. III. To estimate overall survival, progression-free survival, non-relapse mortality and cumulative incidence of relapse/progression at 100-days (non-relapse mortality [NRM] only), 1-year and 2-years. OUTLINE: This is a dose-escalation study of yttrium Y 90 basiliximab. Patients receive yttrium Y 90 basiliximab intravenously (IV) on days -21 and -14, carmustine IV over 1-2 hours on days -7 and -6, cytarabine IV twice daily (BID) on days -5 to -2, etoposide IV BID on days -5 to -2, and melphalan IV on day -1. Patients undergo autologous hematopoietic stem cell transplant on day 0. After completion of study treatment, patients are followed up at 30, 100, and 180 days and 1, 1.5, and 2 years.

Official Title
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Phase I Study of Yttrium-90 Labeled Anti-CD25 Monoclonal Antibody Plus Standard BEAM Conditioning for Autologous Hematopoietic Cell Transplantation in Patients With Mature T-Cell Non-Hodgkin Lymphoma: the aTAC BEAM Regimen

Conditions
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Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Recurrent Mature T- and NK-Cell Non-Hodgkin Lymphoma, Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma, Recurrent Cutaneous T-Cell Non-Hodgkin Lymphoma, Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Yttrium Y 90 Basiliximab
* Drug: Carmustine
* Drug: Etoposide
* Drug: Cytarabine
* Drug: Melphalan
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Other: Laboratory Biomarker Analysis
* Other: Pharmacological Study


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with a pathologically confirmed diagnosis of systemic mature T-cell non-Hodgkin lymphoma (NHL) with City of Hope pathology review as per World Health Organization (WHO) classification of lymphomas 2008, who are deemed eligible for high dose therapy and AHCT including patients in: * T-NHL histologies including peripheral T-cell lymphomas (PTCLs), cutaneous T-cell lymphomas (CTCLs) and natural killer (NK)/T cell lymphomas First remission after initial first-line therapy (CR1) in PTCL patients, except for anaplastic lymphoma receptor tyrosine kinase (ALK)+ anaplastic large cell lymphoma (ALCL) and CTCL; patients with minimal residual disease after induction therapy may also be eligible at the discretion of the principal investigator (PI) Relapsed/refractory disease, stable disease, partial remission (PR) or complete remission (CR), who have received at least 2 lines of therapy, and do not have an adequate allogenetic stem cell transplant option Life expectancy >= 6 months Karnofsky status >= 70% Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry and for six months following duration of study participation; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately Cardiac ejection fraction of >= 50% by echocardiogram or multi gated acquisition scan (MUGA) Forced expiratory volume in one second (FEV1) > 65% of predicted measured, or diffusing capacity of the lung for carbon monoxide (DLCO) > 50% of predicted measured Bilirubin < 1.5 x normal except in cases where abnormal liver function tests (LFTS) are due to involvement with T-NHL Serum glutamic oxaloacetic transaminase (SGOT) AND serum glutamate pyruvate transaminase (SGPT) < 2 x normal except in cases where abnormal LFTS are due to involvement with T-NHL Serum creatinine of < 1.5 mg/dL, and a measured creatinine clearance of > 60 mL/min Patients will be enrolled at collection of at least 3.0 x 10^6 CD34 cells/kg of autologous hematopoietic progenitor cells (HPC-A) by apheresis; a minimum of 2 collection procedures is required, unless collection on day # 1 > 5.0 x 10^6, CD34 cells/kg; a maximum of 10 collections is allowed; bone marrow harvest to supplement apheresis is not allowed Recovery from non-hematologic toxicities of salvage cytoreductive chemotherapy to =< grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version 4 [v4]) Body mass index (BMI) > 35% will be considered on a case-by-case basis by the Radiation Oncology principal investigator (P.I.) All subjects must have the ability to understand and the willingness to sign a written informed consent Systemic chemotherapy or radiation cannot have been given within 4 weeks prior to the Y-90 dose of radioimmunotherapy (RIT), with the exception of single agent cyclophosphamide priming chemotherapy administered for mobilization Exclusion Criteria: Progressive disease Patients should not have any uncontrolled illness including ongoing or active infection requiring therapy Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy; may have received an experimental agent prior to enrolling in the trial History of allergic reactions attributed to compounds of similar chemical or biologic composition to basiliximab Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with indium In 111 (111In-) and 90Y-basiliximab-DOTA Prior high dose chemotherapy for autologous hematopoietic cell transplantation or prior allogeneic transplantation Significant prior external beam dose-limiting radiation to a critical organ based on review of the prior radiation treatment records by the Radiation Oncology PI; patients who have had prior external beam radiation > 2000 cGy (at 180 to 200 cGy per day) to the lung will be ineligible; patients with ANY prior radiation to the heart are ineligible; patients with > 500 cGy to the kidney will be excluded from the study; Note: patients who have had electron beam therapy are still eligible and will be evaluated on a case by case basis by the Radiation Oncology PI Presence of antibody against basiliximab in serum (only required for patients who have received prior antibody) Research participants with presence of other active malignancy; however, research participants with history of prior malignancy treated with curative intent and in complete remission are eligible; any history of myelodysplasia is excluded Active hepatitis B or C viral infection or hepatitis B surface antigen positive Patients with a detectable human immunodeficiency virus (HIV) viral load or who are HIV-positive AND have a resistant genotype Patients with psychosocial circumstances or illnesses that preclude protocol participation (to be determined by P.I.) Any cytogenetic abnormality in the bone marrow that is known to be associated with or predictive of myelodysplasia is excluded; this includes, but is not limited to, del(5), del(7), del(11) Evidence of marrow disease by flow and morphology after upfront or salvage cytoreductive therapy and before stem cell mobilization Bone marrow (BM) harvest required to reach adequate cell dose for transplant Subjects, who in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (yttrium Y 90 basiliximab, BEAM, AHCT)<br>Patients receive yttrium Y 90 basiliximab IV on days -21 and -14, carmustine IV over 1-2 hours on days -7 and -6, cytarabine IV BID on days -5 to -2, etoposide IV BID on days -5 to -2, and melphalan IV on day -1. Patients undergo autologous hematopoietic stem cell transplant on day 0. | Biological: Yttrium Y 90 Basiliximab<br>* Given IV<br>* Other names: 90Y Basiliximab;Drug: Carmustine<br>* Given IV<br>* Other names: BiCNU;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16;Drug: Cytarabine<br>* Given IV<br>* Other names: Cytosar;Drug: Melphalan<br>* Given IV<br>* Other names: L-PAM;Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo AHCT<br>* Other names: Autologous Stem Cell Transplantation;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Other: Pharmacological Study<br>* Correlative studies<br>* Other names: pharmacological studies;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MTD of yttrium Y 90 basiliximab defined as the highest dose in which fewer than 33% of patients experience dose limiting toxicity attributable to study treatment, among those evaluable for toxicity | Dose limiting toxicities will be graded by the Modified Bearman scale. | 30 days post-transplant | 
| Incidence of toxicities assessed using National Cancer Institute (NCI) CTCAE version 4.03 | Observed toxicities will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE version 4.03 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution. | Up to 100 days post-transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease response by Cheson 2007 criteria |  | Up to 2 years post-transplant | 
| Engraftment: neutrophil and platelet recovery |  | Up to 2 years post-transplant | 
| Overall survival | Survival estimates will be calculated using the Kaplan-Meier method. | From start of therapy (stem cell infusion) to death from any cause, assessed up to 2 years post-transplant | 
| Progression-free survival | Survival estimates will be calculated using the Kaplan-Meier method. | From start of therapy (stem cell infusion) to the first observation of disease relapse/progression or death from any cause, assessed up to 2 years post-transplant | 
| Non-relapse mortality | The cumulative incidence of relapse/progression and non-relapse mortality will be calculated as competing risks using the Gray method. | From start of therapy until non-disease related death, or last follow-up, whichever comes first, assessed up to 2 years post-transplant | 
| Cumulative incidence of relapse/progression | The cumulative incidence of relapse/progression and non-relapse mortality will be calculated as competing risks using the Gray method. | From start of therapy (stem cell infusion) to the first observation of disease relapse/progression, assessed up to 2 years post-transplant | 
| Absorbed radiation dose to organs assessed by nuclear scan images |  | Up to day -14 |