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

Phase 1

Completed

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

Interventions: 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

Registration Number: NCT01921387

Lead Sponsor: Fred Hutchinson Cancer Center

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 20

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Laboratory Biomarker Analysis	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Autologous Hematopoietic Stem Cell Transplantation	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Peripheral Blood Stem Cell Transplantation	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Yttrium Y 90 Anti-CD45 Monoclonal Antibody BC8	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Carmustine	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Cytarabine	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Etoposide	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.
Treatment (90Y-BC8-DOTA, chemotherapy, PBSC)	Melphalan	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.

Primary Outcome Measures

Name	Time	Method
Maximum-tolerated Dose (MTD) of Yttrium-90-BC8-DOTA	Within 30 days post-transplant	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.
Progression-free Survival Following Autologous Stem Cell Transplant (ASCT)	1 year	Estimate the 1 year progression-free survival (PFS) rate after ASCT

Secondary Outcome Measures

Name	Time	Method
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	Up to 5 years	Will be evaluated among all patients and among those treated at the estimated MTD.
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