Yttrium-90-labeled Daclizumab With Chemotherapy and Stem Cell Transplant for Hodgkin's Lymphoma
Yttrium-90-labeled Daclizumab With Chemotherapy and Stem Cell Transplant for Hodgkin's Lymphoma
Background:

 -  Hodgkins lymphoma (HL) is a highly treatable cancer. However, if HL does not respond to
 chemotherapy or returns after chemotherapy, further treatments often are not successful.

 -  Some HL cells have a molecule called cluster of differentiation 25 (CD25) on the
 surface. Daclizumab is a drug that can detect CD25 on cells. In a treatment study for HL
 that did not respond to chemotherapy, daclizumab plus a radioactive atom called Yttrium
 90 helped kill these HL cells. Researchers want to combine this 90Y daclizumab with
 high-dose chemotherapy and stem cell transplant. This treatment may be more effective
 than the daclizumab alone.

 Objectives:

 - To see if yttrium-90 daclizumab, high-dose chemotherapy, and stem cell transplants can
 treat HL that has not responded to earlier treatments.

 Eligibility:

 - Individuals at least 18 years of age who have Hodgkins lymphoma that has not responded to
 chemotherapy.

 Design:

 -  Participants will be screened with a physical exam and medical history. They will also
 have blood and urine tests.

 -  Participants will have filgrastim and plerixafor to move stem cells into the blood. Stem
 cells will be collected with apheresis.

 -  Four weeks after stem cells are collected, participants will have the 90Y daclizumab and
 normal daclizumab to treat the HL. Chemotherapy will start 9 days after the first
 treatment.

 -  Most participants will have a second dose of 90Y daclizumab 6 weeks after the first
 dose.

 -  After each daclizumab treatment, participants will have several imaging studies of the
 chest and abdomen. Blood samples will also be collected.

 -  On the day after the last day of chemotherapy, participants will receive the stem cells
 collected earlier. Filgrastim injections will help stimulate stem cell growth....
Background:

 -  Although Hodgkins lymphoma (HL) is considered a highly treatable cancer, patients with
 relapsed and chemotherapy refractory disease represent a major therapeutic challenge.

 -  Only 30-65% of relapsed patients will achieve long-term disease free survival with the
 current standard of care high-dose chemotherapy with autologous hematopoietic stem cell
 transplant (ASCT).

 -  The malignant Reed-Sternberg cells of HL and the surrounding benign T cell infiltrates
 often express CD25, the high affinity interleukin-2 receptor (IL-2R alpha).

 -  In study NCI-97-C-0110, we treated 30 patients with CD25-expressing relapsed or
 refractory HL with radioimmunotherapy (RIT) using (90)Y-labeled daclizumab (anti-CD25),
 and achieved a 63% response rate including 12 complete responses with few serious
 adverse events other than MDS in 4 patients.

 -  We propose integrating (90)Y-labeled daclizumab RIT into the induction regimen of ASCT
 in an effort to improve the response and disease-free survival in relapsed and
 refractory HL.

 Objectives:

 Phase I Primary Objectives:

 -  To assess the safety and adverse events associated with (90)Y-daclizumab (humanized
 anti-CD25) radioimmunotherapy (RIT) in combination with high-dose BEAM (carmustine,
 etoposide, cytarabine, [Ara-C, cytosine arabinoside] and melphalan) chemotherapy and
 autologous hematopoietic stem cell transplantation (ASCT) in patients with relapsed or
 refractory Hodgkin s lymphoma (HL) with adverse prognostic factors.

 -  To determine the maximum tolerated dose in mCi of (90)Y-daclizumab RIT in combination
 with high-dose BEAM chemotherapy and ASCT in patients with relapsed or refractory HL.

 Phase II Primary Objectives:

 -  To assess the frequency of the failure to engraft, myelodysplastic syndrome (MDS),
 secondary leukemia for the development of abnormal bone-marrow cytogenetics in
 refractory or relapsed HL patients treated with (90)Y-daclizumab RIT in combination with
 high-dose BEAM chemotherapy and ASCT.

 -  To estimate the response rate (the number of complete and partial responses) in patients
 with refractory or relapsed HD to (90)Y-daclizumab RIT administered in combination with
 high-dose BEAM chemotherapy and ASCT.

 Eligibility:

 -  Patients must have a confirmed diagnosis of relapsed or refractory HL with at least 10%
 of malignant Reed-Sternberg cells or infiltrating T-cells expressing CD25 (IL-2R alpha).
 A. Patients must have at least one of the following: (1) had an initial relapse less
 than 12 months after achieving a complete response (CR) with primary chemotherapy for
 HL; (2) were Staged at III/IV at diagnosis; (3) exhibited chemotherapy resistant disease
 or (4) did not achieve a CR with cytoreductive chemotherapy prior to a planned
 transplant. B. Patient must have a lesion of at least 1.0 cm in its greatest diameter.
 C. Patients with lymphocyte predominant HL are excluded. D. Patients with pre-existing
 myelodysplastic syndrome (MDS) or marrow cytogenic abnormalities will not be eligible to
 participate.

 -  Omission of cytotoxic chemotherapy or other systemic therapy of HL for at least 4 weeks
 prior to entry into the trial.

 -  No prior ASCT or allogeneic stem cell transplant.

 Design:

 -  A single institution non-randomized open-label phase I/II trial.

 -  Patients will undergo peripheral blood stem cell (PBSC) mobilization with
 granulocyte-colony stimulating factor (G-CSF, filgrastim) and Plerixafor followed by
 apheresis to collect a target dose of 4 x 106 cluster of differentiation 34 (CD34)
 cells/kg (minimal dose of 2 x 106 CD34+ cells/kg) of actual body weight.

 -  Phase I study will be carried out using a standard 3 + 3 cohort dose-escalation design:

 -  Dose level 1: Patients will receive a single dose of 15 mCi 90Y-daclizumab RIT (day
 -15 2 days) followed by high-dose BEAM chemotherapy (beginning Day -6) and ASCT
 (Day 0).

 -  Dose levels 2-7: Patients will receive two doses of 90Y-daclizumab RIT 6 weeks
 apart (Day -56 and -15 2 days) followed by high-dose BEAM chemotherapy (beginning
 day -6) and ASCT (Day 0). The first dose of 90Y-daclizumab will be fixed at 15 mCi.
 The second dose will be escalated in 15 mCi increments from 15 mCi until maximum
 tolerated dose, not to exceed 90 mCi.

 -  Phase II: All patients will receive two doses of 90Y-daclizumab (Day -56 and -15 2 days)
 followed by high-dose BEAM chemotherapy (beginning Day -6) and ASCT (Day 0). The first
 dose of RIT will be 15 mCi. The second dose will be the maximum tolerated dose as
 determined from phase I.

 111In-daclizumab (5 mCi) imaging may be performed concurrently with each 90Ydaclizumab
 RIT and at day 100 after ASCT.
-  INCLUSION CRITERIA:

 2.1.1.1 All patients must have a pathologically confirmed diagnosis of classical Hodgkin's
 lymphoma (HL) as outlined in the World Health Organization (WHO) Classification System of
 Lymphoid Tumours. Patients with nodular lymphocyte-predominant Hodgkin's lymphoma (HL)
 (NLPHL) are not eligible.

 2.1.1.2 Refractory or relapsed HL patients that are also candidates for auto stem cell
 transplant (ASCT).

 2.1.1.3 At least one adverse prognostic factor: (1) initial relapse less than or equal to
 12 months after primary chemotherapy, (2) staged as Ann Arbor Classification initial stage
 III or IV disease, (3) chemotherapy resistant disease, (4) Failure to achieve a complete
 response (CR) with cytoreductive chemotherapy or persistent positive (18)
 fluorodeoxyglucose positron emission tomography (FDGPET) imaging.

 2.1.1.4 At least 10% of the cells obtained from lymph node, or extranodal sites must react
 with anti-cluster of differentiation 25 (CD25) (anti-Tac) on immunofluorescent or
 immunoperoxidase staining. Because of the high frequency of CD25 positivity of the
 infiltrating Tcells in HL tumors, patients with CD25-positive infiltrating T cells will be
 eligible even if their Hodgkin's (Reed-Sternberg) cells are CD25-negative.

 2.1.1.5 Measurable disease as defined by the Cheson Response Criteria for Malignant
 Lymphoma detailed in section 6.2 with at least one lesion greater than or equal to 1.0 cm
 in longest diameter by computed tomography (CT) scan.

 2.1.1.6 Omission of cytotoxic chemotherapy or other systemic therapy of the malignancy for
 greater than or equal to 4 weeks prior to entry into the trial. Patients must be greater
 than or equal to 4 weeks since major surgery, radiotherapy, or biotherapy/targeted
 therapies and recovered from the toxicity of prior treatment to less than or equal to CTC
 grade 1, exclusive of grade 2 alopecia, fatigue, lymphopenia, cluster of differentiation 4
 (CD4)+ circulating T cells, white blood cell (WBC) or bilirubin.

 2.1.1.7 Patients must be greater than or equal to 18-years old.

 2.1.1.8 Patients must have a life expectancy of greater than 3 months.

 2.1.1.9 Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
 of less than or equal to 1.

 2.1.1.10 The patient must have a granulocyte count of at least 1,500/microL and a platelet
 count of greater than 100,000/microL.

 2.1.1.11 Patients must have a creatinine of less than 2.0 mg/dL, or if the patient has a
 serum creatinine greater than or equal to 2.0, a measured creatinine clearance (Ccr) must
 be greater than 60 mL/min/1.73m(2).

 2.1.1.12 Patients must have a serum alkaline phosphatase, alanine aminotransferase (ALT)
 serum glutamic oxaloacetic transaminase (SGOT), and aspartate aminotransferase (AST) serum
 glutamic pyruvic transaminase (SGPT) less than 3 times the upper limit of normal (ULN),
 unless due to liver or bone involvement by HL. Under these circumstances, serum alkaline
 phosphatase, SGPT and SGOT must be less than 5 times ULN.

 2.1.1.13 Patients must have a total serum bilirubin less than 2.5 times ULN.

 2.1.1.14 Patients must have a cardiac ejection fraction greater than 45% on 2D
 echocardiography or multi-gated acquisition scan (MUGA) obtained within 28 days of study
 enrollment.

 2.1.1.15 Lung diffusion capacity for carbon monoxide (DLCO) greater than 50%, or forced
 expiratory volume at 1.0 seconds (FEV1.0) greater than 65% of predicted on pulmonary
 function testing (PFT) obtained within 28 days of study enrollment.

 2.1.1.16 Women of childbearing potential must have a negative serum Beta-human chorionic
 gonadotropin (HCG) pregnancy test at initial screening and within 3 days prior to
 registration.

 2.1.1.17 The effects of (90)Y-daclizumab on the developing human fetus are unknown. Women
 of child-bearing potential and men must agree to use adequate contraception (hormonal or
 barrier method of birth control; abstinence) prior to study entry, while receiving
 treatment and for 4 months after undergoing ASCT. Should a woman become pregnant or suspect
 she is pregnant while she or her partner is participating in this study, she should inform
 her treating physician immediately.

 2.1.1.18 Patients receiving a stable dose (greater than 4 weeks) of corticosteroid therapy
 equivalent to 20 mg of prednisone per day or less are eligible.

 2.1.1.19 Patients must be able to understand and sign informed consent.

 EXCLUSION CRITERIA:

 2.1.2.1 Patients who have relapsed from their initial Adriamycin, bleomycin, vinblastine,
 dacarbazine) ABVD or similar standard treatment regimen and have not received any other
 chemotherapy or salvage systemic treatment.

 2.1.2.2 Patients that have received prior radioimmunotherapy.

 2.1.2.2. Patients enrolled on another therapeutic study.

 2.1.2.3 Patients that have received prior radioimmunotherapy.

 2.1.2.4 Patients that have received a prior autologous or allogeneic stem cell transplant

 2.1.2.5.Patients that have received prior radiation to the lung, excluding prior
 mediastinal

 radiation.

 2.1.2.6 Patients with greater than 25% involvement of the bone marrow with HL.

 2.1.2.7 Patients with evidence of myelodysplasia, leukemia by morphology, immunostains flow
 cytometry or abnormal cytogenetics on a bone- marrow aspirate or biopsy. The diagnosis of
 myelodysplasia will be made by an independent investigator of the Laboratory of Pathology,
 National Cancer Institute (NCI) taking into consideration the totality of the clinical,
 pathological, flow cytometric and cytogenetic information described in Appendix E and
 present in a particular individual s evaluation.

 2.1.2.8 Patients with history of central nervous system (CNS) involvement or active CNS
 involvement by malignancy.

 2.1.2.9 Patients with an active second primary cancer will not be eligible. Patients
 curatively treated for a second cancer greater than 5 years prior to enrollment without a
 recurrence are eligible. Patients curatively treated for a second primary cancer within the
 last 5 years with a less than or equal to 5% risk of recurrence are eligible. Patients with
 a history of curatively treated basal cell carcinoma or intraepithelial neoplasia of the
 uterine cervix will be allowed on study.

 2.1.2.10 Patients with serum human anti-human antibody (HAHA) against daclizumab.

 2.1.2.11 Patients with human immunodeficiency virus (HIV) infection (antibody positive with
 positive confirmatory molecular test).

 2.1.2.2 Patients who have chronic hepatitis B or hepatitis C.

 2.1.2.13 Patients with an uncontrolled serious infection.

 2.1.2.14 Pregnant or breastfeeding women.

 2.1.2.15 Patients with significant medical comorbidities, including uncontrolled
 hypertension (diastolic blood pressure (BP) greater than 115 mmHg), unstable angina,
 congestive heart failure (greater than New York Heart Association (NYHA) class II), poorly
 controlled diabetes, severe chronic pulmonary disease, coronary angioplasty or myocardial
 infarction within the last 6 months, or uncontrolled atrial or ventricular cardiac
 arrhythmias.

 2.1.2.16 Patients with a history of a psychiatric disorder that may interfere with the
 understanding and compliance with this protocol and the required follow up.

 2.1.2.17 Exclusion at the discretion of the principal investigator (PI) or delegate if
 participation to the study is deemed too risky (e.g. clinically significant pleural or
 pericardial effusion or ascites with possibly increased radio-toxicity).