Yttrium-90 Labeled Anti-CD25 Monoclonal Antibody Combined With BEAM Chemotherapy Conditioning for the Treatment of Primary Refractory or Relapsed Hodgkin Lymphoma

Study Overview
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Brief Summary
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This phase II trials studies the effects of yttrium-90 labeled anti-CD25 monoclonal antibody combined with BEAM chemotherapy conditioning in treating patients with Hodgkin lymphoma that does not response to treatment (refractory) or has come back (relapsed). Yttrium-90-labeled anti-CD25 is an antibody (proteins made by the immune system to fight infections) that is attached to a radioactive substance and may kill cancer cells and shrink tumors. Chemotherapy drugs, such as carmustine, etoposide, cytarabine, and melphalan, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving chemotherapy before a peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow.

Detailed Description
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PRIMARY OBJECTIVE: I. Evaluate the anti-lymphoma activity of the aTac-carmustine (BCNU), etoposide, cytarabine (cytosine arabinoside), and melphalan (BEAM) regimen as conditioning for autologous hematopoietic cell transplantation (AHCT); assessed by 2-year progression-free survival (PFS). SECONDARY OBJECTIVES: I. Estimate the overall survival (OS) probability and cumulative incidence of relapse/progression, and non-relapse mortality (NRM) at 100-days, 1-year and 2-years. II. Summarize toxicities by type, frequency, severity, attribution, time course and duration. III. Evaluate short and long-term complications, including: delayed engraftment (neutrophil and platelet), infection, and myelodysplasia (MDS). EXPLORATORY OBJECTIVES: I. Evaluate potential changes in Hodgkin lymphoma biological markers of patients treated with 90Y basiliximab BEAM via analyses of serial blood samples. II. Assess the potential association between pre-AHCT CD25 expression levels and post-AHCT outcomes. OUTLINE: Patients receive 'cold' basiliximab intravenously (IV) followed by yttrium Y 90 basiliximab IV on day -14. Patients also receive carmustine IV on over 4 hours day -6, etoposide IV over 1 hours once daily (QD) and cytarabine IV over 2 hours twice daily (BID) or QD on days -5 to -2, and melphalan IV over 1 hours on day -1. Patients then receive hematopoietic progenitor cell apheresis (HPC-A) product via infusion on day 0. Beginning day 5, patients receive granulocyte colony-stimulating factor (G-CSF) (or biosimilar) subcutaneously (SC) or IV until absolute neutrophil count (ANC) > 500 for 3 consecutive days or according to the treating physician's best clinical judgement. After completion of study treatment, patients are followed up at 30 days, up to 2 years for response, and up to 5 years for survival.

Official Title
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A Phase 2 Trial of Yttrium-90 Labeled Anti-CD25 Monoclonal Antibody Combined With BEAM Chemotherapy (aTac-BEAM) Conditioning for Autologous Hematopoietic Cell Transplantation (AHCT) in Patients With Primary Refractory or Relapsed Hodgkin Lymphoma

Conditions
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Recurrent Hodgkin Lymphoma, Refractory Hodgkin Lymphoma

Intervention / Treatment
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* Biological: Basiliximab
* Drug: Carmustine
* Drug: Cytarabine
* Drug: Etoposide
* Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells
* Biological: Recombinant Granulocyte Colony-Stimulating Factor
* Biological: Yttrium Y 90 Basiliximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Assent, when appropriate, will be obtained per institutional guidelines Age: >= 18 years Karnofsky performance status >= 70% Life expectancy >= 6 months Histologically confirmed Hodgkin lymphoma (HL) Relapsed/refractory disease PIF (primary induction failure): Did not enter complete remission with first line of therapy. Note: a patient with PIF who responds to salvage therapy with a partial response (PR) or complete response (CR) is also eligible (and would be considered PIF-sensitive) Early 1st relapse: Initial CR of > 3 months and < 12 months after 1st line chemotherapy 1st relapsed HL in a patient who is not in CR after 2 different salvage therapy regimens to attain CR In 2nd or subsequent RL whether in CR or not after salvage therapy High risk relapsed or refractory HL disease defined as having any one of the following: B symptoms at relapse Extranodal disease at relapse Primary refractory disease Relapse < 1 year after completion of frontline therapy Not in CR at the time of transplant Relapse after receiving PD1 blockade or brentuximab vedotin as initial therapy Patients will be enrolled after collection of at least 2.0 x 10^6 CD34 cells/kg of autologous hematopoietic progenitor cells (HPC-A) by apheresis Recovery from non-hematologic toxicities of salvage cytoreductive chemotherapy to =< grade 2 (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) Serum creatinine =< 1.5 mg/dL (performed prior to day 1 of protocol therapy) Creatinine clearance of >= 60 mL/min per 24 hour urine test =< 1.5 mg/dL (performed prior to day 1 of protocol therapy) Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (performed prior to day 1 of protocol therapy) Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT) =< 1.5 x ULN (except in cases where abnormal liver function tests (LFTs) are due to involvement with HL) (performed prior to day 1 of protocol therapy) Alanine aminotransferase (ALT)/serum glutamate pyruvate transaminase (SGPT) =< 1.5 x ULN (except in cases where abnormal LFTs are due to involvement with HL) (performed prior to day 1 of protocol therapy) Left ventricular ejection fraction (LVEF) >= 50% (performed prior to day 1 of protocol therapy) Forced expiratory volume in 1 second (FEV1) > 65% of predicted measured, or DLCO (diffusion capacity) >= 50% of predicted measured (corrected for hemoglobin) (performed prior to day 1 of protocol therapy) Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least six months after the last dose of protocol therapy Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only) Exclusion Criteria: Planned BV consolidation after AHCT Prior high dose chemotherapy with autologous stem cell transplant, 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 principal investigator (PI) Patients may not be receiving any other investigational agents, or concurrent biological, chemotherapy, or radiation therapy Myelodysplasia or any active malignancy other than HL, or < 5 years remission from any other prior malignancy, except non-melanoma skin cancer, localized prostate cancer or localized cervical cancer 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) Lymphocyte-predominant Hodgkin lymphoma History of allergic reactions attributed to compounds of similar chemical or biologic composition to 90Y-basiliximab-DOTA Presence of antibodies against basiliximab (only required for patients who have received prior antibody therapy) Persistent marrow involvement (> 10%) with HL after salvage cytoreductive therapy and before stem cell mobilization Bone marrow (BM) harvest required to reach adequate cell dose for transplant Active hepatitis B or C viral infection or hepatitis B surface antigen positive Positive human immunodeficiency virus antibody, patients with undetectable human immunodeficiency virus (HIV) viral load with CD4 >= 300 and are on highly active antiretroviral therapy (HAART) medication are allowed Patients should not have any uncontrolled illness including ongoing or active infection Patients with psychosocial circumstances or illnesses that preclude protocol participation (to be determined by P.I.) Pregnant women are excluded from this study because 90Y-basiliximab/DOTA is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother 90Y-basiliximab/DOTA, breastfeeding should be discontinued if the mother is treated with 90Y-basiliximab/DOTA Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

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, chemotherapy, HPC-A)<br>Patients receive 'cold' basiliximab IV followed by yttrium Y 90 basiliximab IV on day -14. Patients also receive carmustine IV on over 4 hours day -6, etoposide IV over 1 hours QD and cytarabine IV over 2 hours BID or QD on days -5 to -2, and melphalan IV over 1 hours on day -1. Patients then receive HPC-A product via infusion on day 0. Beginning day 5, patients receive G-CSF (or biosimilar) SC or IV until ANC > 500 for 3 consecutive days or according to the treating physician's best clinical judgement. | Biological: Basiliximab<br>* Given IV<br>* Other names: Simulect;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: VP16;Biological: Genetically Engineered Hematopoietic Stem Progenitor Cells<br>* Given via infusion<br>* Other names: Genetically Engineered HSPCs;Biological: Recombinant Granulocyte Colony-Stimulating Factor<br>* Given SC or IV<br>* Other names: rhG-CSF;Biological: Yttrium Y 90 Basiliximab<br>* Given IV<br>* Other names: Yttrium Y 90-DOTA-Basiliximab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Disease relapse or progression, or death from any cause, whichever occurs first. Will be calculated using the Kaplan-Meier method. | From the start of treatment up to 5 years post transplant | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Death from any cause. Will be calculated using the Kaplan-Meier method. | From the start of treatment up to 5 years post transplant | 
| Relapse or progression | Relapse or progression of Hodgkin lymphoma. | From the start of treatment up to 5 years post transplant | 
| Non-relapse mortality | Death from causes other than relapse or progression. | From the start of treatment up to 5 years post transplant | 
| Incidence of toxicities and adverse events | Toxicity information recorded will include the type, severity, and the probable association with the study regimen. Tables will be constructed to summarize the observed incidence by severity and type of toxicity. Toxicities will be recorded using both the Bearman criteria and the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 scale. | Day -14 to day 100 post-transplant | 
| Time to hematopoietic recovery | Time to neutrophil recovery will be the first of three consecutive days of ≥ 500 neutrophils/μL following the expected nadir. Time to platelet engraftment will be the first day of the first of three consecutive daily laboratory values when the platelet count is ≥20,000/μL, without a platelet transfusion in the previous seven days. | Up to day 100 post transplant | 
| Incidence of infection | Microbiologically documented infections will be reported by site of disease, date of onset, severity and resolution, if any. | Day -14 to day 100 post-transplant | 
| Rate of secondary myelodysplastic syndrome | Secondary MDS or AML post therapy | From the start of treatment up to 5 years post transplant |