Radiolabeled Monoclonal Antibody and Combination Chemotherapy Before Stem Cell Transplant in Treating Patients With High-Risk Lymphoid Malignancies

Study Overview
=================
Brief Summary
-----------------
This phase I/II trial studies the side effects and the best dose of radiolabeled monoclonal antibody when given together with combination chemotherapy before stem cell transplant and to see how well it works in treating patients with high-risk lymphoid malignancies. Radiolabeled monoclonal antibodies, such as yttrium Y 90 anti-CD45 monoclonal antibody BC8, can find cancer cells and carry cancer-killing substances to them without harming normal cells. Giving chemotherapy before a stem transplant stops the growth of cancer cells by stopping them from dividing or killing them. Stem cells collected from the patient's blood are then returned to the patient to replace the blood-forming cells that were destroyed by the radiolabeled monoclonal antibody and chemotherapy.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To estimate the maximum-tolerated dose (MTD) of 90Y-BC8-DOTA (yttrium Y 90 anti-CD45 monoclonal antibody BC8) (anti-cluster of differentiation [CD] 45) that can be delivered prior to myeloablative carmustine, etoposide, cytarabine, and melphalan (BEAM) chemotherapy and autologous stem cell transplant (ASCT) for patients with high-risk B-non-Hodgkin lymphoma (NHL), T-NHL, and Hodgkin lymphoma (HL). II. To evaluate the efficacy of 90Y-BC8-DOTA when administered at the estimated MTD prior to BEAM chemotherapy and ASCT for patients with high-risk B-NHL, T-NHL, and HL compared to historical controls treated with BEAM alone. SECONDARY OBJECTIVES: I. To describe the toxicity observed from the addition of 90Y-BC8-DOTA to BEAM. II. To optimize the protein dose (Ab) to deliver a favorable biodistribution in the majority of patients. III. To describe response rates and overall survival of patients with high-risk B-NHL, T-NHL, and HL following administration of 90Y-BC8-DOTA plus BEAM prior to ASCT. IV. To describe the impact of rituximab concentrations, B-cell depletion, and disease burden on CD45 targeting. V. To assess the correlation of lymphoma biomarkers with outcomes. VI. To evaluate the effects of nodal-targeted irradiation by 90Y-BC8-DOTA on immune reconstitution following ASCT. OUTLINE: This is a phase I, dose-escalation study of yttrium Y 90 anti-CD45 monoclonal antibody BC8 followed by a phase II study. Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 intravenously (IV) on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours twice daily (BID) on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous peripheral blood stem cell (PBSC) transplant on day 0. After completion of study treatment, patients are followed up at 3, 6, and 12 months and then annually thereafter.

Official Title
-----------------
A Phase I/II Study Evaluating Escalating Doses of 90Y-BC8-DOTA (Anti-CD45) Antibody Followed by BEAM Chemotherapy and Autologous Stem Cell Transplantation for High-Risk Lymphoid Malignancies

Conditions
-----------------
Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Hodgkin Lymphoma, Recurrent Mantle Cell Lymphoma, Recurrent T-Cell Non-Hodgkin Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Hodgkin Lymphoma, Refractory Mantle Cell Lymphoma, Refractory T-Cell Non-Hodgkin Lymphoma

Intervention / Treatment
-----------------
* Procedure: Autologous Hematopoietic Stem Cell Transplantation
* Drug: Carmustine
* Drug: Cytarabine
* Drug: Etoposide
* Other: Laboratory Biomarker Analysis
* Drug: Melphalan
* Procedure: Peripheral Blood Stem Cell Transplantation
* Radiation: Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients must have a histologically confirmed diagnosis of B-NHL, T-NHL, or HL; only patients with classical HL must have documented histologic demonstration of CD45+ cells adjacent to the Reed Sternberg cells; patients must have received at least one prior standard systemic therapy with documented recurrent or refractory disease; patients with mantle cell lymphoma (MCL), T-NHL, or other high-risk malignancies may be enrolled/transplanted in complete remission (CR)/first partial remission (PR1) Creatinine < 2.0 Bilirubin < 1.5 mg/dL All patients eligible for therapeutic study must have a minimum of >= 2 x10^6 CD34/kg autologous hematopoietic stem cells harvested and cryopreserved Patients must have an expected survival of > 60 days and must be free of major infection Exclusion Criteria: Circulating human anti-mouse antibody (HAMA), to be determined before each infusion Systemic anti-lymphoma therapy given in the previous 30 days before the scheduled therapy dose with the exception of rituximab Inability to understand or give an informed consent Lymphoma involving the central nervous system Other serious medical conditions considered to represent contraindications to ASCT (e.g., abnormally decreased cardiac ejection fraction, diffusion capacity of carbon monoxide [DLCO] < 50% predicted, etc.) Known human immunodeficiency virus (HIV) seropositivity Pregnancy or breast feeding Prior autologous or allogeneic bone marrow or stem cell transplant Prior radiation therapy (RT) > 20 gray (Gy) to a critical organ within 1 year of enrollment Southwestern Oncology Group (SWOG) performance status >= 2.0

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)<br>Patients receive yttrium Y 90 anti-CD45 monoclonal antibody BC8 IV on day -14. Patients also receive carmustine IV over 3 hours on day -7, etoposide IV over 2 hours BID on days -6 to -3, cytarabine IV over 4 hours BID on days -6 to -3, and melphalan IV over 30 minutes on day -2. Patients then undergo autologous PBSC transplant on day 0. | Procedure: Autologous Hematopoietic Stem Cell Transplantation<br>* Undergo autologous PBSC transplant<br>* Other names: autologous stem cell transplantation;Drug: Carmustine<br>* Given IV<br>* Other names: WR-139021;Drug: Cytarabine<br>* Given IV<br>* Other names: WR-28453;Drug: Etoposide<br>* Given IV<br>* Other names: VP-16-213;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Melphalan<br>* Given IV<br>* Other names: WR-19813;Procedure: Peripheral Blood Stem Cell Transplantation<br>* Undergo autologous PBSC transplant<br>* Other names: Peripheral Stem Cell Transplantation;Radiation: Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8<br>* Given IV<br>* Other names: 90Y Anti-CD45 MoAb BC8;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-tolerated Dose (MTD) of Yttrium-90-BC8-DOTA | Single patients will be treated at escalating doses in 2-Gy increments (Table 4) until a DLT is observed. Once a DLT is observed, the second stage will begin at the next lower dose level and patients will be treated in cohorts of 4. | Within 30 days post-transplant | 
| Progression-free Survival Following Autologous Stem Cell Transplant (ASCT) | Estimate the 1 year progression-free survival (PFS) rate after ASCT | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Estimated Dose to Tumor Sites Based on the Tumor to Normal Organ Ratios Derived From Dosimetry Estimates Coupled With the Absorbed Dose to Normal Organs Based on the Administered Activity of Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8 | Will be evaluated among all patients and among those treated at the estimated MTD. | Up to 5 years | 
| The Lowest Antibody (Yttrium 90-BC8-DOTA) Dose (mg/kg) That is Consistent With a Favorable Biodistribution Rate >= 80% in Lymphoma Patients |  | Up to 5 years |