Clinical trial NCT01468311
Conditions: Hodgkin Disease Hodgkin Lymphoma
Keywords: Immunotherapy Resistant Hodgkins Lymphoma Auto Stem Cell Transplant Combination Chemo and Radiolabeled Monoclonal Antibody Hodgkin Lymphoma
Sponsor: National Cancer Institute (NCI)
Start date: 2011-10-11; Completion date: 2020-10-22
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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....

Detailed description:
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.

Arms: arm 1: Yttrium-90-labeled Daclizumab + BCNU, etoposide, cytarabine and melphalan (BEAM) + Auto stem cell transplant (ASCT)
Interventions: intervention 1: Auto stem cell transplant intervention 2: BEAM intervention 3: 111In-daclizumab intervention 4: 90Y-daclizumab
Intervention descriptions: intervention 1: Auto stem cell transplant (ASCT) is given after 90Y-daclizumab intervention 2: BCNU, etoposide, cytarabine and melphalan (BEAM) chemotherapy are given after 90Y-daclizumab intervention 3: 111In-daclizumab will be administered to patients with each therapeutic infusion of 90Y-daclizumab in order to define the distribution of radiolabeled daclizumab, and to allow visualization by scans. intervention 4: 90Y-daclizumab administered with a fixed dose of pentetate calcium trisodium (Ca-DTPA) followed by BEAM Chemo and Auto stem cell transplant

Protocol documents:
Prot_SAP_000.pdf: 
Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
1 
 Abbreviated Title:   90Y-daclizumab + ASCT in HL 
 
CC Protocol #:  12-C-0003 F 
 
Version Date:  02/05/2018 
 
 NCT Number:  NCT01468311 
  
 
Phase I/II Trial of Yttrium-90-labeled Daclizumab (anti-CD25) Radioimmunotherapy with 
High-dose BEAM Chemotherapy and Autologous Hematopoietic Stem Cell Rescue in 
Recurrent and Refractory Hodgkin’s Lymphoma 
 
 
 
NCI Principal Investigator:  Thomas A. Waldmann, M.D.  
Lymphoid Malignancies Branch 
Center for Cancer Research 
National Cancer Institute 
10 Center Drive 
Building 10, Room 4N115 
Bethesda MD 20892-1374 
Phone: 240-760-6091 
Email: tawald@helix.nih.gov 
 
Investigational Agents: 
Drug Name: 
90Y- daclizumab, 111In-daclizumab 
IND Number: 
5014 
Sponsor: 
Center for Cancer Research 
Manufacturer: 
Hoffmann-La Roche 
 
Commercial Agents: filgrastim, plerixafor, Ca2+-DTPA, unlabeled daclizumab, basiliximab, 
carmustine, etoposide, cytarabine, melphalan 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
2 
PRÉCIS 
Background: 
• Although Hodgkin’s 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 90Y-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 90Y-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 
90Y-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 
90Y-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 90Y-daclizumab RIT in combination with 
high-dose BEAM chemotherapy and ASCT. 
• To estimate the response rate [the number of complete and partial responses (CR and 
PR)] in patients with refractory or relapsed HD to 90Y-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).  


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
3 
A.  Patients must have at least one of the following: (1) had an initial relapse less than 12 
months after achieving a 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 MDS or marrow cytogenetic 
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 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: 
o 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). 
o 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 90Y-
daclizumab RIT and at day 100 after ASCT. 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
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TABLE OF CONTENTS 
PRÉCIS ........................................................................................................................................... 2 
TABLE OF CONTENTS ................................................................................................................ 4 
1 INTRODUCTION .................................................................................................................... 10 
1.1 Study Objectives ............................................................................................................... 10 
1.2 Background and Rationale ................................................................................................ 10 
2 ELIGIBILITY ASSESSMENT AND ENROLLMENT .......................................................... 19 
2.1 Eligibility Criteria ............................................................................................................. 19 
2.2 Screening Evaluation ........................................................................................................ 21 
2.3 Registration Procedures .................................................................................................... 22 
2.4 Baseline Evaluation .......................................................................................................... 22 
3 STUDY IMPLEMENTATION ................................................................................................ 22 
3.1 Study Design ..................................................................................................................... 22 
3.2 Study Procedures/Drug Administration ............................................................................ 28 
3.3 Dose Modification for Toxicities ...................................................................................... 33 
3.4 Stopping Rules for Unacceptable Toxicity ....................................................................... 35 
3.5 Monitoring during therapy ................................................................................................ 36 
3.6 Follow-up after the completion of therapy ....................................................................... 37 
3.7 Study Calendar .................................................................................................................. 38 
3.8 Concurrent Therapies ........................................................................................................ 41 
3.9 Surgical Guidelines ........................................................................................................... 41 
3.10 Radiation Therapy Guidelines: ......................................................................................... 41 
3.11 Criteria for Removal from Protocol Therapy and Off-Study Criteria: ............................. 41 
4 SUPPORTIVE CARE .............................................................................................................. 42 
4.1 Blood Component Support ............................................................................................... 42 
4.2 G-CSF (Filgrastim) Support ............................................................................................. 42 
4.3 Antibiotic therapy ............................................................................................................. 42 
4.4 Antiemetics ....................................................................................................................... 42 
4.5 Management of mucositis ................................................................................................. 42 
4.6 Mucositis prophylaxis ....................................................................................................... 43 
4.7 PCP prophylaxis................................................................................................................ 43 
4.8 Fungal prophylaxis............................................................................................................ 43 


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4.9 Herpes simplex and VZV prophylaxis .............................................................................. 43 
4.10 CMV prophylaxis.............................................................................................................. 43 
5 BIOSPECIMEN COLLECTION ............................................................................................. 43 
5.1 Sample Storage, Tracking and Disposition ....................................................................... 43 
6 DATA COLLECTION AND EVALUATION ........................................................................ 44 
6.1 Data Collection ................................................................................................................. 44 
6.2 Response Assessments ...................................................................................................... 46 
6.3 Toxicity Criteria ................................................................................................................ 48 
7 SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN 48 
7.1 Adverse Event Definitions ................................................................................................ 48 
7.2 NCI-IRB and Clinical Director Reporting ........................................................................ 49 
7.3 IND Sponsor Reporting Criteria ....................................................................................... 50 
7.4 Data and Safety Monitoring Plan ...................................................................................... 50 
8 STATISTICAL CONSIDERATIONS ..................................................................................... 51 
9 HUMAN SUBJECTS PROTECTIONS ................................................................................... 53 
9.1 Rationale for Subject Selection ......................................................................................... 53 
9.2 Research Ethics ................................................................................................................. 53 
9.3 Participation of Children ................................................................................................... 53 
9.4 Participation of Subjects Unable to Give Consent ............................................................ 54 
9.5 Evaluation of Benefits and Risks/Discomforts ................................................................. 54 
9.6 Risks/Benefit Analysis ...................................................................................................... 54 
9.7 Consent and Assent Processes and Documents ................................................................ 55 
10 PHARMACEUTICAL INFORMATION ................................................................................ 55 
10.1 Daclizumab ....................................................................................................................... 55 
10.2 Basiliximab ....................................................................................................................... 57 
10.3 CHX-A Daclizumab.......................................................................................................... 58 
10.4 Calcium Diethylenetriaminepentaacetate (Ca-DTPA). .................................................... 60 
10.5 Filgrastim (NEUPOGEN® G-CSF) ................................................................................... 61 
10.6 Plerixafor (Mozobil®) ....................................................................................................... 61 
10.7 BCNU (BiCNU®, Carmustine) ........................................................................................ 62 
10.8 Etoposide........................................................................................................................... 64 
10.9 Cytarabine (Ara-C, cytosine arabinoside) ......................................................................... 66 
10.10 
Melphalan ................................................................................................................... 68 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
6 
10.11 
Administration ............................................................................................................ 69 
10.12 
Storage and Stability ................................................................................................... 70 
10.13 
Palifermin (Kepivance) ........................................................................................... 70 
11 REFERENCES ......................................................................................................................... 72 
12 APPENDICES .......................................................................................................................... 76 
12.1 Appendix A:  World Health Organization (WHO) Classification of Lymphoid Tumors. 76 
12.2 Appendix B:  Revised Response Criteria for Malignant Lymphoma40 ............................ 77 
12.3 Appendix C:  ECOG Performance Status Scale ............................................................... 78 
12.4 Appendix D:  Abnormalities encountered in MDS that can contribute to the diagnosis .. 79 
12.5 Appendix E: Protocol for Autologous PBSC Collection by Apheresis Following 
Mobilization with Filgrastim and Plerixafor............................................................................. 81 
 
 
 


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  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
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Table 1. Phase I dose escalation of 
90Y-daclizumab.  
 
 
 
 
Dose Level 
90Y-daclizumab Dose (mCi) 
1 
Dose #1      15 
2 
Dose #1      15 
Dose #2      15 
3 
Dose #1      15 
Dose #2      30 
4 
Dose #1      15 
Dose #2      45 
5 
Dose #1      15 
Dose #2      60 
6 
Dose #1     15 
Dose #2     75 
7 
Dose #1     15 
Dose #2     90 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
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Treatment Schema 
Figure 1. Hodgkin lymphoma 90Y-daclizumab/BEAM chemotherapy autotransplant schema 
dose level 1. 
 
 
 
 
 
 
 
 
 
 
 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
9 
Treatment Schema 
 
Figure 2. Hodgkin lymphoma 90Y-daclizumab/BEAM chemotherapy autotransplant schema 
dose levels 2 thru 7. 
 
 
 
 
 
 
 
 
 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
10 
1 
INTRODUCTION 
1.1 
STUDY OBJECTIVES 
1.1.1 Phase I Primary Objectives: 
• To assess the safety and adverse events associated with 
90Y-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 
90Y-daclizumab RIT in combination 
with high-dose BEAM chemotherapy and ASCT in patients with relapsed or refractory HL. 
1.1.2 Phase 1 Secondary Objectives: 
• Estimate 90Y-daclizumab organ radiodosimetry in refractory or relapsed HL patients treated 
with 
90Y-daclizumab RIT in combination with high-dose BEAM chemotherapy and ASCT. 
• To assess the time to hematopoietic recovery of refractory or relapsed HL patients treated 
with 90Y-daclizumab RIT in combination with high-dose BEAM chemotherapy and ASCT. 
• To assess treatment-related morbidity and mortality including failure to engraft of refractory 
or relapsed HL patients treated with 90Y-daclizumab RIT in combination with high-dose 
BEAM chemotherapy and ASCT. 
1.1.3 Phase II Primary Objective: 
• 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 
90Y-daclizumab RIT in combination with high-dose 
BEAM chemotherapy and ASCT. 
1.1.4 Secondary Objectives: 
• To estimate the response rate (the number of complete and partial responses) in patients with 
refractory or relapsed HL to 90Y-daclizumab RIT administered in combination with high-
dose BEAM chemotherapy and ASCT. 
• To assess the progression of free survival (PFS) and overall survival (OS) of refractory or 
relapsed HL patients treated with 90Y-daclizumab RIT in combination with high-dose BEAM 
chemotherapy and ASCT. 
1.2 
BACKGROUND AND RATIONALE 
According to the American Cancer Society, there will be approximately 8500 new cases of 
Hodgkin lymphoma (HL) diagnosed this year and more than 1300 patients will die of their 
disease [1]. Although treatment with modern combination chemotherapy regimens such as 
doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) is associated with an 80% 
complete remission rate even in patients with advanced disease, 25-30% of patients will not 
respond to treatment or will relapse [2]. Failure to respond to therapy can be the result of primary 
refractory disease (HL that has not responded to primary and secondary therapy), progressive 
disease (disease that increases in size after an initial partial response), or relapsed disease 
(disease that reappears in original sites, new sites, or both after a complete remission).  High-
dose chemotherapy with autologous stem cell support (ASCT) has become the treatment of 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
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choice for all three of these groups [3-6]. Between 30% and 65% of patients will achieve long-
term disease-free survival with ASCT. However, despite this aggressive treatment a significant 
fraction of patients will not respond and a proportion of patients will develop recurrent disease.  
Newer approaches are needed to improve these numbers. 
1.2.1 Prognostic Factors at Relapse 
Prognostic models have been developed to help identify subgroups of relapsed patients likely to 
have a poor outcome with conventional ASCT [7-11]. Josting et al retrospectively analyzed 422 
patients with early (≤ 12 months), or late (> 12 months) from completion of first-line 
chemotherapy relapsed HL registered in the database of the German Hodgkin’s Lymphoma 
Study Group (GHSG) [7]. Fifty-seven percent of patients had received prior radiotherapy, 25% 
as a single modality for early stage disease and 32% (n = 133) as combined modality 
chemoradiation for intermediate stage disease. Forty-three percent (n = 182) of patients had 
advanced disease and received combination chemotherapy with radiotherapy only to sites of 
bulky disease. Patients who relapsed after radiotherapy for early stage disease had a higher 4-
year freedom from second failure (FF2F) than patients who relapsed after salvage chemotherapy 
(81% vs. 33%, and 43% for patients with an early and late relapse, respectively). Time to 
recurrence, clinical stage and anemia were independent risk factors for relapse on multivariate 
analysis. 
In a separate multivariate analysis of prognostic factors influencing time to progression (TTP) 
and overall survival (OS) in 357 patients with HL undergoing an ASCT at a first relapse, 
detectable disease at the time of ASCT was an adverse factor for both TTP and OS [11]. 
Chemosensitivity was in fact one of the most important prognostic factors for TTF with 68% of 
patients autografted in second complete remission (CR) being disease free at 5 years vs. 34% and 
11% with chemosensitive and chemorefractory disease, respectively. Other prognostic factors for 
TTP included advanced stage at diagnosis, complementary radiation, and CR <12 months.  
Chemosensitivity was also an important prognostic factor for OS, with an OS of 75% at 5 years 
for patients autografted in second CR and of 43% and 19% at 5 years for those autografted with 
chemosensitive and chemorefractory disease, respectively. 
1.2.2 Autologous Stem Cell Transplantation in Refractory HL 
Autologous hematopoietic stem cell transplant has become the standard of care for relapsed HL.  
In addition to a number of single arm studies, two randomized clinical trials have demonstrated 
that ASCT improves freedom from treatment failure (FFTF) over conventional therapy for 
relapsed disease [5, 6, 12-14]. In a small study from the British National Lymphoma 
Investigation (BNLI) by Linch et al, 40 patients with active HL who failed conventional therapy, 
were randomized to receive BEAM (carmustine, etoposide, cytarabine, and melphalan) plus 
ASCT, or mini-BEAM (reduced doses of the same drugs) [5]. At three years, the actuarial event-
free survival was 53% in the BEAM group and 10% in the mini-BEAM group (p = 0.025).  
There was no difference in overall survival between the two arms. Schmitz et al randomized 161 
patients with relapsed HL to 2 cycles of dexamethasone-BEAM (Dexa-BEAM) and either two 
further courses of Dexa-BEAM, or high-dose BEAM with ASCT [6]. Only the 117 patients who 
achieved a CR or partial remission (PR) were able to continue treatment on the protocol such that 
56 patients were treated with Dexa-BEAM and 61 patients were treated with BEAM and ASCT.  
FFTF at 3 years was significantly better for patients given BEAM-HSCT (55%) than for those on 
Dexa-BEAM (34%) (p = 0.019) regardless of the length of the initial remission.  Again, overall 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
12 
survival did not differ significantly between the two treatment groups. 
1.2.3 Autologous Stem Cell Transplant in Primary Refractory HL 
Patients who progress during first-line chemotherapy or within 3 months of the end of 
chemotherapy are defined as having “primary refractory disease.” Although these patients 
generally have an extremely poor prognosis, two retrospective registry-based analyses suggest 
that primary refractory patients may also benefit from high-dose therapy and ASCT.  The 
European Group for Blood and Marrow Transplantation (EBMT) reported on 175 HL patients of 
whom 75 received ASCT after failure of an induction regimen [15]. Actuarial 5-year OS and 
PFS were 36% and 32%, respectively, for patients receiving ASCT. On multivariate analysis, 
only the interval between diagnosis and ASCT was prognostic for OS (p = 0.02). The 
Autologous Blood and Marrow Transplant Registry (ABMTR) reported on 122 HL patients who 
failed to achieve complete remission after one or more conventional therapy regimens and 
subsequently received an ASCT [16]. Probabilities of PFS and OS at 3 years were 38% and 50%, 
respectively.  In multivariate analysis, ‘‘B’’ symptoms at diagnosis and poor performance score 
at transplantation were adverse prognostic factors for outcome. 
1.2.4 Radioimmunotherapy in Lymphoma 
Following the approval of the chimeric anti-CD20 monoclonal antibody rituximab for the 
treatment of relapsed and refractory follicular low-grade non-Hodgkin lymphoma (NHL) by the 
US Food and Drug Administration (FDA), therapeutic radioimmunoconjugates were developed 
given the frequent radiosensitivity of lymphoma [17]. Either yttrium-90 or iodine-131 was 
attached to the monoclonal antibody to enhance the cytotoxic potential of the antibody and target 
both the cell to which the antibody is bound and the surrounding tumor cells by the radiological 
bystander or “cross-fire effect.”  The FDA ultimately approved two radioimmunoconjugates, I-
131-tositumomab (Bexar®) and yttrium-90-ibritumomab tiuxetan (Zevalin®), for patients with 
refractory, relapsed, and transformed CD20-positive indolent lymphomas. Yttrium-90-
ibritumomab tiuxetan is composed of a murine immunoglobulin G1-kappa monoclonal antibody 
ibritumomab linked to yttrium-90 by the chelator tiuxetan (MX-DTPA).  I-131-tositumomab is 
composed of the murine immunoglobulin G2 monoclonal antibody tositumomab (B-1) antibody 
linked to I-131 by a chemical bond.  Whereas iodine-131 delivers 0.81 MeV over a path length 
of 0.8 mm and a half-life of 8 days, yttrium-90 is a pure beta emitting isotope that delivers more 
energy (2.3 MeV) over a longer path length (5 mm) and a shorter half-life (2.5 days) [18]. 
In the initial multicenter phase I/II study of yttrium-90-ibritumomab administered at 0.4 mCi/kg 
in 51 patients with relapsed or refractory CD20+ NHL, the overall response rate (ORR) was 67% 
(26% CRs and 41% PRs) [19].   In 34 patients with low-grade NHL, an 82% response rate was 
achieved.  All patients had received a median of two prior regimens, and 37% of treated patients 
had bulky disease.  Estimated median time to progression (TTP) by Kaplan-Meier analysis was 
12.9 months while the median duration of response was 11.7 months. The major hematologic 
toxicity, transient and reversible, was thrombocytopenia.  The nadir count typically occurred at a 
median of 43 days after radioimmunotherapy, unlike chemotherapy after which nadir counts 
occur within 1-2 weeks following therapy. The mean nadir values were 50,000/µL for platelets 
and 1,100/µL for granulocytes. The most common non-hematological toxicities included 
asthenia, nausea, infection, chills, fever, and abdominal pain. Of note, when yttrium-90-
ibritumomab was compared to rituximab alone in a randomized controlled trial of 143 patients 
with relapsed or refractory low-grade/follicular, or transformed B-cell NHL, the ORR was 80% 


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13 
for the radioimmunoconjugate vs. 56% for the rituximab group alone (p = 0.002) [20]. 
Kaminski et al, published early efficacy data using iodine-131-tositumomab in 9 patients with 
relapsed CD20-positive lymphomas in 1993 [21]. Six of 9 patients had tumor responses 
including 4 patients with complete remissions lasting from 8-11 months and 2 with PR. Most 
patients had reversible grade 1 myelosuppression 4-7 weeks after radioimmunotherapy.  Long-
term follow up of the University of Michigan database that included these 9 patients and 50 other 
patients with relapsed and refractory NHL was reported in 2000 [22]. Eighty-eight percent of 
patients had Ann Arbor stage III-IV disease at study entry and were heavily pretreated with a 
median of 4 prior regimens. Seventy-one percent of patients (n = 42) responded to treatment, 
including 20 patients who entered a CR. For all 42 responders, the median progression-free 
survival (PFS) was 12 months and reached 20.3 months for patients in a CR. As with yttrium-90-
ibritumomab, the most common non-hematological toxicities were fever, asthenia, nausea, and 
chills.  The major dose-limiting toxicity, albeit reversible, was hematological with the mean time 
to platelet and neutrophil nadir following treatment of 35 and 43 days, respectively. Of note, five 
heavily pretreated patients were diagnosed with myelodysplastic syndrome 1.2-7.5 years after 
treatment. Three patients also developed solid tumors, including 2 superficial transitional cell 
bladder cancers and one with squamous cell carcinoma of the rectum. 
1.2.5 Radioimmunotherapy in Autologous Stem Cell Transplantation 
The radiosensitivity of lymphomas is the basis for the inclusion of external beam total body 
irradiation (TBI) into transplant conditioning regimens [23, 24]. Among 96 patients with 
recurrent or refractory HL and poor-risk NHL treated with 12 Gy of total body irradiation (TBI), 
etoposide, and cyclophosphamide and autologous stem cell support following cytoreduction with 
conventional chemotherapy, the event-free survival (EFS) rate at 3 years was 47% and 53% for 
patients with HL and NHL, respectively [24]. In another series of 53 lymphoma patients treated 
with a similar approach using TBI, etoposide, and cyclophosphamide, the 2-year Kaplan-Meier 
estimates of survival, EFS, and relapse were 54%, 45%, and 43%, respectively [23]. The major 
morbidities seen in both studies were mucositis and skin toxicities.  However, other potential 
toxicities of fractionated TBI include nausea, vomiting, diarrhea, interstitial pneumonitis, 
venocclusive disease of the liver, renal insufficiency, cataracts, hypothyroidism, and the 
development of either myelodysplasia, or acute myeloid leukemia [25]. Integrating a 
radiolabeled monoclonal antibody into the induction regimen to achieve higher doses of radiation 
to tumor sites, while delivering lower doses to normal organs, maximizes the therapeutic benefit 
of radiation while minimizing toxicity. 
Press et al, first documented the feasibility and efficacy of using radiolabeled monoclonal anti-B-
cell-antibodies with high-dose therapy in patients with relapsed B cell lymphomas [26-28] Long 
term follow up in 29 patients treated with myeloablative iodine-131-anti-CD20 antibody and 
autologous stem cell rescue was reported by Liu et al [28]. All patients were previously treated 
with a median of three different regimens.  Major tumor responses occurred in 25 of 29 patients 
with 23 patients achieving a CR.  Kaplan-Meier estimates of overall survival (OS) and PFS at 4 
years were 68% and 42%, respectively.  With a median follow up of 42 months, the median time 
to treatment failure (TTF) after radioimmunotherapy was 37 months. Although severe 
myelosuppression occurred in all patients following treatment with iodine-131-anti-CD20 
antibody, hematological reconstitution was achieved with autologous stem cells in all but one 
patient (one patient spontaneously recovered their blood counts without reinfusion of stem cells).  
Late toxicities were uncommon except for elevated thyroid-stimulating hormone levels in 60% 


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of patients. No patients developed MDS although 2 patients developed solid tumors (noninvasive 
transitional cell carcinoma of the bladder and metastatic colon cancer). When high-dose 
etoposide and cyclophosphamide were added to the same transplant regimen in 52 patients with 
relapsed B cell lymphomas, the 2-year OS and PFS were 83% and 68%, respectively [29]. 
Yttrium-90-ibritumomab tiuxetan has also been incorporated into transplantation regimens with 
high-dose chemotherapy [30-32]. Nademenee et al treated 31 poor-risk or relapsed patients with 
CD20+ NHL with high-dose yttrium-90-ibritumomab tiuxetan (71.6 mCi) in combination with 
high-dose etoposide and cyclophosphamide followed by ASCT [30]. Fifty-five percent of 
patients had bone-marrow involvement at diagnosis and the median number of prior 
chemotherapy regimens was 2. At a median follow up of 22 months, the 2-year estimated OS and 
relapse free survival were 92% and 78%, respectively.  The therapy was relatively well tolerated 
with around 80% of patients developing mucositis, neutropenic sepsis and nausea. The only 2 
deaths on the study were one patient who died at day +164 after transplantation from alcohol-
induced liver failure and one patient who died from graft failure at day +44. Krishnan et al 
evaluated the safety and efficacy of combining yttrium-90-ibritumomab tiuxetan with high-dose 
carmustine, cytarabine, etoposide, and melphalan (BEAM) followed by ASCT in 41 patients 
with refractory, relapsed, or poor-risk NHL [32]. The median age of the patients was 60 years, 
and the median number of previous therapies was 2. Twenty out of 41 patients on the study had 
diffuse large B cell lymphoma.  The median dose of yttrium-90-ibritumomab tiuxetan was 32.9 
mCi. With a median follow-up of 18.4 months, the Kaplan-Meier estimated 2 year OS and PFS 
were 88.9% and 69.8%, respectively. There was only one incidence of grade 4 hepatic and 
pulmonary toxicity each, and they occurred in the same patient. Transplantation-related mortality 
at 100 days was 0%. 
1.2.6 Clinical Experience with 90Y-daclizumab  
Our Branch developed daclizumab (Zenapax®), a humanized IgG1 monoclonal antibody that 
targets human CD25 (IL-2R alpha subunit) at the IL-2 binding site [33]. Unmodified daclizumab 
has been used in the treatment of HTLV-1-associated adult T-cell leukemia (ATL). To enhance 
the cytotoxicity of the antibody in the treatment of ATL and other CD25-expressing 
malignancies, daclizumab was conjugated to the pure beta-emitting isotope yttrium-90, i.e. 90Y-
daclizumab, as a means of delivering targeted radiation therapy to the tumor [34, 35]. 
In NCI protocol 96-C-0147, 90Y-daclizumab was administered to 29 patients with HTLV-
associated adult T-cell leukemia (ATL) (Waldmann et al, unpublished data). The starting dose in 
this trial was 15 mCi and was to be escalated in 5 mCi increments in patient cohorts. Bone- 
marrow suppression with repeated doses limited the ability to administer the same dose of 
radioimmunotherapy with each six-week cycle. The revised protocol dose escalated only the first 
dose and all subsequent treatments were given at a 5 mCi dose. Immediately following infusion 
of the radiolabeled antibody, Ca-DTPA, a decorporation agent, was infused over five hours and 
repeated on each of two subsequent days. The phase I portion of the trial accrued 20 patients and 
52 cycles of therapy were administered. The first eight patients received initial 15 mCi doses 
under the original version of the protocol and the remaining patients were treated with the 
revised protocol treatment plan. Three patients were treated with initial doses of 20 mCi, 7 with 
25 mCi, and 2 with 30 mCi. The hematologic toxicity was the major observed effect of 
treatment. The maximum tolerated dose (MTD) was 25 mCi with dose-limiting 
thrombocytopenia observed in both patients treated at the 30 mCi dose. One patient had grade 4 
thrombocytopenia and the other failed to recover a platelet count of greater than 100,000/mm3 at 


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10 weeks after treatment. Of the 20 patients entered in the phase I study 11 patients (55%) 
developed grade 3 or 4 neutropenia, 3 patients (15%) had grade 3 anemia and 7 patients (35%) 
had grade 3 or 4 thrombocytopenia.  Fourteen patients had grade 1 or greater granulocytopenia 
and all but two patients had grade 1 or greater thrombocytopenia. Only one patient developed 
grade 3 or 4 non-hematologic toxicity that occurred in conjunction with tumor lysis, and 
consisted of cardiac dysfunction with a drop in ejection fraction and hypoxia requiring intensive 
care support, but not intubation. There were two grade 2 infectious complications, herpetic and 
fungal, respectively. Mild nausea, vomiting, fever, and fatigue were reported in occasional 
patients. Nine patients entered the phase II study.  Hematologic toxicity was similar to that 
observed in the phase I portion of the study with 6 patients (66%) with grade 3 or 4 
granulocytopenia, and 3 patients (33%) with grade 3 or 4 thrombocytopenia. The only grade 3 
non-hematologic toxicity was stomatitis and occurred in a patient with tumoral deposits in the 
oral mucosa. There were nine responses to treatment in the phase I portion of the study with 2 
complete remissions (5 and 32 months) and 7 partial remissions (2, 2, 4, 5, 6, 8, 16 months). 
In a separate protocol (97-C-0110), we treated 16 patients with CD25-positive malignancies 
other than ATL, including 8 CTCL, 3 PTCL, 1 ALCL, and 48 Hodgkin lymphoma patients with 
90Y-daclizumab doses of up to 20 mCi in association with Ca-DTPA in the phase I part 
(unpublished data). Repeat doses were administered as permitted by toxicity and lack of tumor 
progression. In contrast with the ATL study, the dose of 90Y-daclizumab was maintained at the 
same level on subsequent treatment cycles. The maximum tolerated dose in this study was 15 
mCi with dose-limiting thrombocytopenia seen in two of the three patients treated at the 20 mCi 
dose level. Both patients had thrombocytopenia that did not recover to a value of ≥100,000/mm3 
by ten weeks after their initial treatment. Fifteen patients were treated with 26 cycles of therapy.  
Myelosuppression was the major treatment-related toxicity. Of the 16 patients entered in the 
study, 2 patients (13%) had grade 3 or 4 granulocytopenia, 5 patients (31%) grade 3 or 4 
thrombocytopenia, and 4 patients (25%) grade 3 or 4 hemoglobin. There were two grade 3 or 
greater non-hematologic toxicities; one patient with a pre-existing hearing loss complained of a 
further decrement in hearing and one patient had hyperglycemia. As with the study in ATL, 
occasional patients experienced nausea, vomiting, fatigue, and low-grade fever.  Response to 
treatment was not as frequent; 11 patients progressed, 3 had stable disease and 1 responded. 
1.2.7 Rationale 
Although an expanding number of monoclonal antibodies and RIT have been well studied in 
NHL, their successes in HL have been limited [36-38]. This is due to a number of factors 
including a limited number of unique surface antigens expressed in HL and their relatively low 
density.  In HL, both the Reed-Sternberg cell and the T-cell infiltrate that surrounds the Reed-
Sternberg cells may express CD25 (Figure 2) [36, 39]. 


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Figure 3. Lymph node biopsy showing classical HL (H&E stain; panel 1).  
Immunohistochemical stain demonstrating expression of CD25 by Reed-Sternberg cells (panel 
2). In another patient’s biopsy, an immunohistochemical stain demonstrating CD25-negative 
Reed-Sternberg cells, but strongly CD25-positive rosetting T-cells (panel 3). 
While a significant fraction of Reed-Sternberg cells may lack expression of CD25, it is almost 
uniformly expressed on the associated rosetting polyclonal T-cells that increases the number of 
targets for the radiolabeled antibody and therefore the amount of radiation delivered to the 
tumor. 
Hypothesizing that radioimmunoconjugate would enhance cytotoxicity to tumor cells while 
sparing normal tissues, in a single institution phase II study, 30 heavily pre-treated patients with 
recurrent or refractory HL were treated with up to 7 doses of 90Y-daclizumab (Janik JE et al, 
manuscript submitted). These patients had received a median of 4 (range, 1-8) prior 
chemotherapy regimens with 20 having received a prior autologous stem cell transplant.  Four 
patients had received both a prior autologous and allogeneic hematopoietic stem cell transplant.  
Even among this heavily pretreated group, 12 patients achieved a complete response while 7 
achieved a partial response for an overall response rate of 63%. An example of a patient response 
is shown in Figures 4 and 5.  Despite achieving this impressive response rate in a heavily pre-
treated population, the median response duration was a somewhat disappointing 129 days (range, 
28 to 720 days).  


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Figure 4. Indium-111-daclizumab (111In) single photon-emission capture tomography (SPECT) 
imaging during 90Y-daclizumab treatment in patient that achieved a complete response (upper 
panels). Imaging demonstrated binding of 111In-daclizumab to HL in the spleen and lymph 
nodes. 18FDG-PET demonstrated serial decrease and resolution of tracer uptake consistent with 
the patient achieving a complete response. 
 
Figure 5. Computerized tomography (CT) demonstrated a complete response after 3 cycles of 15 
mCi 90Y-daclizumab in a patient with HL and multiple relapses. Arrows indicate enlarged left 
axillary lymph nodes and a posterior mediastinal mass that resolved with RIT. 
The major toxicity, bone-marrow suppression, was transient in the majority of patients. 
However, ultimately six of forty eight HL patients treated on this protocol developed 
MDS/AML. Four of these patients started protocol treatment with normal bone marrow (BM) 
cytogenetics and two others had no pre-treatment assessment of their BM because they received 
the study therapy before the protocol required a pre-treatment cytogenetic assessment.   With 
regards to the contribution of Yttrium Anti-Tac to their subsequent MDS, three of these patients 


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were heavily pretreated with known genotoxic regimens and received 3, 6, and 7 cycles of 
Yttrium daclizumab, respectively.   
The preliminary analysis of response presented in the “waterfall” analysis shown in Figure 6 
shows the number and quality of responses achieved in the initial 30 patients treated in this 
protocol; the remaining 18 patients are being analyzed. 
 
Figure 6. Waterfall analysis of 30 relapsed or refractory HL patients treated with 90Y-
daclizumab. 
Given that recurrent disease remains the single most common cause of treatment failure after 
ASCT in patients with relapsed HL and given the 63% response rate achieved with 90Y-
daclizumab RIT in the heavily pretreated population reported above, we now seek to improve the 
long-term disease-free survival achievable with ASCT by incorporating 90Y-daclizumab into the 
transplant pre-conditioning regimen.  90Y-daclizumab provides a vehicle to target not only to the 
lymphoma cells that express CD25, but also rosetting CD25-expressing polyclonal T-cells that 
infiltrate the tumor.  Furthermore, through a radiobiological “crossfire” or “bystander” effect, 
90Y-daclizumab provides radiation exposure to neighboring antigen negative tumor cells that are 
ordinarily inaccessible to the unmodified antibody. To maximize the crossfire effect 90Y-
daclizumab will be used as cytoreductive therapy. A maximal effect is obtained with 
macroscopic tumor volumes rather than minimal residual disease. We will administer 2 doses of 
90Y-radiolabeled daclizumab prior to BEAM conditioning therapy and autologous hematopoietic 
stem cell transplant.  This is based on our observation that none of the 12 patients that achieved a 
complete remission did so following the first dose of radioimmunotherapy. It is expected that 2 
cycles of radioimmunotherapy combined with ASCT will be well tolerated by patients while 
providing significant anti-tumor effects, thereby allowing a greater proportion of these patients to 
achieve a superior freedom from disease progression. 
 
 


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2 
ELIGIBILITY ASSESSMENT AND ENROLLMENT 
2.1 
ELIGIBILITY CRITERIA 
2.1.1 Inclusion Criteria 
2.1.1.1 All patients must have a pathologically confirmed diagnosis of classical Hodgkin's 
lymphoma (HL) as outlined in the WHO Classification System of Lymphoid 
Tumours [41].  Patients with nodular lymphocyte-predominant HL (NLPHL) are not 
eligible. 
2.1.1.2 Refractory or relapsed HLpatients that are also candidates for ASCT. 
2.1.1.3 At least one adverse prognostic factor:  (1) initial relapse ≤ 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 18FDG-PET imaging.   
2.1.1.4 At least 10% of the cells obtained from lymph node, or extranodal sites must react 
with anti-CD25 (anti-Tac) on immunofluorescent or immunoperoxidase staining. 
Because of the high frequency of CD25 positivity of the infiltrating T-cells 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  1.0 cm in longest 
diameter by CT scan.[40]. 
2.1.1.6 Omission of cytotoxic chemotherapy or other systemic therapy of the malignancy for 
≥ 4 weeks prior to entry into the trial. Patients must be ≥ 4 weeks since major 
surgery, radiotherapy, or biotherapy/targeted therapies and recovered from the 
toxicity of prior treatment to ≤ CTC grade 1, exclusive of grade 2 alopecia, fatigue, 
lymphopenia, CD4+ circulating T cells, WBC or bilirubin. 
2.1.1.7 Patients must be ≥ 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 ECOG performance status of ≤1. 
2.1.1.10 The patient must have a granulocyte count of at least 1,500/µL and a platelet count 
of greater than 100,000/µL. 
2.1.1.11 Patients must have a creatinine of less than 2.0 mg/dL, or if the patient has a serum 
creatinine≥ 2.0, a measured creatinine clearance (CrCl) must be > 60 
mL/min/1.73m2. 
2.1.1.12 Patients must have a serum alkaline phosphatase, ALT (SGOT), and AST (SGPT) < 
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 < 5x ULN. 
2.1.1.13 Patients must have a total serum bilirubin < 2.5 x ULN. 
2.1.1.14 Patients must have a cardiac ejection fraction >45% on 2D echocardiography or 
MUGA obtained within 28 days of study enrollment. 
2.1.1.15 Lung diffusion capacity for carbon monoxide (DLCO) > 50%, or forced expiratory 
volume at 1.0 seconds (FEV1.0) > 65% of predicted on pulmonary function testing 


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(PFT) obtained within 28 days of study enrollment. 
2.1.1.16 Women of childbearing potential must have a negative serum β-HCG pregnancy test 
at initial screening and within 3 days prior to registration. 
2.1.1.17 The effects of 90Y-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 (> 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. 
2.1.2 Exclusion Criteria 
2.1.2.1 Patients who have relapsed from their initial ABVD or similar standard treatment 
regimen and have not received any other chemotherapy or salvage systemic 
treatment. 
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, NCI taking into consideration the totality of the clinical, 
pathological, flow cytometric and cytogenetic information described in Section 12.4 
Appendix D and present in a particular individual’s evaluation. 
2.1.2.8 Patients with history of 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 > 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 ≤ 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 HIV infection (antibody positive with positive confirmatory molecular 
test). 
2.1.2.12 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.  


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2.1.2.15 Patients with significant medical comorbidities, including uncontrolled hypertension 
(diastolic BP > 115 mmHg), unstable angina, congestive heart failure (> 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 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) 
2.2 
 SCREENING EVALUATION  
2.2.1 Complete medical history and physical examination with vital signs and performance 
status with documentation of all measurable or evaluable abnormalities.  Measurable 
disease will be documented in two dimensions. 
2.2.2 Studies must be completed within 28 days prior to study entry with the exception of the 
bone- marrow aspirate and biopsy with cytogenetics that must be completed within 60 
days prior to study entry. 
2.2.3 Complete blood count (CBC) including differential leukocyte and platelet count, Acute 
Care, Mineral and Hepatic Panels, creatinine clearance if serum creatinine is > 2 mg/dL. 
2.2.4 Blood will be tested for antibodies to HIV.  Positive serologic tests will be confirmed by 
molecular assays. 
2.2.5 Hepatitis B and hepatitis C serologies will be obtained. Positive serologic tests will be 
confirmed by molecular assays. 
2.2.6 Assessment of serum [two 4 mL or one 8 mL serum separator tube (SST tube)] 
human anti-human antibody (HAHA) against daclizumab will be performed on the 
patients’ serum by ELISA to detect immune responses against Yttrium- daclizumab. 
Samples are to be sent to Dr. William Kopp/Ms. Helen Rager at NCI/OD, Clinical 
Support Laboratory 560/11-27, Building 1050, Boyles Street, Frederick, Maryland 
21702, telephone number: 301-846-1707 or 301-846-1917. 
2.2.7 Serum pregnancy test (serum β-HCG) in women of child-bearing potential. 
2.2.8 Computerized tomography (CT) scan of the neck, chest, abdomen, and pelvis 
2.2.9 Echocardiogram or MUGA to determine cardiac ejection fraction 
2.2.10 Pulmonary function testing (PFT) with diffusing capacity DLCO. 
2.2.11 Bone-marrow aspirate and biopsy with cytogenetics within 60 days prior to study entry. 
Results must be available before registration.  Bone-marrow specimens will be reviewed 
by the Hematology Laboratory of the Clinical Center.  HL will be classified according to 
the WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues [41]. 
2.2.12 Lumbar puncture, MRI and CSF analysis will be performed in patients with neurological 
signs or symptoms (e.g., cranial nerve palsies, leg weakness, bowel or bladder 
dysfunction, etc.) that are not known to be due to some other diagnosis and that could be 


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indicative of CNS involvement by lymphoma. 
2.2.13 A pre-therapy lymph node biopsy may be obtained if required for diagnostic purposes, 
and to determine the expression of the CD25 antigen. All lymph node biopsies should be 
submitted fresh in saline to the Hematopathology Section, Laboratory of Pathology, NCI, 
(Bldg. 10/2N110–112, Ms. Theresa Davies-Hill at 301-496-1567, or 301-435-2628). 
Biopsy specimens will be processed for routine histopathology as well as 
immunohistochemistry in frozen sections and/or flow cytometry for expression of CD25 
and other surface antigens as appropriate. 
2.3 
 REGISTRATION PROCEDURES 
 Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent.  A registration Eligibility Checklist from the web site 
(http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) must be completed and sent via 
encrypted email to: NCI Central Registration Office (HOIS) ncicentralregistration-
l@mail.nih.gov.  After confirmation of eligibility at Central Registration Office, CRO staff will 
call pharmacy to advise them of the acceptance of the patient on the protocol prior to the release 
of any investigational agents.  Verification of Registration will be forwarded electronically via e-
mail to the research team. A recorder is available during non-working hours. 
2.4 
BASELINE EVALUATION  
Blood drawing for research purposes will not exceed 10.5 mL/kg or 550 mL, whichever is 
smaller, over any eight-week period.  
The following test/procedures are to be performed within 28 days of starting treatment except as 
listed below. 
2.4.1 CBC including differential leukocyte and platelet count, Acute Care, Mineral and Hepatic 
Panels and serum pregnancy test (β-HCG) will be repeated within three days before study 
entry.  
2.4.2 LDH, uric acid, total protein, reticulocytes, PT, PTT, fibrinogen, creatine kinase (CK) 
zinc, cholesterol, triglycerides, quantitative immunoglobulins.  
2.4.3 Baseline CMV serology and antigenemia. 
2.4.4 Serum soluble IL-2R alpha (sCD25) will be measured by ELISA. 
2.4.5 Urinalysis. 
2.4.6 Whole body 18fluorodeoxyglucose (18FDG) positron emission tomography (PET) 
imaging.  
2.4.7 Magnetic resonance imaging and/or ultrasonography may be performed if clinically 
indicated. 
2.4.8 Baseline 12-lead electrocardiogram. 
3 
STUDY IMPLEMENTATION 
3.1 
STUDY DESIGN 
The study will be conducted in accordance with the procedures established by the NCI, NIH 
Radiation Safety Branch, NIH Clinical Center Department of Nuclear Medicine, the Nuclear 


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Regulatory Commission (NRC) and the U.S. Food and Drug Administration (FDA). 
The study and Consent Document will be fully discussed with each patient and written Informed 
Consent obtained. It is the objective of this study to determine the dose of 
90Y-daclizumab in mCi 
that can be safely administered in combination with high-dose BEAM (carmustine, etoposide, 
cytarabine and melphalan) chemotherapy and autologous stem cell transplant (ASCT) in patients 
with refractory or relapsed HL, and to estimate the tumor response and duration of response to 
this treatment. Treatment will be administered on an inpatient basis. 
 


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3.1.1 Study Schema Phase I, Dose Level 1ƒ. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ƒ Dates between Week -6 and Day -15 are approximate and may be adjusted based on 
scheduling, stem cell harvest and other considerations. Patients that have evidence of rapidly 
progressive symptomatic disease requiring urgent salvage treatment after their stem cell 
mobilization and harvest will have their stem cells stored and receive the appropriate therapy to 
achieve disease control. These patients will be reconsented and allowed to re-enter the protocol 
treatment without having to undergo another stem cell mobilization/harvest.   
Stem Cell Mobilization  
Filgrastim (G-CSF) 10-16 µg/kg/d x 5-6d 
Plerixafor 240 μg/kg on day 5 (6 if needed) 
Apheresis/Stem Cell Harvest 
BCNU (Carmustine) 300 mg/m2 
Etoposide 200 mg/m2 
Cytarabine (Ara-C) 200 mg/m2 
Infusion of Autologous Stem Cells 
Filgrastim 5 µg/kg/d until ANC 
≥ 1000/µL for 3 consecutive days 
Melphalan 140 mg/m2 
Day -6 
Days -5, -4, -3, -2 
Day -1 
Day 0 ± 
2 days 
Day + 5 
Week -6 
90Yttrium-Daclizumab (anti-CD25) 15 mCi 
111Indium-Daclizumab 5 mCi 
Unlabeled daclizumab 5 mg 
Ca2+_DTPA 250mg/m2 x 3 days 
Day -15 


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3.1.2 Study Schema, Phase I, Dose Levels 2-7 and Phase II*. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Apheresis/Stem Cell Harvest 
Dose #1 
90Yttrium-Daclizumab (anti-CD25) 
111Indium-Daclizumab 5 mCi 
Unlabeled daclizumab 5 mg 
Ca2+_DTPA 250mg/m2 x 3 days 
Dose #2 
90Yttrium-Daclizumab (anti-CD25) 
BCNU (Carmustine) 300 mg/m2 
Etoposide 200 mg/m2 
Cytarabine (Ara-C) 200 mg/m2 
Melphalan 140 mg/m2 
Filgrastim 5 µg/kg/d until ANC 
≥ 1000/µL for 3 consecutive days 
Infusion of Autologous Stem Cells 
Stem Cell Mobilization  
Filgrastim (G-CSF) 10-16 µg/kg/d x 5-6d 
Plerixafor 240μg/kg on day(s) 5 (6 if needed) 
* Dates between Week -12 and 
Day -15 are approximate and 
may be adjusted based on 
scheduling, stem cell harvest 
and other considerations. 
Week -12 
Day -56 
Day -15 
Day -6 
Days -5, -4, 
-3, -2 
Day -1 
Day 0 ± 2 
days 
Day + 5 
* Patients that have evidence 
of rapidly progressive 
symptomatic disease requiring 
urgent salvage treatment after 
their stem cell mobilization 
and harvest will have their 
stem cells stored and receive 
the appropriate therapy to 
achieve disease control. These 
patients will be reconsented 
and allowed to re-enter the 
protocol treatment without 
having to undergo another 
stem cell mobilization/harvest.   


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
26 
3.1.3 Phase I dose-escalation of 
90Y-daclizumab 
The first part of the study will be a phase I dose-escalation of 
90Y-daclizumab administered with 
a fixed dose of Ca-DTPA (trisodium calcium diethylenetriaminepentaacetate), a chelating agent 
that scavenges and binds free radioactive 90Y and enhances its excretion [43]. Three patients will 
be entered at each sequential dose level of 90Y-daclizumab. Based on dosimetric estimates for 
90Y-daclizumab in monkeys and humans and on our experience with 90Y-murine-anti-CD25 and 
90Y-daclizumab in clinical trials, the initial intravenous dose of 90Y-daclizumab will be 15 mCi. 
Assuming no dose-limiting toxicity (see Section 3.1.4), subsequent cohorts will receive 2 
sequential doses of 90Y-daclizumab each separated by 6 weeks. The second dose of 90Y-
daclizumab will be escalated by 15 mCi increments from 15 mCi to a maximum dose of 90 mCi 
until the maximum tolerated dose is reached (the dose level below the dose at which 2 of 6 
patients develop dose-limiting toxicity, as defined in Section 3.1.4). We have already confirmed 
multiply relapsed heavily pretreated Hodgkin’s disease patients including patients who in some 
cases have already undergone stem cell transplants that 90Y-daclizumab at a dose of 15 mCi can 
be given for up to 7 cycles. Never-the less, all treatments for dose levels 1 and 2 for this protocol 
will be the 15 mCi dose to reconfirm the tolerability in this patient population. For dose levels 2 
through 7, at least three patients must have received both of their radiolabeled antibody infusions 
and undergone a 4-week post-transplant evaluation before patients can be started at the next dose 
level. 
If 1/3 of patients treated at dose level 2 develop a DLT, the cohort will be expanded to 6 patients. 
If a second patient (2 of 6) experiences a DLT, the study will be terminated as not being feasible.  
All patients enrolled on dose levels 2-7 will receive 2 sequential doses of 
90Y-daclizumab. The 
second dose of 
90Y-daclizumab will be escalated in increments of 15 mCi from 15 mCi to a 
maximum dose of 90 mCi as shown in Table 1. The highest dose that allows 0/6 or 1/6 DLT will 
be used in the Phase II portion of the trial. 
We anticipate treating a maximum of 42 patients in the initial dose escalation phase of the study 
and up to 48 evaluable patients in the Phase II segment of the study, who will receive a dose 
defined during the dose escalation study.   
Table 1. Phase I dose escalation of 
90Y-daclizumab.  
Dose Level 
90Y-daclizumab Dose (mCi) 
1 
Dose #1:      15 
2 
Dose #1:      15                 Dose #2:     15 
3 
Dose #1:      15                 Dose #2:     30 
4 
Dose #1:      15                 Dose #2:     45 
5 
Dose #1:      15                 Dose #2:     60 
6 
Dose #1:      15                 Dose #2:     75 
7 
Dose #1:      15                 Dose #2:     90 
If a dose limiting toxicity (DLT) is observed in 2 patients at any time in a given dose level, 
accrual to that dose level will be halted.  The event must be considered to be either possibly, 
probably or definitely related to the study therapy.  The immediate previous dose level will then 
be increased as follows:  the second dose of 90Y-daclizumab will then be increased in groups of 3 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
27 
to 6 patients by 5 mCi (e.g., 25, 30, 35 mCi) etc., rather than the 15 mCi increments until there 
have either been 2 incremental dose increases or 2 out of 2 to 6 patients at a given dose level 
develop DLT.  There can be no more than 1 out of 6 patients with DLT at the MTD.  The true 
MTD level must be confirmed in a cohort of 6 patients.  111In-daclizumab 5 mCi will be 
administered with both 90Y-daclizumab doses.  In the Phase II portion of the study 48 patients 
will receive two doses of 90Y-daclizumab (if demonstrated to be safe) followed by BEAM high-
dose chemotherapy and ASCT.   The first dose will be fixed at 15 mCi.  The second dose of 90Y-
daclizumab will be the maximum tolerated dose determined from Phase I.  111In-daclizumab 5 
mCi will be administered with both 90Y-daclizumab doses and at day 100 ±7 days for imaging 
purposes. 
3.1.4 Dose-limiting Toxicity  
Patients who develop either a CTCAE v4.0 grade 3 or greater non-hematological toxicity, with 
the exception of fatigue, of more than 5 days’ duration possibly, probably or definitely related to 
the infusion of 90Y-daclizumab prior to the start of BEAM chemotherapy (Day-6) will have 
developed by definition a dose-limiting toxicity (DLT) and may only continue on the study if the 
dose modifications described in Section 3.3.1 are made.  Patients will receive a 2nd dose of 90Y-
daclizumab regardless of the level of hematologic toxicity at day -15. Patients who sustained 
CTCAE v4.0 grade 3 or greater non-hematological toxicity will not be eligible to receive further 
90Y-daclizumab.  Once toxicity has recovered to grade 1 or less, the patient would proceed with 
BEAM chemotherapy and ASCT for medical and ethical reasons.  
Hematologic toxicity following the 2nd dose of 90Y-daclizumab will not be considered in 
determining DLT. 
 
3.1.5 Maximum Tolerated Dose 
A dose-limiting event in 2 patients at a given dose level will result in a halt to accrual at that dose 
level.  These events must be considered to be either possibly, probably or definitely related to the 
study therapy.  The second dose of 90Y-daclizumab will then be increased from the previous dose 
level in increments of 5 mCi as described in Section 3.1.3. The maximum tolerated dose (MTD) 
will be defined as the dose level below the dose at which 2 out of 2 to 6 patients at a given dose 
level develop DLT.  There can be no more than 1 out of 6 patients with DLT at the MTD.   
On completion of the Phase I study, a Phase II study will be initiated using the same schema 
outlined in Section 3.1.2.  The initial dose of 90Y-daclizumab at day -56 would be 15 mCi 
whereas the second dose at day -15 would be the maximum tolerated dose determined from 
Phase I.  Early termination would occur based on a 100-day post-transplant mortality of 15% or 
greater. 
3.1.6 Phase II Study Design 
For the Phase II Study the following considerations apply. 
Two main goals of the Phase II portion of the trial are to assess the rate of engraftment and to 
assess if an adequate fraction of patients can avoid MDS or cytogenetic abnormalities. 
Since the purpose of high-dose chemotherapy and ASCT is to achieve a steep-dose response in 
the tumor, the absolute hematological values achieved except for a CTCAE v4.0 grade 5 events 
(death) are of little value in assessing dose-limiting toxicity.  Rather failure of the autologous 
hematopoietic stem cells to achieve engraftment as defined below will be DLT: 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
28 
Failure to achieve neutrophil engraftment by day 21, defined from day 0 (the day when 
autologous stem cells are infused) as the first of three consecutive days on which the patient’s 
absolute neutrophil count is greater than 0.5 x 109/L following the nadir. 
Failure to achieve platelet engraftment by day 28, defined from day 0 (the day when autologous 
stem cells are infused) as the first of seven consecutive days on which the patient’s unsupported 
platelet count is greater than 20 x 109/L following the nadir. 
The first 20 patients in the Phase II portion of the trial will be evaluated with respect to the 
number that fails to engraft as explained in detail in Section 8.  If there are 2 or more patients 
who fail to engraft in the initial 20 patients, this is more likely to be consistent with an 
unacceptably high rate of engraftment failure such as 15% than a potentially reasonable rate of 
engraftment failure, and the trial would stop under these circumstances.  If it does not stop 
accrual prior to 20 patients, future patients will continue to be monitored for engraftment failure, 
and if at any point beyond the first 20 patients, greater than 10% are cumulatively noted to fail to 
engraft, the study will no longer accrue further patients unless a revision to the design is 
approved.  
At all times during the trial patients will be monitored for the occurrence of an unacceptably high 
day-100 Transplant Related Mortality (TRM) as detailed in Section 8.  
We will perform bone-marrow aspirates/biopsies for morphology and cytogenetics prior to study 
entry, at day 100 (± 7 days) post-transplant, then yearly for 5 years, and as medically indicated 
following treatment for early detection of MDS/secondary leukemia.  Patients with pre-existing 
MDS or cytogenetic abnormalities will not be eligible to participate in this trial.  The study will 
be conducted in order to rule out an unacceptably low 75% proportion avoiding MDS (p0 = 0.75) 
in favor of a higher MDS avoidance rate of 90% (p1 = 0.90).  As detailed in Section 8, if 11 or 
more of the first 13 avoid engraftment failure and/or MDS and/or cytogenetic abnormality 
initially, then accrual would continue until a total of 48 evaluable patients have been enrolled.  If 
there are 11-40 of 48 patients who avoid MDS or its corresponding cytogenetic abnormality, this 
would be an unacceptably low rate of avoiding MDS while if there were 41 or more of 48 
patients who do not develop MDS then this would be sufficiently interesting to warrant further 
study.   
3.2 
STUDY PROCEDURES/DRUG ADMINISTRATION 
3.2.1 Peripheral blood stem cell (PBSC) mobilization 
Approximately one month prior to the first planned dose of 90Y-daclizumab, patients will 
undergo apheresis to collect a minimum CD34+ cell dose of 2.0 x 106 CD34+ cells/kg following 
mobilization with filgrastim (granulocyte-colony stimulating factor, G-CSF) and plerixafor 
(AMD3100, Mozobil). Patients are required to have adequate hematological recovery (platelet 
count >100,000/µL and ANC >2500/µL) prior to starting stem cell mobilization.   
3.2.1.1 Granulocyte-colony stimulating factor (G-CSF, filgrastim) 
G-CSF will be administered subcutaneously at 10-16 µg/kg/day (See Section 12.5 Appendix 
E for G-CSF dosing algorithm) for five to six days (dependent on achieving an adequate 
collection of stem cells), beginning at least one month prior to the first planned dose of 
90Y-
daclizumab. The G-CSF will be given between 8:00 A.M. to 5:00 P.M. on days 1-4, and 6 
hours prior to starting apheresis on days 5-6.  Cells will be processed, cryopreserved in 
DMSO, and frozen according to DTM Cell Processing Section SOP.  If mobilization of 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
29 
CD34+ cells does not yield sufficient numbers (minimum of 2 x 106 CD34+ cells/kg of actual 
body weight), G-CSF will be discontinued for a minimum of three weeks, after which 
mobilization and collection will be attempted again. Patients from whom adequate numbers of 
CD34+ cells cannot be collected in two mobilization cycles will be removed from the study. 
If the initial week -6 mobilization and harvest has a poor CD34+ cell yield (i.e. < 1 X 106 
CD34+ cells/kg), consideration will be given to withdrawing the patient from the protocol at 
that time rather than proceeding with a futile second round of stem cell mobilization. 
Patients enrolled in this study will have undergone many prior cycles of alkylator-based 
chemotherapy, often in combination with radiation therapy, and are expected to have poor 
marrow reserve.  To optimize the likelihood of robust mobilization of CD34+ cells into the 
circulation and thus collection of the targeted CD34+ cell dose during the first mobilization 
cycle, G-CSF will be administered according to a weight- and vial-based algorithm, as 
described in Section 12.5 Appendix E.  This algorithm is in widespread use in NIH protocols 
for patients predicted to have poor marrow reserve.   
3.2.1.2 Plerixafor administration 
A single dose of plerixafor (Mozobil™, Genzyme), 240 mcg/kg subcutaneous injection, will 
be given on the fifth day of mobilization 6 hours prior to apheresis along with G-CSF. 
3.2.2 Peripheral blood stem cell (PBSC) collection by apheresis and cryopreservation 
On the fifth day of mobilization, patients will undergo PBSC collection by apheresis in the 
Dowling Clinic of the Clinical Center Department of Transfusion Medicine (DTM), see Section 
12.5 Appendix E for detail.  They will receive intravenous calcium prophylaxis to prevent citrate 
toxicity during apheresis, in accordance with DTM standard operating procedures (SOP).  
Targeted cell dose is 4 x 106 CD34+ cells/kg of actual body weight, with a minimum cell dose of 
2 x 106 CD34+ cells/kg necessary for continued participation in protocol. Apheresis and G-CSF / 
Plerixafor administration will continue daily for up to two consecutive days (maximum number 
of apheresis procedures is two) until the minimum cell dose of 2 x 106 CD34+ cells/kg of actual 
body weight is obtained.  Fifteen to 25 ml of blood may be processed daily, with the exact 
volume processed per procedure determined by DTM medical staff on the day of apheresis, 
based on stat peak CD34 cell count drawn immediately prior to starting apheresis. Cells will be 
processed, cryopreserved in DMSO, and frozen according to DTM Cell Processing Section SOP. 
The total hematopoietic stem cell product yield will be aliquoted and cryopreserved in multiple 
bags such that separate infusions of cryopreserved hematopoietic stem cells, each with a CD34+ 
cell dose of at least 2 x 106/kg actual body weight can occur. 
If collection of CD34+ cells does not yield at least 2 x 106 CD34+ cells/kg of actual body weight 
during the first mobilization and apheresis cycle, G-CSF / Plerixafor will be discontinued for a 
minimum of three weeks, after which the mobilization and collection will be attempted again 
using the schedule and procedures described above. Patients from whom adequate numbers of 
CD34+ cells cannot be collected will be excluded and removed from the study. 
3.2.3 Administration of 
90Y-daclizumab and 
111In-daclizumab: Dose level 1, Day -15; dose 
levels 2 – 7, and phase II days -56 & -15 
Five mCi of 
111In-daclizumab will be administered to patients with each therapeutic infusion of 
90Y-daclizumab in order to follow the kinetics of disappearance of CD25 from the plasma, to 
define the distribution of radiolabeled daclizumab, and to allow visualization by scans. 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
30 
Radiolabeled antibody will be administered by the Radiolabeled Biologics Section of the Nuclear 
Medicine Department, Clinical Center, in the Nuclear Medicine Department suites. 
90Y-
daclizumab and 111In-daclizumab will be intravenously administered simultaneously over 2 
hours. The radiolabeled antibodies will be diluted in normal saline 5% human serum albumin 
solution and administered intravenously with a slow infusion over 2 hours. Vital signs will be 
monitored during administration (hourly for the first 4 hrs. and then per routine), and emergency 
support for anaphylactic reactions will be available. All patients will receive their infusions as 
inpatients. A physician or trained research nurse will be present to handle problems arising from 
the infusion. For dose levels beyond dose level 1, 2 doses of 90Y-daclizumab will be 
administered 6 weeks apart such that the second dose of 90Y-daclizumab is administered 15 days 
prior to the administration of the autologous stem cells. 111In-daclizumab will be administered 
with each dose of 90Y-daclizumab and the patient will undergo CT-SPECT imaging to assess 
antibody binding to tumor. 
3.2.4 Estimate 90Y-daclizumab organ radiodosimetry in refractory or relapsed HL patients 
treated with 90Y-daclizumab RIT in combination with high-dose BEAM chemotherapy 
and ASCT. 
As 90Y is difficult to image, with each 90Y-daclizumab injection, 111In daclizumab will also be 
injected to permit estimation of 90Y-daclizumab radiation dose to the tumor and organs. 90Y- 
daclizumab and111In daclizumab are expected to have near identical biodistributions and the 
biodistribution will be driven by the larger daclizumab components (not the small amount of 
radionuclide (90Y or 111In).  In a similar situation, 111In rituximab is used clinically to estimate 
90Y rituximab biodistribution.  
A series of three images will be obtained following the administration of 111In daclizumab:  
The day of injection [2-8 hours post-injection] 
24-72 (+/-12) hours after injection 
96-168 (+/-12) hours after injection 
The images will consist of SPECT CT of the torso (2-3 fields of view) which will result in a 
volume image.  As no significant uptake has been noted in the brain, only the torso will be 
imaged. The expecting imaging time is 45-75 mins. A scatter window will be set to improve 
quantification. A small amount of a known activity of 111In will be included in each field of view 
to permit calibration of imaging counts to activity. 
Volumetric regions of interest (VOIs) will be drawn on images at each time point to create time-
activity curves. For the solid organs, the VOI will be in a homogenous area of the organ and an 
activity concentration will be calculated. For the hollow organs (i.e. gut, gallbladder, urinary 
bladder) and the whole body, generous VOIs will be drawn to include all of the organ activity 
(including spillover) and the total organ activity at each time point will be calculated. 
The resultant time activity curves will be used to calculate the organ residence times from which 
dosimetry estimates will be obtained using OLINDA/EXM software. 
The total activity in the tumor will also be measured and an integrated tumor dose will be 
estimated. 
3.2.5 Administration of unlabeled daclizumab  


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
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31 
Simultaneous with each dose of radiolabeled 90Y-daclizumab administered in the phase I and 
phase II studies, patients will receive a fixed dose of 5 mg of unlabeled daclizumab (Zenapax™, 
humanized anti-CD25, anti-IL-2R alpha, anti-Tac).  The quantity of unlabeled daclizumab 
administered is based on studies of ATL patients with circulating malignant cells and elevated 
soluble CD25 levels.  The rationale for administering an unlabeled antibody directed to CD25 
(e.g., daclizumab) is that there is an increase in the serum concentration of the released IL-2R 
alpha (Tac peptide, CD25) in patients with IL-2R alpha expressing malignancies such as HL.  
The administered unlabeled daclizumab binds to this circulating IL-2R alpha and increases the 
proportion of the radiolabeled 90Y-daclizumab that binds to the CD25 expressing target cell.  In 
those patients it is estimated to yield binding of radiolabeled daclizumab to all circulating CD25-
expressing tumor cells and to produce approximately 25 to 75% saturation of the IL-2 receptors 
in patients with soluble CD25 levels of 2,000 to 10,000 units/mL. These estimates are made on 
the basis of the observations during the Phase I trial of 
90Y-murine anti-CD25 (anti-Tac) 
antibody, where binding was assessed by FACS analysis and by binding to the circulating cells 
of  
111In-murine anti-CD25 antibody co-administered with 
90Y-murine anti-CD25 antibody. The 
soluble CD25 levels of the majority of patients on this study are expected to be in the above 
range.   
3.2.6 Administration of unlabeled basiliximab 
If unlabeled daclizumab is unavailable, 5 mg basiliximab that defines the same epitope of IL-2R 
alpha can be used in lieu of unlabeled daclizumab. 
3.2.7 Days -15, -14, -13 Calcium diethylenetriaminepentaacetate (Ca-DTPA). 
Ca-DTPA in normal saline will be administered as a 5 hr intravenous infusion daily for 3 days, 
starting immediately after 
90Y-daclizumab is administered. The dose of Ca-DTPA will be 250 
mg/m2/day x3. The Ca-DTPA will be supplied by the NIH Pharmacy using commercially 
available FDA-approved Ca-DTPA.  
3.2.8 Mucositis prophylaxis 
Keratinocyte Growth Factor (Palifermin/Kepivance) will be used at the dose of 60 g/kg 
starting at day -9 of ASCT (see Sections 4.5 and 10.13 for dose and schedule). 
3.2.9 Day -6: Initiation of the BEAM conditioning chemotherapy. 
Day -6: 
BCNU (Carmustine). 
Intravenous BCNU will be administered at a dose of 300 mg/m2 on day -6 based on adjusted 
ideal body weight. BCNU will be diluted in 500 mL 5% dextrose and administered IV over 2 
hours. Patients will be premedicated with a sedative and anti-emetics according to the BMT 
Consortium Guidelines (http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml).  
Days -5, -4, -3, and -2: Cytarabine (cytosine arabinoside, Ara-C). 
Cytarabine 200 mg/m2 calculated based on adjusted ideal body weight is to be administered 
every 12 hours on Days -5, -4, -3 and -2 for a total of 8 doses. Cytarabine will be infused in 100 
mL 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP, IV over 30 minutes 
every 12 hours. Anti-emetics should be given according to NIH BMT Consortium guidelines 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
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32 
http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml). Daily dose = 400 mg/m2 for 4 
consecutive days for a total dose = 1600 mg/m2. 
Days -5, -4, -3, and -2: Etoposide (VP-16). 
Intravenous hydration should be continued before, during and after the etoposide.  Etoposide 200 
mg/m2 calculated on adjusted ideal body weight is to be administered daily on Days -5, -4, -3, 
and -2 for a total of 4 doses. Etoposide injection must be diluted prior to use with either 5% 
Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP to give a final concentration of 
0.2 to 0.4 mg/mL and administered over 2 to 4 hours. A longer duration of administration may be 
used if the volume of fluid to be infused is a concern.  
Appropriate antiemetics should be given according to Consortium guidelines 
(http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml). Two hours before infusion, 25 mg 
of diphenhydramine HCl and 50 mg of hydrocortisone will be given to prevent allergic reactions. 
If necessary, diuretics may be given.   
Day -1: Melphalan. 
Melphalan 140 mg/m2 calculated according to adjusted ideal body weight will be administered 
Day -1. The drug will be diluted in 0.9% NS at a concentration of 0.4 mg/mL and administered 
at a rate of 5 mg/min will be infused over 30 min. 
Hydration during the conditioning regimen (BEAM): 
a) 
Hydration will be initiated 12 hours prior to BCNU infusion (on Day –7 of the 
transplant), consisting of 0.9% sodium chloride supplemented with 10 mEq/L potassium chloride 
(KCl) at an initial rate of 100 mL/hour. For patients with poor oral intake, the rate of hydration 
may be increased as clinically indicated to meet fluid requirements. Hydration will continue until 
24 hours after the last chemotherapy dose has been completed. 
b) 
During hydration, serum potassium level will be monitored every 12 hours and adjusted 
accordingly. 
c) 
During hydration, if urine output is < 1.5 mL/kg/hour or if fluid intake exceeds urine 
output by greater than 500 mL during an 8-hour period, an additional furosemide 20 mg will be 
administered. 
3.2.10 Day 0: Peripheral Blood Stem Cell Infusion 
Hematopoietic progenitor cells obtained from DTM will be thawed and infused according to 
NIH standard operating guidelines on Day 0 (7 days after initiation of high-dose chemotherapy, 
i.e., BEAM). They are rapidly brought to physiologic temperature in a 37oC water bath. They are 
then infused at a rate of 100 mL/hr. Patients should be pre-medicated with diphenhydramine 50 
mg PO or IV and acetaminophen 500 mg PO 30 minutes prior to the infusion. Toxicities that can 
be associated with the reinfusion of autologous progenitor cells include “garlic”-like taste and 
odor due to dimethylsulfoxide (DMSO), nausea and vomiting, hypotension, fever and 
hemoglobinuria. 
3.2.11 Day +5: filgrastim (G-CSF) 
All patients will receive G-CSF 5 µg/kg/day subcutaneously beginning on Day +5 after PBSC 
are infused and continued daily until ANC > 1000/µL for 3 consecutive days. 


Abbreviated Title:
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33 
3.3 
DOSE MODIFICATION FOR TOXICITIES 
3.3.1 Phase I management of 
90Y-daclizumab for non-hematological toxicity 
 
 
 
Grade 
Occurrence 
Immediate Action 
Resumption of Therapy 
1 
Any 
None 
No interruption 
2 
Any 
Hold therapy until grade ≤ 1 
1) Continue BEAM chemotherapy and 
ASCT if toxicity occurred after the 
second dose of 
90Y-daclizumab was 
administered. 
 
2) Resume 
90Y-daclizumab if toxicity 
occurred after the first dose of 
90Y-
daclizumab was administered. 
3 or 4 
Any 
Discontinue 
90Y-daclizumab 
and hold BEAM 
chemotherapy/ASCT until 
grade ≤ 1 
1) May proceed with BEAM 
chemotherapy and ASCT if toxicity 
occurred after the second dose of 90Y-
daclizumab was administered. 
 
2) Do not proceed with second dose of 
90Y-daclizumab if toxicity occurred 
after the first dose of 90Y-daclizumab 
was administered but may proceed 
with BEAM chemotherapy and ASCT 
once recovered to ≤ grade 1 


Abbreviated Title:
  90Y-daclizumab + ASCT in HL 
Version Date:  02/05/2018 
34 
3.3.2 Phase II Dose Modification 
90Y-daclizumab for non-hematological toxicity 
Table 2. Dose modification 
90Y-daclizumab dose for non-hematological toxicity. 
 
Grade Occurrence Immediate Action 
Resumption of Therapy 
1 
Any 
None 
No interruption 
2 
Any 
Hold therapy until grade ≤ 1 
1) Continue BEAM chemotherapy and 
ASCT if toxicity occurred after the 
second dose of 
90Y-daclizumab was 
administered. 
 
2) Resume 
90Y-daclizumab if toxicity 
occurred after the first dose of 
90Y-
daclizumab was administered. 
3 
Any 
Discontinue 
90Y-daclizumab and 
hold BEAM chemotherapy/ 
ASCT until grade ≤ 1 
1) May proceed with BEAM 
chemotherapy and ASCT if toxicity 
occurred after the second dose of 
90Y-
daclizumab was administered. 
 
2) Do not proceed with second dose of 
90Y-daclizumab if toxicity occurred after 
the first dose of 
90Y-daclizumab was 
administered. May proceed with BEAM 
chemotherapy and ASCT once 
recovered to ≤ grade 1 
4 
Any 
Discontinue 
90Y-daclizumab 
therapy and hold BEAM 
chemotherapy/ ASCT until 
grade ≤ 1 
1) May continue with BEAM 
chemotherapy and ASCT once 
recovered to ≤ grade 1 


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35 
3.3.3 Phase I and Phase II Dose Modification 
90Y-daclizumab for hematological toxicity: 
Table 3. Dose modification 
90Y-daclizumab for hematological toxicity. 
3.3.4 Additional Dose Modifications of 
90Y-daclizumab: 
If grade 3 or greater allergic toxicity occurs, the patient is to discontinue 
90Y-daclizumab, but 
may proceed with BEAM chemotherapy and ASCT. 
3.4 
STOPPING RULES FOR UNACCEPTABLE TOXICITY 
3.4.1 Unacceptable toxicity from this treatment will be defined as two or more events of the 
following occurring in the first 20 patients during the phase II part of the study: 
o Failure to achieve neutrophil engraftment by day 21, defined from day 0 (the day 
when autologous stem cells are infused) as the first of three consecutive days on 
which the patient’s absolute neutrophil count is greater than 0.5 x 109/L following 
the nadir. 
o Failure to achieve platelet engraftment by day 28, defined from day 0 (the day 
when autologous stem cells are infused) as the first of seven consecutive days on 
which the patient’s unsupported platelet count is greater than 20 x 109/L following 
the nadir. 
o Development of MDS in over 3 of the first 13 patients in phase II of the study. 
3.4.2 Unacceptably high transplant related mortality (TRM) will be defined as: 
o TRM in 2 or more of the first 20 patients during the first one hundred days 
following transplant;  
o TRM during the first one hundred days following transplant is greater than 15%, 
at any point beyond the first 20 patients 
Grade 
Occurrence 
Immediate Action 
Resumption of Therapy 
1 
Any 
None 
No interruption 
2 
1st Cycle  
 
 
 
2nd Cycle 
None  
 
 
 
None 
Continue 90Y-daclizumab at protocol 
specified dose for the second dose of 90Y-
daclizumab and may proceed with BEAM 
chemotherapy/ ASCT as per protocol 
 
Proceed with BEAM chemotherapy/ ASCT 
as per protocol 
3 
1st Cycle 
 
 
2nd Cycle 
Hold therapy until grade ≤ 1 
 
 
None 
Then resume 2nd dose of 90Y –daclizumab 
at protocol specified dose.  
 
Proceed with BEAM chemotherapy/ ASCT 
as per protocol. 
4 
1st Cycle 
 
 
 
2nd Cycle 
Hold therapy until grade ≤ 1 
 
 
 
None 
Then resume 90Y-daclizumab with 5 mCi 
decrease in the second dose of 90Y-
daclizumab.  
 
Proceed with BEAM chemotherapy/ ASCT 


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3.5 
MONITORING DURING THERAPY  
3.5.1 Weekly evaluation starting 1 week prior to administration of 90Y-daclizumab and 
continuing until administration of either second dose of 90Y-daclizumab, or 
administration of BEAM preparative regimen to include: 
• History, physical examination, vital signs, and performance status 
• CBC with differential, platelet count, reticulocyte count 
• Coagulation studies: PT, PTT, fibrinogen 
• Acute Care, Mineral and Hepatic panels, LDH, uric acid, total protein, CK and zinc.  
3.5.2 Evaluation starting with administration of BEAM preparative regimen and continuing 
until ANC > 1000/µL for 3 consecutive days following infusion of autologous stem cells: 
• Once daily: History, physical examination, vital signs and performance status 
• Twice daily: CBC with differential and platelet count 
• Twice daily: Acute Care, Mineral and Hepatic panels, LDH, uric acid, total protein 
and CK 
3.5.3 When ANC > 1000/µL for 3 days: At a minimum of every week for 4 weeks, then at a 
minimum of every 2 weeks x 2.  
• History, physical examination, vital signs and performance status 
• CBC with differential and platelet count  
• Acute Care, Mineral and Hepatic panels, LDH, uric acid, total protein, CK and zinc 
• Weekly CMV antigenemia, if CMV serology positive at baseline 
3.5.4 Serum soluble IL-2R alpha days -56 and -15 and every 4 weeks after -15 till day 100 
3.5.5 Collection of blood for radioimmunotherapy (i.e., 90Y-daclizumab): 
3.5.5.1 7 mL of blood in a green-top tube and 4 mL of blood in an SST tube will be drawn 
prior to administration of 90Y-daclizumab.  Similar volumes will be drawn at 
midpoint of infusions if deemed necessary by principal investigator.   
3.5.5.2 Furthermore 8 mL of blood will be divided into a green-top tube and a tiger-top tube 
at the following time points after the infusion of 90Ydaclizumab:  
• ½ hour,  
• 1 hour, 
• 2 hours,  
• 6 hours,  
• 12 hours,  
• 24 hours and  
• daily up to 7 days following infusion of 90Y-daclizumab. 
3.5.6 Collection of blood to asses for antibodies to daclizumab: 
3.5.6.1 Human antibody to daclizumab (HAHA) must be assessed prior to the first and 
second infusion of 90Y-daclizumab and must be deemed negative for infusion and 
day -15.   
3.5.6.2 Between days -35 and -21, Collect two 4 ml or one 8 mL SST and send sample to 
Dr. William Kopp/Ms. Helen Rager at NCI/OD, Clinical Support Laboratory 560/11-


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37 
27, Building 1050, Boyles Street, Frederick, Maryland 21702, telephone number: 
301-846-1707 or 301-846-1917.   
3.5.7 To evaluate effect of 90Y-daclizuamb administered on day -56, perform CT scan of 
C/A/P/neck and FDG- PET (torso) scan at the following time points:  
• baseline and  
• post therapy at day 100 ± 7 days post-transplant  
3.5.8 SPECT/CT scans will be performed using SPECT/CT on days -56 and -15 to assess RIT 
organ distribution, uptake and clearance.  
3.5.9 Response evaluations will be performed on the patients at day 100 ± 7 days following 
infusion of autologous stem cells: 
• History, physical examination, vitals and performance status 
• CBC with differential, platelet count and reticulocyte count 
• Acute Care, Mineral and Hepatic panels, LDH, uric acid, total protein and CK  
• Serum soluble IL-2R alpha  
• Urinalysis 
• Tumor Assessment with CT of chest/abdomen/pelvis (C/A/P) and 18FDG-PET-scan 
• Bone marrow biopsy to assess for abnormal cytogenetics 
• Pulmonary function tests 
• EKG 
• Echocardiogram or MUGA 
3.6 
FOLLOW-UP AFTER THE COMPLETION OF THERAPY  
After Day 100, patients will be followed at 4, 6, 9, 12, 16, 20, 24 (± 14 days) months after the 
end of treatment. During the 3rd, 4th and 5th year, patients will be followed every 6 months (± 
28 days) and yearly thereafter for regular physical and laboratory examinations. : 
3.6.1.1 History, physical examination, vital signs and performance status 
3.6.1.2 CBC with differential  
3.6.1.3 Acute Care, Mineral and Hepatic panels, LDH, uric acid, total protein and CK  
3.6.1.4 Serum soluble IL-2R alpha  
3.6.1.5 Urinalysis 
3.6.1.6 Tumor assessment with CT chest/abdomen/pelvis/neck and FDG-PET will be 
performed at the follow-up visits that occur 6, 12, 16 and 24 months after the end of 
treatment, then as clinically indicated  
3.6.1.7 Pulmonary function tests should be repeated at the follow-up visit that occurs 12 
months after the end of treatment 
 
 
 


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38 
3.7 
STUDY CALENDAR  
Except for chemotherapy and stem cell reinfusion, all time points can be obtained within ±5 days (unless otherwise indicated) of 
scheduled measurement to allow for holidays, travel and other events.  
Table 4 Study Calendar 
Procedure 
Scree
ning 
Eligib
ility 
Baseline 
Week -12,  
 
Week 
-9 
D -561 
Week -6 
D-
15 
D 
-6 
to 
D-
1 
Day 
03 
D +5 
until  
ANC> 10004 
Day 100 
± 7 days 
Post 
Therapy5 
Follow up 
D-84 
to -
80 
D -
79 (-
78) 
Days 
-42 to 
-38 
Day  
-37 
(-36) 
Study Drug Administration/Procedures 
G-CSF.  
 
 
X 
X 
 
 
X 
X 
 
 
 
 
 
 
Plerixafor, Apheresis 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
Administration of unlabeled, 90Y and 
111In daclizumab2 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Ca2+DTPA 
 
 
 
 
 
Xa 
 
 
Xa 
 
 
 
 
 
BEAM  
 
 
 
 
 
 
 
 
 
Xb 
 
 
 
 
ASCT 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Clinical Assessments 
History and PEd 
X  
 
 
 
 
X 
Xf 
 
 
 
 
 
X 
Xf 
Vitals 
X  
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Performance Status 
X  
 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
EKG 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Echocardiogram or MUGA 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pulmonary Function Tests 
X  
 
 
 
 
 
 
 
 
 
 
 
X 
 
Laboratory Assessments 
CBC with differential 
X  
X 
 
 
Xe 
 
 
 
 
 
 
 
X 
Xe 
Reticulocyte Count 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
X 
 
PT, PTT, Fibrinogen  
 
X 
 
 
Xe 
 
 
 
 
 
 
 
X 
 
Acute Care, Mineral and Hepatic 
panels 
Xc  
X 
 
 
Xe 
 
Xe 
 
 
 
 
 
X 
Xe 
LDH, uric acid, total protein, CK 
 
X 
 
 
Xe 
 
Xe 
 
 
 
 
 
X 
Xe 
Total cholesterol and triglycerides 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Zinc 
 
X 
 
 
 
Xg 
 
 
Xg 
 
 
 
 
 
Quantitative Immunoglobulins 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HBV & HCV serologies 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ELISA 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV Serology, Antigenemiah 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 


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Procedure 
Scree
ning 
Eligib
ility 
Baseline 
Week -12,  
 
Week 
-9 
D -561 
Week -6 
D-
15 
D 
-6 
to 
D-
1 
Day 
03 
D +5 
until  
ANC> 10004 
Day 100 
± 7 days 
Post 
Therapy5 
Follow up 
D-84 
to -
80 
D -
79 (-
78) 
Days 
-42 to 
-38 
Day  
-37 
(-36) 
Green Top Tube for RITi 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Serum Soluble IL2R j, l 
X 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
Ab to daclizumab k, l 
X  
 
 
 
 
X 
 
 
X 
 
 
 
 
 
UAm 
 
X 
 
 
 
Xm 
 
 
Xm 
 
 
 
X 
X 
Serum β-HCG 
X  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Biopsyn 
Xn 
 
 
 
 
 
 
 
 
 
 
 
Xn 
 
Lymph Node Biopsyo 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
Radiologic Proceduresp,q 
CT scan C/A/P and neck 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
FDG-PET Scan 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
X 
SPECT/CT 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
Response Assessments 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Concomitant Medications 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
Footnotes: 
1 - D-56: Week 1, Day 1. 
2 - RIT: radioimmunotherapy (i.e., 
90Y-daclizumab.) 
3- Day -4: 4 days prior to infusion of stem cells; day 0 is the day of infusion of stem cells. 
4- ANC must be > 1000/µl on 3 consecutive days. 
5- Post Therapy: After Day 100± 7 days, patients will be followed at 4, 6, 9, 12, 16, 20, 24 (± 14 days) months after the end of treatment. During the 3rd, 4th and 
5th year, patients will be followed every 6 months (± 28 days) and yearly thereafter for regular physical and laboratory examinations.  
a. CaDTPA is to be administered for three consecutive days starting on the day of radiolabeled antibody infusion. 
b. The components of BEAM will be administered as follows:  carmustine on day -6; etoposide and cytarabine on days -5 to -2;melphalan on day -1. 
c. Creatinine clearance to be performed if serum creatinine ≥2.0 mg/dL.  
d. History, physical exam, vital signs and performance status assessed weekly from day -63+/-3days until second dose of daclizumab or administration of BEAM 
regimen.   Daily following BEAM until ANC >1000/µl. 
e. To be assessed weekly from week -9 to day -6; assessed BID day -6 through ANC recovery and as indicated in post-therapy follow- up. 
f. To be assessed daily from day -6 through ANC recovery and as indicated post-therapy follow up. 
g.  Serum zinc levels: For three days following infusion of CaDTPA.h. If CMV serology positive, CMV antigenemia will be obtained weekly until Day 100; then 
as clinically indicated. 


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i.  Green-top tube for RIT: For analysis in nuclear medicine, 7 mL of blood in a green-top tube and 4 mL of blood in an SST tube will be drawn prior to 
administration of 
90Y-daclizumab.  Similar volumes will be drawn at the midpoint of the infusion and at the completion of the infusion if deemed necessary by the 
PI.  Furthermore, 8 mL of blood will be divided into a green-top tube and a tiger-top tube at ½ hour, 1 hr, 2 hr, 6 hr, 12 hr, 1 day, and daily up to 7 days 
following infusion of 
90Y-daclizumab.   
j. Serum soluble IL-2R alpha to be tested on days -56 and -15, and then every 4 weeks till day 100 and at every follow-up visit. Collect two 4 ml SST and send 
sample to Dr. William Kopp/Ms. Helen Rager at NCI/OD, Clinical Support Laboratory. 
k. Antibodies to daclizumab: Human anti-human antibody (HAHA) responses must be assessed prior to the first and second infusion of 
90Y-daclizumab and must 
be deemed negative for infusion on day -15; draw between days -35 to -21. Collect two 4 ml or one 8 ml SST and send sample to Dr. William Kopp/Ms. Helen 
Rager at NCI/OD, Clinical Support Laboratory. 
l. When Serum soluble IL-2R alpha and Antibodies to daclizumab samples are drawn at same time, they may be drawn in the same tube. 
m. UA: Collected into separate bottles labeled with date and time for radioactivity counting in the Nuclear Medicine Department, Clinical Center, at 0-2 hr, 2-24 
hr, 24-48 hr, 48-72 hr, and 72-96 hr. 
n. Bone- marrow biopsy and aspirate with cytogenetics: Unilateral aspirate and biopsy will be performed pretreatment to rule out abnormal cytogenetics and 
post-treatment at day 100. 
o. Lymph node biopsy: Lymph node biopsy will be performed pre-treatment to establish CD25 positivity if necessary.   
p. SPECT/CT: Scans will be performed using SPECT-CT to assess RIT organ distribution, uptake, and clearance. 
q. Tumor assessment with CT chest/abdomen/pelvis/neck and FDG-PET will be performed at the follow-up visits that occur 6, 12, 16 and 24 months after the end 
of treatment. 
 
 


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3.8 
CONCURRENT THERAPIES 
With the exception of drugs that would exclude the patient from the protocol (e.g., other 
investigational antineoplastic drugs, or chemotherapy), patients can take other medications as 
indicated. All medications, their dose and frequency, as well as the start and stop dates are to be 
recorded. 
3.9 
SURGICAL GUIDELINES 
3.9.1 Bone-Marrow Aspirate and Biopsy. 
Bone-marrow examination is required prior to study enrollment to assess for the presence of HL 
and its extent CD25 expression, myelodysplastic changes or cytogenetic abnormalities. A second 
bone-marrow biopsy will be performed at day 100 ± 7 days following the infusion of autologous 
stem cells. In addition, bone-marrow aspirate and biopsy will be performed yearly for 5 years.  
Any other bone-marrow aspirate and biopsy will be obtained as clinically indicated during the 
course of the patient’s treatment.  
3.9.2 Lymph Node and Tumor Biopsies: 
A lymph node or tumor biopsy will be obtained for diagnostic purposes and to determine the 
expression of CD25 antigen.  A separate consent will be obtained for this procedure. 
3.10 
RADIATION THERAPY GUIDELINES: 
No external radiation therapy is planned as part of this protocol.   
3.11 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF-STUDY CRITERIA:  
3.11.1 Patients will be removed from protocol therapy for any of the following: 
• Progression of disease 
• Unacceptable toxicity as defined in Section 3.4 
• If chelated daclizumab becomes unavailable 
• If judged by the Principal Investigator to be in the best interest of the patient 
• See 3.1.4 Dose-Limiting Toxicity 
• Patient requests to be withdrawn from active therapy 
• Patients that have evidence of rapidly progressive symptomatic disease requiring urgent 
salvage treatment after their stem cell mobilization and harvest will have their stem cells stored 
and receive the appropriate therapy to achieve disease control. These patients may be 
reconsented and allowed to re-enter the protocol treatment without having to undergo another 
stem cell mobilization/harvest.   
3.11.2 Off Study Criteria 
• Patient noncompliance or refusal to continue with the study 
• Patient withdraws consent to continue participation in study 
• Inadequate harvest of stem cells- less than 2 x 106 CD34+ stem cells/kg obtained after 2 
attempts 3 weeks apart to mobilize stem cells  
• Unrelated medical illness or complications that unacceptably increase the risks of participation 
in this trial 
• Death 


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3.11.3 Off Protocol Therapy and Off-Study Procedure 
Authorized staff must notify Central Registration Office (CRO) when a subject is taken off 
protocol therapy and when a subject is taken off-study. A Participant Status Updates Form from 
the website (http://home.ccr.cancer.gov/intra/eligibility/welcome.htm) main page must be 
completed and sent via encrypted email to:  NCI Central Registration Office at  
ncicentralregistration-l@mail.nih.gov. 
4 
SUPPORTIVE CARE 
4.1 
BLOOD COMPONENT SUPPORT 
Platelets and red blood cell (RBC) support will be given as medically indicated with the general 
guideline to maintain a hemoglobin > 8.0 g/dl and to maintain the platelet count at a level of at 
least 10,000/µl (unless there is evidence of significant bleeding in which case a platelet count of 
50,000/µl will be maintained). Final decision of the necessity of transfusion will remain in the 
hands of the treating team.  All administered blood products will be irradiated and depleted of 
leukocytes. 
4.2 
G-CSF (FILGRASTIM) SUPPORT 
G-CSF, in the commercially available form, will be administered subcutaneously at a dose of 5 
µg/kg daily to patients whose neutrophil count falls below 500/µl following treatment with 
90Y-
daclizumab and continued until the neutrophil count exceeds 5,000/µL. G-CSF may be continued 
until the neutrophil count exceeds 1,000/µL for 3 consecutive days after ASCT. Patients will be 
instructed regarding the self-administration of G-CSF if being discharged from the hospital. G-
CSF will be obtained from the Clinical Center Pharmacy. 
4.3 
ANTIBIOTIC THERAPY 
Antibiotic therapy for neutropenic patients will be managed in accordance with NIH BMT 
Consortium guidelines.   http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml)  
4.4 
ANTIEMETICS 
Adequate antiemetics should be given as outlined in the NIH BMT Consortium guidelines.   
http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml) 
4.5 
MANAGEMENT OF MUCOSITIS 
All patients with severe mucositis should receive adequate hydration and pain control using 
continuous intravenous narcotics or patient controlled analgesia (PCA). Additional nutritional 
support should be considered in the event of prolonged inability to acquire adequate nutrition by 
the oral route. Mouth care consistent with established NCI guidelines should be instituted in all 
patients 24 hours prior to high-dose chemotherapy.  The suggested regimen is described below: 
Sodium bicarbonate mouth rinse: (1 teaspoonful powder per 500 mL) 15 mL swish for 30-60 
seconds and spit, daily at 8 am, noon, 4 pm, 8 pm, and midnight.  The solution is to be prepared on 
the unit every other day. Patients may rinse their mouths at night if they awaken. Patients should 
rinse their mouth after the bicarbonate rinse with water to avoid inactivating chlorhexidine. 
Biotene mouthwash: 15 mL swishes for 30-60 second swish and spit q 2 hrs while awake.  This 
medication, when used as directed, binds to mucosal tissues to provide a prolonged effect.  Do not 
leave at the bedside to be used as a “prn" medication. 


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Sucralfate suspension: Use only AFTER establishment of mucositis. Sucralfate suspension 
MUST be used last as it will block the effect of the other medications above.  15-30 mL are 
swished in mouth for 15-30 seconds and then remainder swallowed three times a day. Additional 
doses may be given; up to six total doses in a 24 hr. period. 
4.6 
MUCOSITIS PROPHYLAXIS 
Keratinocyte Growth Factor (Palifermin/Kepivance) will be used at the dose of 60 g/kg iv push 
as follows: 
4.6.1 daily for three days starting day -9 pre-ASCT (i.e., days -9, -8 and -7) 
4.6.2 then for three additional daily doses on days +1, +2 and +3 of ASCT 
4.6.3 Palifermin should not be used during or within 24 hours preceding or following myelotoxic 
therapy administration 
4.7 
PCP PROPHYLAXIS 
All patients will receive prophylaxis against Pneumocystis jiroveci (carinii) pneumonia, beginning 
with the first dose of 
90Y-daclizumab, continuing until the preparative regimen is to be 
administered prior to transplantation (Day -6), and resuming at the time of platelet recovery (> 
50,000) following the infusion of autologous stem cells. All patients will receive empiric treatment 
with one trimethoprim/sulfamethoxazole (TMP/SMX) DS tablet twice daily, three times per week 
unless they are allergic to this medication. If the patient is allergic to trimethoprim or 
sulfamethoxazole, alternatives include dapsone (100 mg daily), atovaquone (750 mg twice daily) 
or inhaled pentamidine through day 100 and/or until CD4 count is confirmed to be > 200/mL. 
4.8 
FUNGAL PROPHYLAXIS 
All patients will receive fluconazole (100 mg) prophylaxis against Candida infections, beginning 
with the first dose of 90Y-daclizumab, continuing until the preparative regimen is to be 
administered prior to transplantation (Day -6), and then resuming after transplantation for a 
minimum of 3 months unless clinical contraindication develops. 
4.9 
HERPES SIMPLEX AND VZV PROPHYLAXIS 
All patients will receive acyclovir or valacyclovir for prophylaxis against herpes simplex virus and 
varicella zoster virus infection/reactivation. This therapy will start with the first dose of 
90Y-
daclizumab, and continue through transplantation, for a minimum of 3 months unless clinical 
contraindication develops. 
4.10 
CMV PROPHYLAXIS 
Patients with positive pre-transplant serology for cytomegalovirus (CMV) will be monitored for 
CMV reactivation by weekly testing for CMV PCR CMV reactivation will be managed according 
to NIH BMT Consortium guidelines.   http://intranet.cc.nih.gov/bmt/clinicalcare/guidelines.shtml)   
5 
BIOSPECIMEN COLLECTION 
5.1 
SAMPLE STORAGE, TRACKING AND DISPOSITION 
Samples will be ordered in CRIS and tracked through a Clinical Trial Data Management system.  
Should a CRIS screen not be available, the CRIS downtime procedures will be followed.  Samples 


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will not be sent outside NIH without IRB notification and an executed MTA.  
The Clinical Support Laboratory, Leidos Biomedical Research, Inc -Frederick, processes and 
cryopreserves samples in support of IRB-approved, NCI clinical trials. The laboratory is located in 
a controlled access building and laboratory doors are kept locked at all times. Upon specimen 
receipt each sample is assigned a unique, sequential laboratory accession ID number. All products 
generated by the laboratory that will be stored either in the laboratory freezers or at a central 
repository facility are identified by this accession ID. An electronic database is used to store 
information related to patient samples processed by the laboratory. Vial labels do not contain any 
personal identifier information. Samples are stored inventoried in locked laboratory freezers and 
are routinely transferred to the NCI-Frederick repository facilities for long-term storage. These 
facilities are operated under subcontract to Leidos Biomedical Research, Inc.-Frederick. Access to 
stored clinical samples is restricted. Investigators establish sample collections under “Source 
Codes” and the investigator responsible for the collections, typically the protocol Principal 
Investigator, specifies who has access to the collection. 
When requests are submitted by the NCI investigator for shipment of samples outside of the NIH it 
is the policy of the laboratory to request documentation that a Material Transfer Agreement is in 
place that covers the specimen transfer. The laboratory does not provide patient identifier 
information as part of the transfer process but may, at the discretion of the NCI investigator, group 
samples from individual patients when that is critical to the testing process. The NCI investigator 
responsible for the sample collection is responsible for ensuring appropriate IRB approvals are in 
place and that a Material Transfer Agreement has been executed prior to requesting the laboratory 
to ship samples outside of the NIH.  
Blood and tissue specimens collected in the course of this research project may be banked and 
used in the future to investigate new scientific questions related to this study. However, this 
research may only be done if the risks of the new questions were covered in the consent document 
and the proposed research has undergone prospective IRB review and approval. If new risks are 
associated with the research (e.g. analysis of germ line genetic mutations...) the principal 
investigator must amend the protocol and obtain informed consent from all research subjects. 
Once primary research objectives for the protocol are achieved, intramural researchers can request 
access to remaining samples providing they have an IRB approved protocol and patient consent.  
Any loss or unintentional destruction of samples or data will be reported to the NCI IRB.  
The P.I. will report any loss or destruction of samples to the IRB. 
Serum samples for IL-2R alpha and for detection of antibodies to daclizumab will be sent to Dr. 
William Kopp/Ms. Helen Rager at NCI/OD, Clinical Support Laboratory 560/11-27, Building 
1050, Boyles Street, Frederick, MD 21702, TEL: +1-301-846-1707 or +1-301-846-1917. The 
primary contact for courier scheduling is Ms. Jennifer Bangh, telephone number +1-301-846-5893 
or at E-mail address banghj@mail.nih.gov.   
6 
DATA COLLECTION AND EVALUATION 
6.1 
DATA COLLECTION 
The PI will be responsible for overseeing entry of data into an in-house password protected 
electronic system (C3D) and ensuring data accuracy, consistency and timeliness. The principal 
investigator, associate investigators/research nurses and/or a contracted data manager will assist 


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with the data management efforts. All human subjects personally identifiable information (PII) as 
defined in accordance to the Health Insurance Portability and Accountability Act, eligibility and 
consent verification will be recorded. Primary data obtained during the conduct of the protocol will 
be kept in secure network drives or in approved alternative sites that comply with NIH security 
standards. Primary and final analyzed data will have identifiers so that research data can be 
attributed to an individual human subject participant. 
All adverse events, including clinically significant abnormal findings on laboratory evaluations, 
regardless of severity, will be followed until return to baseline or stabilization of event. Patients 
will be followed for adverse events for at least 30 days after removal from study treatment or until 
off-study, whichever comes first.  
An abnormal laboratory value will be recorded in the database as an AE only if the laboratory 
abnormality is characterized by any of the following: 
• 
Results in discontinuation from the study 
• 
Is associated with clinical signs or symptoms  
• 
Requires treatment or any other therapeutic intervention 
• 
Is associated with death or another serious adverse event, including hospitalization.  
• 
Is judged by the Investigator to be of significant clinical impact 
• 
If any abnormal laboratory result is considered clinically significant, the investigator will 
provide details about the action taken with respect to the test drug and about the patient’s 
outcome. 
End of study procedures: Data will be stored according to HHS and FDA regulations as 
applicable.  
Loss or destruction of data: Should we become aware that a major breach in our plan to protect 
subject confidentiality and trial data has occurred, the IRB will be notified.  
6.1.1 Recording of Grade 3 and 4 BEAM Related Toxicity 
Toxicity such as profound pancytopenia is expected to occur in every instance the BEAM 
preparative regimen is administered and this toxicity is well accepted as part of the standard of 
care during ASCT. 
• Grade 3 and 4 toxicity that will not be reported:  
• Toxicity occurring within 24 hours of the stem cell infusion deemed attributable to the 
infusion. 
• Hematologic toxicity, unless it constitutes a dose limiting toxicity as defined in Section 
3.1.4:   
o Failure to achieve neutrophil engraftment by day 21 post ASCT 
o Failure to achieve platelet engraftment by day 28 post ASCT  
• Grade 3 and 4 toxicity which is a direct consequence of an expected toxicity of the BEAM 
preparative regimen: 
o Pancytopenia (e.g. fever, infections),  
o Nausea, vomiting, diarrhea (e.g. dehydration or electrolytes imbalance) 
o Mucositis (pain requiring narcotics and / or parenteral nutrition). 
o Transient altered mental status at the time of BCNU administration 


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o Signs and symptoms consistent with Cytarabine (Ara-C) Syndrome as described in 
Section 10.9.3.3. 
• The decision of relatedness to expected toxicity during ASCT will be made PI or delegate 
based on their clinical judgment and expertise in the field of transplantation. As examples, the 
following events would not be reported as they represent complications of a well- known and 
expected toxicity during ASCT:  
o Systemic infection with septic shock during the initial period of pancytopenia  
o Acute respiratory distress syndrome (possibly requiring mechanical ventilation) and 
renal failure (possibly requiring hemodialysis) secondary to septic shock during the 
initial period of neutropenia. Nausea, vomiting, diarrhea and mucositis of any grade as 
well as electrolyte and secondary other biochemical abnormalities. 
• Grade 3 or 4 toxicity that will be reported 
• Grade 3 or 4 infections with septic shock occurring several weeks after initial marrow 
engraftment will be reported. 
• Any grade 3 or 4 acute liver toxicity (although possibly related to the preparative regimen) 
will be reported. 
• Any grade 3 or 4 toxicity occurring after recovery from and not the consequence of the 
initial preparative regimen toxicity. 
6.1.2 
90Y-daclizumab Related Toxicity That Will Not Be Reported: 
• Grade 3 and 4 hematologic toxicity including thrombocytopenia, lymphocytopenia, 
neutropenia and anemia is expected in the 4 to 7-week period following Y90-daclizumab 
therapy and will not be reported.   
6.2 
RESPONSE ASSESSMENTS 
Response assessments will be performed at day -15 and 100 days (± 7 days) post-ASCT and 
subsequent post ASCT follow up visits. Response assessment will be based on the definitions 
recently published by Cheson BD et al, in the Revised Response Criteria for Malignant Lymphoma 
[40]. Cervical, thoracic, abdominal, and pelvic CT-scans are recommended if those nodal areas are 
involved. A bone-marrow aspirate and biopsy should only be performed to confirm CR if initially 
positive or if clinically indicated by new abnormalities in the peripheral blood count or blood 
smear. 18FDG-PET will also be used for assessment of response. 
6.2.1 Complete Response 
The designation of a complete response (CR) requires all of the following: (1) Complete 
disappearance of all detectable clinical evidence of disease and disease-related symptoms if 
present before therapy; (2) A post-treatment residual mass is permitted as long as it is PET 
negative. If a pretreatment PET scan was negative, all lymph nodes and nodal masses must have 
regressed on CT to normal size (< 1.5 cm in their greatest transverse diameter for nodes > 1.5 cm 
before therapy); (3) Previously involved nodes that were 1.1 to 1.5 cm in their long axis and more 
than 1.0 cm in their short axis before treatment must have decreased to < 1.0 cm in their short axis 
after treatment; (4) The spleen and/or liver if considered enlarged before therapy based on a 
physical examination or CT scan, should not be palpable on physical examination and should be 
considered normal size by imaging studies, and (5) If the bone marrow was involved by lymphoma 
before treatment the infiltrate must have cleared on repeat bone-marrow biopsy. 
6.2.2 Partial Response 


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The designation of a partial response (PR) requires all of the following: (1) At least a 50% 
reduction in the sum of the product of the diameters of up to six of the largest dominant nodes or 
nodal masses. These nodes or masses should be selected according to all of the following: they 
should be clearly measurable in at least two perpendicular dimensions; if possible they should be 
from disparate regions of the body; and they should include mediastinal and retroperitoneal areas 
of disease whenever these sites are involved; (2) No increase in the size of other nodes, liver, or 
spleen; (3) Splenic and hepatic nodules must regress by >50% in their SPD or for single nodules in 
the greatest transverse diameter; (4) With the exception of splenic and hepatic nodules, 
involvement of other organs is usually assessable and no measurable disease should be present.  
Bone-marrow assessment is irrelevant for determination of a PR if the sample was positive before 
treatment. Patients who achieve a CR by the above criteria but who have persistent morphologic 
bone-marrow involvement will be considered partial responders; (5) No new sites of disease; (6) If 
the pretreatment PET scan was positive, the post-treatment PET should be positive in at least one 
previously involved site; and (7) If a pretreatment PET was negative, CT criteria should be used. 
6.2.3 Stable Disease 
A patient is considered to have stable disease (SD) when he or she fails to attain the criteria needed 
for a CR or PR, but does not fulfill those for progressive disease.  The PET should be positive at 
prior sites of disease with no new areas of involvement on the post-treatment CT or PET.  If the 
pretreatment PET was negative, there must be no change in the size of the previous lesions on the 
post-treatment CT scan. 
6.2.4 Progressive Disease 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm regardless of the 
short axis.  If a lymph node has a long axis of 1.1 to 1.5 cm, it should only be considered abnormal 
if its short axis is more than 1.0 cm.  Lymph nodes < 1.0 X < 1.0 cm will not be considered as 
abnormal for relapse or progressive disease. Other criteria for progressive disease include the 
following: (1) Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a previously 
unaffected site should only be considered relapsed or progressive disease after confirmation with 
other modalities. (2) At least a 50% increase from nadir in the sum of the products of the diameters 
of any previously involved nodes, or in a single involved node, or the size of other lesions A 
lymph node with a diameter of the short axis of less than 1.0 cm must increase by >50% and to a 
size of 1.5 X 1.5 cm or more than 1.5 cm in the long axis. (3) At least a 50% increase in the 
longest diameter of any single previously identified node more than 1 cm in its short axis; (4) 
Lesions should be PET positive if the lesion was PET positive before therapy unless the lesion is 
too small to be detected by PET; (5) Measurable extranodal disease should be assessed in a manner 
similar to that for nodal disease.  For these recommendations, the spleen is considered nodal 
disease. Disease that is only assessable will be recorded as present or absent only, unless, while an 
abnormality is still noted by imaging studies or physical exam, it is found to be histologically 
negative. 
6.2.5 Progression Free Survival 
PFS is defined as the time from the date of registration to the date of first observation of 
progressive disease or death due to any cause.  If none of these occur the patient will be censored 
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6.2.6 Overall Survival 
This is defined as the time from the date of registration to the date of death due to any cause or if 
no death occurs to the last documented information on the patient. 
6.3 
TOXICITY CRITERIA 
Toxicity will be assessed according to the NCI Common Toxicity Criteria for Adverse Event 
version 4.0. A copy of CTC version 4.0 can be downloaded from 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_40. 
7 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING 
PLAN 
7.1 
ADVERSE EVENT DEFINITIONS 
7.1.1 Adverse Event 
An adverse event is defined as any untoward medical occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom or disease, 
temporarily associated with the subject’s participation in the research, whether or not considered 
related to the subject’s participation in the research.   
7.1.2 Suspected Adverse Reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
7.1.3 Unexpected Adverse Reaction 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in the 
investigator brochure or is not listed at the specificity or severity that has been observed; or, if an 
investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application. "Unexpected”, 
also refers to adverse events or suspected adverse reactions that are mentioned in the investigator 
brochure as occurring with a class of drugs or as anticipated from the pharmacological properties 
of the drug, but are not specifically mentioned as occurring with the particular drug under 
investigation. 
7.1.4 Serious  
An Unanticipated Problem or Protocol Deviation is serious if it meets the definition of a Serious 
Adverse Event or if it compromises the safety, welfare or rights of subjects or others. 
7.1.5 Serious Adverse Event 
An adverse event or suspected adverse reaction is considered serious if in the view of the 
investigator or the sponsor, it results in any of the following: 
• Death, 
• A life-threatening adverse drug experience 
• Inpatient hospitalization or prolongation of existing hospitalization 


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• A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• A congenital anomaly/birth defect. 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
7.1.6 Disability 
A substantial disruption of a person’s ability to conduct normal life functions. 
7.1.7 Life-threatening adverse drug experience 
Any adverse event or suspected adverse reaction that places the patient or subject, in the view of 
the investigator or sponsor, at immediate risk of death from the reaction as it occurred, i.e., it does 
not include a reaction that had it occurred in a more severe form, might have caused death. 
7.1.8 Protocol Deviation (NIH definition) 
Any change, divergence, or departure from the IRB-approved research protocol.  
7.1.9  Non-compliance (NIH Definition) 
The failure to comply with applicable NIH Human Research Protections Program (HRPP) policies, 
IRB requirements, or regulatory requirements for the protection of human research subjects. 
7.1.10 Unanticipated Problem 
Any incident, experience, or outcome that: 
• Is unexpected in terms of nature, severity, or frequency in relation to  
(a) the research risks that are described in the IRB-approved research protocol and informed 
consent document; Investigator’s Brochure or other study documents, and 
(b) the characteristics of the subject population being studied; AND 
• Is related or possibly related to participation in the research; AND 
• Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
7.2 
NCI-IRB AND CLINICAL DIRECTOR REPORTING 
7.2.1 NCI-IRB Expedited Reporting of Unanticipated Problems and Deaths 
The Protocol PI will report in the NIH Problem Form to the NCI-IRB and NCI Clinical Director: 
• All deaths, except deaths due to progressive disease  
• All Protocol Deviations 
• All Unanticipated Problems 
• All non-compliance 
Reports must be received within 7 days of PI awareness via iRIS. 
7.2.2 NCI-IRB Requirements for PI Reporting at Continuing Review 


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The protocol PI will report to the NCI-IRB:  
1. A summary of all protocol deviations in a tabular format to include the date the deviation 
occurred, a brief description of the deviation and any corrective action. 
2. A summary of any instances of non-compliance 
3. A tabular summary of the following adverse events: 
• All Grade 2 unexpected events that are possibly, probably or definitely related to the 
research;  
• All Grade 3 and 4 events that are possibly, probably or definitely related to the research 
except as excluded in Section 6.1.2 
• All Grade 5 events regardless of attribution;  
• All Serious Events regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  
7.2.3 NCI-IRB Reporting of IND Safety Reports 
Only IND Safety Reports that meet the definition of an unanticipated problem will need to be 
reported to the NCI IRB. 
7.3 
IND SPONSOR REPORTING CRITERIA  
During the first 30 days after the subject receives investigational agent/intervention, the  
investigator must immediately report to the sponsor, using the mandatory MedWatch form 3500a, 
any serious adverse event, whether or not considered drug related, including those listed in the 
protocol or investigator brochure and must include an assessment of whether there is a reasonable 
possibility that the drug caused the event. For serious adverse events that occur more than 30 days 
after the last administration of investigational agent/intervention, only report those that have an 
attribution of at least possibly related to the agent/intervention. 
Required timing for reporting per the above guideline: 
• Deaths (except death due to progressive disease) must be reported via email within 24 
hours.  A complete report must be submitted within one business day.  
• Other serious adverse events as well as deaths due to progressive disease must be 
reported within one business day 
Events will be submitted to the Center for Cancer Research (CCR) at: CCRsafety@mail.nih.gov 
and to the CCR PI and study coordinator. 
7.4 
DATA AND SAFETY MONITORING PLAN 
7.4.1 Principal Investigator/Research Team 
The clinical research team will meet on a weekly basis when patients are being actively treated on 
the trial to discuss each patient. Decisions about dose level enrollment and dose escalation if 
applicable will be made based on the toxicity data from prior patients.  
All data will be collected in a timely manner and reviewed by the principal investigator or a lead 
associate investigator. Adverse events will be reported as required above. Any safety concerns, 
new information that might affect either the ethical and or scientific conduct of the trial, or 
protocol deviations will be immediately reported to the IRB using iRIS. 
The principal investigator will review adverse event and response data on each patient to ensure 


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safety and data accuracy. The principal investigator will personally conduct or supervise the 
investigation and provide appropriate delegation of responsibilities to other members of the 
research staff.  
As information is gathered from this trial, clinical results will be shared with the patients.   
7.4.2 Sponsor Monitoring Plan 
As a sponsor for clinical trials, FDA regulations require the CCR to maintain a monitoring 
program. The CCR’s program allows for confirmation of: study data, specifically data that could 
affect the interpretation of primary study endpoints; adherence to the protocol, regulations, and 
SOPs; and human subjects protection. This is done through independent verification of study data 
with source documentation focusing on: 
• Informed consent process 
• Eligibility confirmation 
• Drug administration and accountability 
• Adverse events monitoring 
• Response assessment. 
The monitoring program also extends to multi-site research when the CCR is the coordinating 
center. 
This trial will be monitored by personnel employed by a CCR contractor. Monitors are qualified 
by training and experience to monitor the progress of clinical trials. Personnel monitoring this 
study will not be affiliated in any way with the trial conduct. 
8 
STATISTICAL CONSIDERATIONS    
The primary objectives of this study are to determine the maximum tolerated dose of 90Y-
daclizumab in combination with BEAM chemotherapy and autologous transplant in patients with 
refractory/relapsed Hodgkin’s lymphoma, and to determine the safety of this combination in a 
moderately large group of patients.   Safety will primarily be evaluated in terms of determining if 
the combination of treatments at the MTD is associated with a sufficiently high fraction of patients 
who are able to avoid MDS.  Obtaining an acceptably low rate of engraftment failure as well as of 
Transplant Related Mortality at day 100 are also of great importance.  Evaluation of clinical 
outcomes, such as overall response rate, complete response rate, DFS and OS are also of interest as 
secondary endpoints.   
The study will initially have a Phase I dose escalation portion that uses a standard 3 + 3 design. 
Thus, with a maximum of 7 dose levels of 90Y-daclizumab to be explored, the maximum number 
of patients to be evaluated in the Phase I portion of the trial is 42.  Once the MTD has been 
determined, the trial will plan to enroll subsequent patients using an optimal two-stage phase II 
trial design, which will be focused on estimating the ability to avoid MDS development and 
cytogenetic abnormalities.  Currently, the fraction of patients with MDS on other studies is 
approximately 10%.  It would be desirable if the rate of developing MDS on this trial were 
approximately the same or not much worse than 10%.  Since it can take years for MDS to 
materialize, development of MDS (which may include the development of isolated cytogenetic 
abnormality associated with it, based on the expert judgment of the NCI Laboratory of Pathology 
pathologists) must be considered a negative outcome and all events pertaining to a putative 
diagnosis of MDS will be considered in determining whether the trial may continue past the first 


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stage of accrual.  The study will be conducted in order to rule out an unacceptably low 75% 
proportion avoiding MDS (p0=0.75) in favor of a higher MDS avoidance rate of 90% (p1=0.90).  
With alpha=0.05 (probability of accepting a poor treatment=0.05) and beta=0.20 (probability of 
rejecting a good treatment=0.20), the first stage of the phase II trial will initially enroll 13 
evaluable patients and if 0 to 10 of the 13 avoid MDS then no further patients will be accrued.  If 
11 or more of the first 13 avoid both issues initially, then accrual would continue until a total of 48 
patients have been enrolled.  As it may take several weeks to determine if a patient has a 
cytogenetic abnormality that would be a precursor to MDS, and much longer for actual MDS to 
develop, a temporary pause of 3 months time for the 13 patients in the accrual to the trial may be 
necessary to ensure that enrollment to the second stage is warranted.  If there are 11-40 of the 48 
patients who avoid MDS this would be an unacceptably low rate of avoiding MDS while if there 
were 41 or more of 48 patients who do not have either problem, then this would be sufficiently 
interesting to warrant further study.  Under the null hypothesis (75% avoidance of MDS rate), the 
probability of early termination is 67%. 
In addition, the rate of engraftment will be evaluated, and an early stopping rule on the basis of this 
endpoint will also be incorporated in the trial.  The first 20 patients in the phase II portion of the 
trial will be evaluated with respect to the number which fails to engraft.  If there are 2 or more 
patients who fail to engraft in the initial 20 patients, the probability of this occurring would be 
12.0% if the true rate of engraftment failure were 3% and it would be 82.4% if the true rate of 
engraftment failure were 15%.  Thus, if there are 2 or more patients who fail to engraft in the first 
20 patients, this is more likely to be consistent with an unacceptably high rate of engraftment 
failure such as 15% than a potentially reasonable rate of engraftment failure, and the trial would 
stop under these circumstances.  If engraftment failure does not stop accrual prior to 20 patients, 
future patients will continue to be monitored for engraftment failure, and if at any point beyond the 
first 20 patients, greater than 10% are cumulatively noted to fail to engraft, the study will no longer 
accrue further patients unless a revision to the design is approved. 
The one-hundred day Transplant Related Mortality (TRM) will be evaluated as well in an early 
stopping rule.  The first 20 patients in the phase II portion of the trial will be evaluated with respect 
to TRM.  If there are 2 or more patients who die during the first one hundred days following 
transplant in the initial 20 patients, the probability of this occurring would be 12.0% if the true rate 
of TRM were 3% and it would be 82.4% if the true rate of TRM were 15%.  Thus, if there are 2 or 
more patients who die during the first one hundred days following transplant in the first 20 
patients, this is more likely to be consistent with an unacceptably high TRM such as 15% than a 
potentially reasonable TRM, and the trial would stop under these circumstances.  If TRM does not 
stop accrual prior to 20 patients, future patients will continue to be monitored for TRM, and if at 
any point beyond the first 20 patients, TRM is greater than 15%, the study will no longer accrue 
further patients unless a revision to the design is approved.   
Clinical outcomes such as overall response rate, complete response rate, DFS and OS will also be 
evaluated and reported as secondary outcomes.  Because the study may enroll a heterogeneous 
population with respect to risk categories, following completion of the trials, patients will be 
evaluated on the basis of their underlying risk category as well as overall, and results will be 
reported accordingly.  Since the historical comparison for response rates is not clearly determined 
for this population, there will not be any formal two-stage stopping rule on the basis of clinical 
response. 
In order to complete the initial single arm phase I portion of this trial, up to 42 evaluable patients 


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may be required and up to 48 in the phase II portion based on safety.  Up to 6 patients who are 
enrolled at the MTD may be included in the first stage of the phase II portion of the trial if they are 
fully eligible for this portion of the trial.  Thus, up to 84-90 patients may be required.  It is 
anticipated that up to 1-2 patients per month may be enrolled onto this trial, and thus 
approximately 4-6 years may be required to enroll up to 90 evaluable patients.  To allow for the 
possibility of a small number of inevaluable patients, the accrual ceiling for the trial will be set at 
95. 
9 
HUMAN SUBJECTS PROTECTIONS 
9.1 
RATIONALE FOR SUBJECT SELECTION 
CD25 is expressed on the malignant cells of patients with Hodgkin’s lymphoma and the non-
malignant infiltrating lymphocytes found in Hodgkin’s tumors. Antibodies to CD25 can be used to 
target radioimmunotherapy to the sites of tumor and have demonstrated antitumor activity in 
animal models and in patients with cancer. In a Phase II trial, we treated 30 patients with CD25-
expressing recurrent or refractory HL with single agent 90Y-labeled daclizumab.  Twelve of these 
patients achieved a complete response and 7 a partial response for an overall response rate of 
63.3%; however, despite this high response rate in a group of refractory and heavily pretreated HL 
patients including ones that had failed to respond or relapsed after autologous and allogeneic stem 
cell transplants, the median response duration was a disappointing 129 days (range, 28 to 720 
days). 
The current standard of care for patients with relapsed or refractory Hodgkin lymphoma is, 
however, autologous stem cell transplant.  Although between 30% and 65% of patients will 
achieve long-term disease free survival with high-dose chemotherapy followed by ASCT, a 
significant proportion of these patients will develop recurrent disease after transplantation.  We 
are, therefore, attempting to improve long-term disease free survival by using the combination of 
radioimmunotherapy and ASCT.  Patients with refractory and relapsed HL except nodular 
lymphocyte predominant HL that have at least 10% of the cells from the lymph node or extranodal 
site reactive with anti-CD25 will be eligible in the study.  Patients will be recruited from those 
referred to the NCI. 
9.2 
RESEARCH ETHICS 
The investigational nature and objectives of this trial, the procedures and treatments involved and 
their attendant risks and discomforts, potential benefits, and potential alternative therapies will be 
carefully explained to the patient and a signed informed consent document will be obtained. No 
imbalance of ethnic, racial or sex ratios are expected in the accrual to this trial other than that 
which may naturally be observed in patients diagnosed with Hodgkin’s lymphoma. 
9.3 
PARTICIPATION OF CHILDREN 
Children will not be permitted to participate in this study due to the increased risk from radiation 
exposure in children and until the safety and efficacy of this treatment has been demonstrated in 
adults. 


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9.4 
PARTICIPATION OF SUBJECTS UNABLE TO GIVE CONSENT 
Adults unable to give consent are excluded from enrolling in the protocol. However, re-consent 
may be necessary as well as ongoing follow-up after the completion of treatment, and there is a 
possibility, though unlikely, that subjects could become decisionally impaired. For this reason and 
because there is a prospect of direct benefit from research participation, including long-term 
follow-up for disease status and outcomes (Section 9.6), all subjects will be offered the opportunity 
to fill in their wishes for research and care, and assign a substitute decision maker on the “NIH 
Advance Directive for Health Care and Medical Research Participation” form so that another 
person can make decisions about their medical care in the event that they become incapacitated or 
cognitively impaired during the course of the study. Note: The PI or AI will contact the NIH 
Ability to Consent Assessment Team for evaluation.  For those subjects that become incapacitated 
and do not have pre-determined substitute decision maker, the procedures described in MAS 
Policy 87-4 for appointing a surrogate decision maker for adult subjects who are (a) decisionally 
impaired, and (b) who do not have a legal guardian or durable power of attorney, will be followed. 
9.5 
EVALUATION OF BENEFITS AND RISKS/DISCOMFORTS 
The potential benefits to the subject are that the patient may undergo a partial or complete 
remission. Radioimmunoconjugates directed against CD25 have antitumor activity against CD25 
positive malignancies in animal models, and specifically, remissions have been observed in 
patients with Hodgkin’s lymphoma. Patients entered on the study will need to be hospitalized in 
order to receive both the antibody treatment and the autologous stem cells.  They will remain in the 
hospital until they recover their blood counts. They will have to undergo bone-marrow biopsy after 
therapy to determine to assure engraftment of the infused autologous stem cells. 
Patients treated with 90Y-labeled daclizumab may experience side effects associated with infusions 
of monoclonal antibodies, but the major side effect of treatment is bone-marrow suppression, 
especially thrombocytopenia and neutropenia. There is the possibility of life-long transfusion 
dependence, life-threatening infections when the blood counts are low, the development of 
myelodysplasia, secondary leukemias, and even death due to treatment. We hope to minimize the 
possibility of life-long transfusion dependence by reinfusing the patient’s autologous stem cells 
following treatment with the 90Y-labeled daclizumab and high-dose chemotherapy with BCNU, 
etoposide, cytarabine and melphalan. We hope to minimize hospitalizations associated with life-
threatening infections and low blood counts by using granulocyte-colony stimulating growth factor 
(G-CSF, filgrastim) to raise the white blood cell count. 
The amount of whole body radiation received in this study is 200 rad, with the most exposed 
organs, the liver, red bone marrow and bone surfaces receiving 1600 rad, 1000 rad and 710 rad 
respectively. The amount of radiation received in this study exceeds the dose guideline established 
by the NIH Radiation Safety Committee for research subjects (this radiation is therapeutic so it is 
deemed reasonable). The guideline is an effective dose of 5 rad (or 5,000 mrad) received per year. 
9.6 
RISKS/BENEFIT ANALYSIS  
Patients entered on this study will have relapsed after standard chemotherapy or have disease that 
is refractory to standard chemotherapy. Although autologous stem cell transplant would be the 
next step in many of these patients, only 30-65% of patients will achieve long-term disease free 
survival with this therapy. The combination of an autologous stem cell transplant and 
radioimmunotherapy has the potential to increase the number of patients achieving long-term 


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disease free survival.  No cognitively impaired patients requiring durable power of attorney will be 
included in the study. 
9.7 
CONSENT AND ASSENT PROCESSES AND DOCUMENTS  
Informed consent will be obtained in all patients on this trial.  There will be no minors enrolled < 
18 years of age; therefore, assent is unnecessary.  The attached informed consent contains all 
elements required for consent.  In addition, the Principal Investigator and/or associate investigators 
will discuss the protocol in detail with the patient and will be available to answer all patient 
questions to allow the patient to give informed consent. 
9.7.1 Telephone reconsent 
Reconsent on this study may be obtained via telephone according to the following procedure: the 
informed consent document will be sent to the subject.  An explanation of the study will be 
provided over the telephone after the subject has had the opportunity to read the consent form.  
The subject will sign and date the informed consent document. A witness to the subject’s signature 
will sign and date the consent.   
The original informed consent document will be sent back to the consenting investigator who will 
sign and date the consent form with the date the consent was obtained via telephone.   
A fully executed copy will be returned via mail for the subject’s records.   
The informed consent process will be documented on a progress note by the consenting 
investigator.  
9.7.2 Informed consent of non-English speaking subjects 
If there is an unexpected enrollment of a research participant for whom there is no translated extant 
IRB approved consent document, the principal investigator and/or those authorized to obtain 
informed consent will use the Short Form Oral Consent Process as described in MAS Policy M77-
2, OHSRP SOP 12, 45 CFR 46.117 (b) (2) and 21 CFR 50.27 (b) (2).  The summary that will be 
used is the English version of the extant IRB approved consent document.  Signed copies of both 
the English version of the consent and the translated short form will be given to the subject or their 
legally authorized representative and the signed original will be filed in the medical record. 
Unless the PI is fluent in the prospective subject’s language, an interpreter will be present to 
facilitate the conversation. Preferably someone who is independent of the subject (i.e., not a family 
member) will assist in presenting information and obtaining consent. Whenever possible, 
interpreters will be provided copies of the relevant consent documents well before the consent 
conversation with the subject (24 to 48 hours if possible).  
We request prospective IRB approval of the use of the short form process and will notify the IRB 
at the time of continuing review of the frequency of the use of the Short Form. 
10 PHARMACEUTICAL INFORMATION 
10.1 
Daclizumab 
10.1.1 Source 
Unlabeled daclizumab will be provided from the existing supply held by the NIH Clinical Center 
Pharmacy.   


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10.1.2 Toxicity 
Toxicities that may follow the administration of monoclonal antibodies include all of the well-
recognized allergic reactions to foreign protein: fever, urticaria, bronchospasm, anaphylaxis, 
Arthus reaction, vasculitis, and serum sickness. The most frequently reported adverse events of 
daclizumab administration were gastrointestinal disorders, which were reported at 67% frequency.  
Placebo treated patients experienced GI toxicity at 68%.   
Please see package insert for complete toxicity information. 
10.1.3 Formulation and Preparation: 
Daclizumab is supplied as a clear, sterile, colorless concentrate (25 mg/5mL) for further dilution 
and intravenous administration. Each mL of Zenapax contains 5 mg of daclizumab and 3.6 mg 
sodium phosphate monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg 
sodium chloride, 0.2 mg polysorbate 80 and may contain hydrochloric acid or sodium hydroxide to 
adjust the pH to 6.9.  No preservatives are added. 
10.1.4 Stability and Storage: 
Daclizumab storage and stability, based on a 1 mg/kg dose, diluted in 50 mL of 0.9% Sodium 
Chloride Injection, USP.  See package insert for more information.   
• Storage: 
Store the intact vials in the refrigerator (2°C – 8°C) (36°F - 46°F). Protect from light and freezing.  
If the infusion solution is not administered immediately, it should be stored in the refrigerator. 
• Stability: 
Daclizumab does not contain preservatives. Prepared solutions of daclizumab should be 
administered within 4 hours. If not administered immediately following preparation, the infusion 
solution should be refrigerated (2°C – 8°C) (36°F - 46°F) and administered within 24 hours of 
preparation.  After 24 hours, the solution should not be administered.  The prepared solution 
should be inspected for particulate matter and clarity before administration to the patient, and 
should be discarded if particulate matter is present.  
10.1.5 Administration Procedures: 
Simultaneous with each dose of radiolabeled 90Y-daclizumab administered in the phase I and 
phase II studies, patients will receive a fixed dose of 5 mg of unlabeled daclizumab (Zenapax™, 
humanized anti-CD25, anti-IL-2R alpha, anti-Tac).  The quantity of unlabeled daclizumab 
administered is based on studies of ATL patients with circulating malignant cells and elevated 
soluble CD25 levels.  The rationale for administering an unlabeled antibody directed to CD25 
(e.g., daclizumab) is that there is an increase in the serum concentration of the released IL-2R 
alpha (Tac peptide, CD25) in patients with IL-2R alpha expressing malignancies such as HL.  The 
administered unlabeled daclizumab binds to this circulating IL-2R alpha and increases the 
proportion of the radiolabeled 90Y-daclizumab that binds to the CD25 expressing target cell [42].  
In those patients it is estimated to yield binding of radiolabeled daclizumab to all circulating 
CD25-expressing tumor cells and to produce approximately 25 to 75% saturation of the IL-2 
receptors in patients with soluble CD25 levels of 2,000 to 10,000 units/mL. These estimates are 
made on the basis of the observations during the Phase I trial of 
90Y-murine anti-CD25 (anti-Tac) 
antibody, where binding was assessed by FACS analysis and by binding to the circulating cells of  


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111In-murine anti-CD25 antibody co-administered with 
90Y-murine anti-CD25 antibody. The 
soluble CD25 levels of the majority of patients on this study are expected to be in the above range.   
10.1.6 Incompatibilities: 
Please refer to daclizumab package insert for drug interactions. 
10.2 
BASILIXIMAB 
Basiliximab (trade name Simulect) is a chimeric mouse-human monoclonal antibody to the alpha 
chain (CD25) of the IL-2 receptor of T cells.  It is a Novartis Pharmaceuticals product that was 
approved by the Food and Drug Administration (FDA) in 1998.  It is a chimeric CD25 directed 
antibody of the IgG1 isotope.  It acts as an antagonist at the interleukin-2 (IL-2) binding site of the 
p55 subunit (Tac antigen) of the high-affinity IL-2 receptor (CD25) on the surface of activated T 
lymphocytes and of ATL cells.   
10.2.1 Source 
Basiliximab will be obtained from the commercial supply by the Clinical Center Pharmacy. 
10.2.2 Mechanism of Action: 
Basiliximab functions as an IL-2 receptor antagonistic by binding with high-affinity (Kalpha = 1 x 
1010m-1) to the alpha chain of the high-affinity IL-2 receptor complex thereby inhibiting IL-2 
binding.  Basiliximab is specifically targeted against IL-2R alpha which is both selectively 
expressed on the surface of activated T lymphocytes and ATL cells but also circulates as the 
soluble released sIL-2R alpha peptide.  Basiliximab blocks the binding of 90Y-CHX-A” 
daclizumab to the circulating IL-2R alpha peptide. 
10.2.3 Toxicity 
The incidence of adverse events for basiliximab was determined in four randomized double-blind 
placebo controlled clinical trials for the prevention of renal allograft rejection.  Basiliximab did not 
appear to add to the background of adverse events seen in organ transplantation patients as a 
consequence of their underlying disease and in concurrent administration of immunosuppressants 
and other medications.  Adverse events were reported by 96% of the patients in the placebo-treated 
group and 96% in the basiliximab-treated groups.  The pattern of adverse events with the 
recommended dose of basiliximab was similar to that of patients receiving a placebo.  Basiliximab 
did not increase the incidence of serious adverse events observed compared to the placebo.  
Reported adverse events were gastrointestinal disorders reported by 69% of basiliximab-treated 
patients and 67% of placebo-treated patients.  Basiliximab like daclizumab has the toxicities that 
may follow the administration of monoclonal antibodies including all the well-known recognized 
allergic reactions to foreign protein:  fever, urticaria, bronchospasm, anaphylactic reactions, 
vasculitis, and serum sickness.   
Please see package insert for complete toxicity information. 
Basiliximab should not be administered to patients with a known allergy to basiliximab.   
10.2.4 Formulation and Preparation: 
Basiliximab (Simulect) is a sterile lyophilisate which is available in 6 mL colorless glass vials and 
it is available in 10 mg and 20 mg strengths (use the 10 mg strength).  Each 10 mg vial contains 10 
mg basiliximab, 3.61 mg monobasic potassium phosphate, 0.5 mg disodium hydrogen phosphate 


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(anhydrous), 0.8 mg sodium chloride, 10 mg sucrose, 40 mg mannitol, and 20 mg glycine to be 
reconstituted in 2.5 mL of Sterile Water for Injection (USP).  No preservatives are added. 
10.2.5 Stability and Storage: 
• Storage:  
Store the basiliximab in a refrigerator at between 36 and 46 degrees F. (2 and 8C.) protected from 
light and moisture.  Do not freeze. 
• Stability:  
Basiliximab does not contain preservatives.  Prepared solutions of basiliximab should be 
administered within 4 hours.  If not administered immediately following preparation the solution 
should be refrigerated (2C - 8C) (36F - 46F) and administered within 24 hours of preparation.  
After 24 hours the solution should not be administered.  The prepared solution should be inspected 
for particulate matter and clarity before administration to the patient and should be discarded if 
particulate matter is present.   
10.2.6 Administration Procedures: 
To prepare the reconstituted solution add 2.5 mL of Sterile Water for Injection, USP using aseptic 
techniques to the vial containing the basiliximab (Simulect) powder, shake the vial gently to 
dissolve the powder. 
The reconstituted solution is isotonic and may be given either as a bolus injection or diluted in a 
volume of 25 mL with normal saline or dextrose 5% for infusion.  When mixing this solution, 
gently invert the bag in order to avoid foaming, do not shake.   
10.2.7 Incompatibilities: 
None are listed.  Please refer to the basiliximab (Simulect) package insert for drug interactions. 
10.3 
CHX-A DACLIZUMAB 
90Y-daclizumab (humanized anti-CD25, humanized anti-Tac, Zenapax®) monoclonal antibody is a 
radioimmunoconjugate linking daclizumab, a humanized IgG1 monoclonal antibody directed 
against the IL-2 binding site of the human IL-2R alpha subunit (CD25), to the radioisotope, 
yttrium-90. 
111In-Daclizumab (humanized anti-CD25, humanized anti-Tac, Zenapax®) monoclonal antibody) 
111In-daclizumab is a radioimmunoconjugate linking daclizumab, a humanized IgG1 monoclonal 
antibody directed against the IL-2 binding site of the human IL-2R alpha subunit (CD25), to the 
radioisotope, indium-111. 
10.3.1 Preparation 
Daclizumab was obtained from Roche Pharmaceuticals (Nutley, NJ). Daclizumab (Zenapax®) 25 
mg/5mL is supplied as a clear, sterile, colorless concentrate for further dilution and intravenous 
administration. Each mL of Zenapax contains 5 mg of daclizumab and 3.6 mg sodium phosphate 
monobasic monohydrate, 11 mg sodium phosphate dibasic heptahydrate, 4.6 mg sodium chloride, 
0.2 mg polysorbate 80 and may contain hydrochloric acid or sodium hydroxide to adjust the pH to 
6.9.  No preservatives are added. 
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amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine N, N, N’, N”,  
N”-pentaacetic acid) as well as Drug Substance and Drug Product testing. CHX-A”DTPA, was 
manufactured under controlled conditions, tested for purity, and vialed and stored by Dr. Thomas 
A. Waldmann, Bldg 10, Room 4N115, 10 Center Drive, 9000 Rockville Pike, Bethesda, MD 
20892. The chelate modification of daclizumab was performed using good manufacturing practices 
by Goodwin Biotechnology Incorporated (Plantation, FL).  
Figure 6. Structural formula of CHX-A’’ chelating agent (N-[(R)-2-amino-3-(p-isothiocyanato-
phenyl)propyl]-trans-(S, S)-cyclohexane-1,2-diamine N, N, N’, N”,  N”-pentaacetic acid). 
10.3.2 Toxicity 
Toxicities that may follow the administration of monoclonal antibodies include all of the well-
recognized allergic reactions to foreign protein: fever, urticaria, bronchospasm, anaphylaxis, 
Arthus reaction, vasculitis, and serum sickness. The major expected toxicity from the 
radioisotopes, is bone-marrow suppression, although the potential exists for additional toxicities 
including renal, lung, or hepatic dysfunction.  
Yttrium in its elemental form is considered mildly toxic with its primary effects on the liver 
(elevated serum transaminases) and it can cause a mild perturbation of calcium homeostasis. We 
are able to report on our own experience giving 90Y-labeled daclizumab to 30 patients with 
relapsed or refractory Hodgkin’s lymphoma enrolled on a Phase II trial (Janik et al, manuscript 
submitted). Patients on this study actually received multiple doses of the drug (up to 7) every 6-10 
weeks. The median aggregate radiation dose administered was 40 mCi. No infusion reactions were 
observed. Thrombocytopenia and granulocytopenia were the predominant toxicities occurring at 
weeks 4-5 after the 90Y-labeled daclizumab infusion with the nadirs usually occurring during 
weeks 5-7 after treatment. Seven patients experienced cytopenias that persisted for more than 10 
weeks although no blood component support was required and all patients recovered hematologic 
values to baseline. Three patients developed myelodysplastic syndrome at 5, 9.5, and 35 months 
after the first dose of 90Y-labeled daclizumab, respectively. 
Pure indium in metal form is considered non-toxic. At the doses used in the present study there are 
no reports of toxicity from Indium-111. 
10.3.3 Storage of CHX-A” daclizumab chelate 
The CHX-A”-daclizumab chelate is stored at -70°C in 0.15 M NaCl, 10 mM KPO4, 1 mM EGTA, 
pH 7.2. The material is stable in this form. Over several months, no detectable decrease in binding 
to CD25-positive cells has been noted. The chelator currently used is CHX-A” DTPA (N-[(R)-2-
Amino-3-(p-isothiocyanato-phenyl)propyl]-trans-(S,S)-cyclohexane-1,2-diamine N, N, N’, N”, 
N”-pentaacetic acid.  Prior to storage, the material is filtered through a MILLEX-GV 0.22 µm 
filter that is "pre-wet" with human serum albumin. Each chelate preparation will be assayed for 


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ability to bind to CD25-expressing HUT102 and for sterility, pyrogenicity and general safety. 
10.4 
CALCIUM DIETHYLENETRIAMINEPENTAACETATE (CA-DTPA). 
 
Figure 7. Structural formula of calcium-DTPA (sodium calcium diethylenetriaminepentaacetic 
acid). 
10.4.1 Formulation and Preparation 
Ca-DTPA (diethylenetriaminepenta-acetic acid) with an empirical formula C14H23N3O10 
belongs to the group of synthetic polyamino-polycarboxylic acids that form stable complexes 
(metal chelates) with a large number of metal ions [45, 46]. When releasing a metal such as 
calcium it binds to another metal of greater affinity and carries it to the kidney where it is excreted 
in the urine. The plasma half-life of DTPA is 20–60 minutes. Almost the entire administered dose 
is excreted in 12 hours with only a small amount bound to plasma proteins.  This bound form has a 
half-life of > 20 hours. DTPA undergoes only a minimal amount of metabolic change in the body. 
Only a very minor release of acetate groups has been demonstrated and splitting of ethylene 
groups has not been detected. Following intravenous administration Ca-DTPA is rapidly 
distributed throughout the extracellular fluid space. No significant amount of DTPA penetrates 
into erythrocytes or other tissues. No accumulation of DTPA in specific organs has been observed. 
There is little or no binding of the chelate by the renal parenchyma and it is promptly cleared from 
the body by glomerular filtration. Ca-DTPA can deplete the body of zinc and to a lesser extent, 
manganese with repeated dosing. 
Ca-DTPA is commercially available as an FDA-approved agent for the treatment of radiation 
exposure emergencies. It is available through Hameln Pharmaceuticals through Akorn, Inc. 
(Buffalo Grove, IL). It is available as single use ampoules containing 5 mL of solution containing 
Ca DTPA at a concentration of 200 mg/mL. 
10.4.2 Toxicity 
When given with repeated doses at short intervals, Ca-DTPA treatment may cause nausea, 
vomiting, diarrhea, chills, fever, pruritus, and muscle cramps in the first 24 hours. Anosmia (loss 
of sense of smell) was observed in one individual after 123 grams of Ca-DTPA over 27 months of 
therapy, possibly related to zinc depletion. After 100 days of no further Ca-DTPA administration 
the patient's sense of smell began to return.  At higher doses Ca-DTPA has caused renal tubular 
damage and, in two cases, death. 
Studies in animals indicate that the toxicity of Ca-DTPA depends on total dose and the dose 
schedule [45,46]. When administered to animals in high doses (>2000 mmol/kg- the clinical dose 
range is 10–30 mmol/kg), it can produce lesions of the kidney, intestinal mucosa, and liver and can 
even be lethal [44-47]. When fractionated doses are used, toxicity may result from depletion of Zn 


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and Mn ions needed in enzymatic steps leading to DNA synthesis that renews epithelial cells in the 
intestinal epithelium.  Zn concentrations will be determined prior to therapy and 24 and 48 hours 
following Ca-DTPA treatment. Normal serum Zn levels are 70–130 mcg/L.  The infusions of Ca-
DTPA will be terminated and oral Zn sulfate 220 mg/day will be administered if the concentration 
of Zn falls below 35 mcg/L and I.V. zinc sulfate 220 mg diluted with 0.9N saline if the serum Zn 
level falls below 25 mcg/L. 
10.5 
FILGRASTIM (NEUPOGEN® G-CSF) 
NEUPOGEN® (filgrastim, G-CSF) is a human granulocyte colony-stimulating factor (G-CSF) 
produced by recombinant DNA technology. NEUPOGEN® is indicated to decrease the incidence 
of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies 
receiving myelosuppressive anti-cancer drugs associated with a significant incidence of severe 
neutropenia with fever. NEUPOGEN® will be obtained from the commercial supply in the Clinical 
Center Pharmacy. 
10.5.1 Formulation, Storage, and Stability 
Recombinant granulocyte-colony stimulating factor (G-CSF) manufactured by Amgen (Thousand 
Oaks, CA) is supplied as a clear sterile solution of 300 mcg/mL packaged into either 1-mL (300 
mcg) or 1.6-mL (480 mcg) vials.  NEUPOGEN® should be stored in the refrigerator at 2° to 8°C 
(36° to 46°F). Avoid shaking. Prior to injection, NEUPOGEN® may be allowed to reach room 
temperature for a maximum of 24 hours. Any vial or prefilled syringe left at room temperature for 
greater than 24 hours should be discarded. Do not freeze. G-CSF is stable for at least 1 year when 
refrigerated. 
10.5.2 Administration 
G-CSF 10-16 µg/kg will be administered for five to six consecutive days as a subcutaneous 
injection to mobilize peripheral blood stem cells for collection by apheresis. See Section 12.5 
Appendix E for sliding scale G-CSF dosing algorithm.  
Patients may be instructed on the self-administration of G-CSF. 
10.5.3 Toxicity  
Bone pain, which can sometimes be severe. Other adverse reactions include fatigue, muscle 
cramps, back/leg pain, splenomegaly and thinning hair. 
10.6 
PLERIXAFOR (MOZOBIL®) 
Plerixafor is a CXCR4 chemokine receptor antagonist that blocks the binding of stromal cell-
derived factor 1α (SDF-1α). It inhibits the retention of hematopoietic stem cells in bone marrow, 
and increases their number in peripheral blood. It is used, with granulocyte colony-stimulating 
factor (G-CSF), to mobilize stem cells for collection and subsequent autologous transplantation 
Mozobil® will be obtained from the commercial supply in the Clinical Center Pharmacy. 
10.6.1 Formulation, Storage, and Stability 
Subcutaneous Solution: 20 mg/mL 
Inspect vial for particulate matter and discoloration prior to administration; do not use if particulate 
matter present or solution is discolored. (Prod Info MOZOBIL(R) subcutaneous injection, 2008). 
Store at controlled room temperature, 25 degrees C (77 degrees F), with excursions permitted 


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between 15 and 30 degrees C (59 and 86 degrees F)  
10.6.2 Administration 
Plerixafor 240µg/kg will be administered for one to two consecutive days as a subcutaneous 
injection to mobilize peripheral blood stem cells for collection by apheresis. See Section 12.5 
Appendix E for dosing algorithm.  
Plerixafor will be administered on the 5th day of filgrastim administration, 6 to 8 hours before the 
apheresis. In case stem cell collection is insufficient with one apheresis, an additional dose of 
Plerixafor may be administered the next day at the same dose, 6 to 8 hours before the apheresis 
procedures. 
10.6.3  Pharmacokinetics 
Peak plasma concentrations of plerixafor occur about 30 to 60 minutes after a subcutaneous dose. 
It is about 58% bound to plasma proteins and largely confined to the extravascular fluid space. 
About 70% of a dose is eliminated in the urine within 24 hours after a dose, and the terminal half-
life is about 3 to 5 hours.  
Plerixafor is not metabolized using human liver microsomes or human primary hepatocytes. 
Additionally, plerixafor does not exhibit inhibitory activity towards the major drug metabolizing 
cytochrome P450 enzymes nor did it induce CYP1A2, CYP2B6, or CYP3A4 enzymes.  
10.6.4 Adverse effects  
Common adverse effects include diarrhea, nausea, vomiting, flatulence, fatigue, arthralgia, 
headache and dizziness, mild injection site reactions.  
Less commonly, insomnia or systemic reactions occurring about 30 minutes after injection 
(urticaria, periorbital swelling, dyspnea, and hypoxia).  
Some cases of vasovagal reactions, orthostatic hypotension, and syncope, within 1 hour of 
injection, have also been reported.  
10.7 
BCNU (BICNU®, CARMUSTINE) 
BiCNU® (carmustine for injection) is a nitrosourea that alkylates DNA and RNA. It is not cross-
resistant with other alkylators. It may also inhibit several key enzymatic processes by 
carbamoylation of amino acids in proteins. 
 
Figure 8. Structural formula of carmustine. 
10.7.1 Formulation and Preparation 
It is lyophilized pale yellow flakes or congealed mass with a molecular weight of 214.06. It is 
highly soluble in alcohol and lipids, and poorly soluble in water. First, dissolve BCNU with 3 mL 
of the supplied sterile diluent (Dehydrated Alcohol Injection, USP). Second, aseptically add 27 mL 
Sterile Water for Injection, USP. Each mL of resulting solution contains 3.3 mg of BCNU in 10% 


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ethanol. Such solutions should be protected from light. Reconstitution as recommended results in a 
clear, colorless to yellowish solution which may be further diluted with 5% Dextrose Injection, 
USP. Parenteral drug products should be inspected visually for particulate matter and discoloration 
prior to administration, whenever solution and container permit. BCNU is administered by 
intravenous infusion after reconstitution as recommended. Accidental contact of reconstituted 
BCNU with the skin has caused transient hyperpigmentation of the affected areas. The use of 
gloves is recommended. If BCNU lyophilized material or solution contacts the skin or mucosa, 
immediately wash the skin or mucosa thoroughly with soap and water. 
10.7.2 Clinical Pharmacology 
Intravenously administered carmustine is rapidly degraded, with no intact drug detectable after 15 
minutes. However, in studies with 14C-labeled drug, prolonged levels of the isotope were detected 
in the plasma and tissue, probably representing radioactive fragments of the parent compound. It is 
thought that the antineoplastic and toxic activities of carmustine may be due to metabolites. 
Approximately 60% to 70% of a total dose is excreted in the urine in 96 hours and about 10% as 
respiratory CO2. The fate of the remainder is undetermined. Because of the high lipid solubility 
and the relative lack of ionization at physiological pH, carmustine crosses the blood-brain barrier 
quite effectively. Levels of radioactivity in the CSF are ≥50% of those measured concurrently in 
plasma. 
10.7.3 Toxicity 
10.7.3.1 Pulmonary Toxicity 
Pulmonary toxicity characterized by pulmonary infiltrates and/or fibrosis has been reported to 
occur from 9 days to 43 months after treatment with BiCNU and related nitrosoureas. Most of 
these patients were receiving prolonged therapy with total doses of BiCNU greater than 1400 
mg/m2. However, there have been reports of pulmonary fibrosis in patients receiving lower total 
doses. Other risk factors include past history of lung disease and duration of treatment. Cases of 
fatal pulmonary toxicity with BiCNU have been reported.  
10.7.3.2 Hematologic Toxicity 
A frequent and serious toxicity of BiCNU is delayed myelosuppression. It usually occurs 4 to 6 
weeks after drug administration and is dose related. Thrombocytopenia occurs at about 4 weeks 
post-administration and persists for 1 to 2 weeks. Leukopenia occurs at 5 to 6 weeks after a 
dose of BiCNU and persists for 1 to 2 weeks. Thrombocytopenia is generally more severe than 
leukopenia. However, both may be dose-limiting toxicities.  BiCNU may produce cumulative 
myelosuppression, manifested by more depressed indices or longer duration of suppression 
after repeated doses. The occurrence of acute leukemia and bone-marrow dysplasias have been 
reported in patients following long-term nitrosourea therapy. Anemia also occurs, but is less 
frequent and less severe than thrombocytopenia or leukopenia. 
10.7.3.3 Gastrointestinal Toxicity 
Nausea and vomiting after I.V. administration of BiCNU are noted frequently. This toxicity 
appears within 2 hours of dosing, usually lasting 4 to 6 hours, and is dose related. Prior 
administration of antiemetics is effective in diminishing and sometimes preventing this side 
effect. 
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A reversible type of hepatic toxicity, manifested by increased transaminase, alkaline 
phosphatase, and bilirubin levels, has been reported in a small percentage of patients receiving 
BiCNU. 
10.7.3.5 Nephrotoxicity 
Renal abnormalities consisting of progressive azotemia, decrease in kidney size and renal 
failure have been reported in patients who received large cumulative doses after prolonged 
therapy with BiCNU and related nitrosoureas. Kidney damage has also been reported 
occasionally in patients receiving lower total doses. 
10.7.3.6 Other Toxicities 
Accidental contact of reconstituted BiCNU with skin has caused burning and 
hyperpigmentation of the affected areas. Rapid I.V. infusion of BiCNU may produce intensive 
flushing of the skin and suffusion of the conjunctiva within 2 hours, lasting about 4 hours. It is 
also associated with burning at the site of injection although true thrombosis is rare. 
Neuroretinitis, chest pain, headache, allergic reaction, hypotension and tachycardia have been 
reported as part of ongoing surveillance. 
10.7.4 Storage and Stability 
Unopened vials of the dry drug must be stored in a refrigerator (2°C to 8°C; 36°F to 46°F). The 
recommended storage of unopened vials provides a stable product for 2 years. After reconstitution 
as recommended, BiCNU is stable for 8 hours at room temperature (25°C; 77°F), protected from 
light. 
10.8 
ETOPOSIDE 
Etoposide (also known as VP-16) is a semisynthetic derivative of podophyllotoxin whose 
predominant macromolecular effect is DNA synthesis inhibition. 
 
 
 
Figure 9. Structural formula of etoposide (VP-16). 
10.8.1 Formulation and Preparation 
Etoposide Injection is available for intravenous use as a sterile 20 mg/mL solution in 5 mL, 25 mL, 
or 50 mL sterile multiple dose vials.  The solution is clear yellow.  It has a molecular weight of 
588.56 and a molecular formula of C29H32O13. 
Etoposide injection must be diluted prior to use with either 5% Dextrose Injection, USP or 0.9% 


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Sodium Chloride Injection, USP to give a final concentration of 0.2 to 0.4 mg/mL. If solutions are 
prepared at concentrations above 0.4 mg/mL, precipitation may occur. Hypotension following 
rapid intravenous administration has been reported, hence, it is recommended that the etoposide 
solution be administered over a 2 to 4 hour period. A longer duration of administration may be 
used if the volume of fluid to be infused is a concern. Etoposide should not be given by rapid 
intravenous injection.  Parenteral drug products should be inspected visually for particulate 
matter and discoloration prior to administration whenever solution and container permit. 
As with other potentially toxic compounds, caution should be exercised in handling and preparing 
the solution of etoposide. Skin reactions associated with accidental exposure to etoposide may 
occur. The use of gloves is recommended. If etoposide solution contacts the skin or mucosa, 
immediately wash the skin or mucosa thoroughly with soap and water. 
10.8.2 Clinical Pharmacology 
On intravenous administration, the disposition of etoposide is best described as a biphasic process 
with a distribution half-life of about 1.5 hours and terminal elimination half-life ranging from 4 to 
11 hours.  In vitro, etoposide is highly protein bound (97%) to human plasma proteins. 
After intravenous administration of 3H-etoposide (70-290 mg/m2), mean recoveries of radioactivity 
in the urine range from 42 to 67%, and fecal recoveries range from 0 to 16% of the dose. Less than 
50% of an intravenous dose is excreted in the urine as etoposide with mean recoveries of 8 to 35% 
within 24 hours. 
Biliary excretion appears to be a minor route of etoposide elimination. Only 6% or less of an 
intravenous dose is recovered in the bile as etoposide. Metabolism accounts for most of the 
nonrenal clearance of etoposide. The major urinary metabolite of etoposide in adults is the 
hydroxy acid [4'-demethylepipodophyllic acid-9-(4,6-0-(R)-ethylideneß-D-glucopyranoside)], 
formed by opening of the lactone ring. It is also present in human plasma, presumably as the trans 
isomer. Glucuronide and/or sulfate conjugates of etoposide are excreted in human urine and 
represent 5 to 22% of the dose. 
10.8.3 Toxicity 
10.8.3.1 Hematologic Toxicity 
Myelosuppression is dose related and dose limiting, with granulocyte nadirs occurring 7 to 14 
days after drug administration and platelet nadirs occurring 9 to 16 days after drug 
administration. Bone-marrow recovery is usually complete by day 20, and no cumulative 
toxicity has been reported. The occurrence of acute leukemia with or without a preleukemic 
phase has been reported rarely in patients treated with etoposide in association with other 
antineoplastic agents. 
10.8.3.2 Gastrointestinal Toxicity 
Nausea and vomiting are the major gastrointestinal toxicities. The severity of such nausea and 
vomiting is generally mild to moderate with treatment discontinuation required in 1% of 
patients.  Nausea and vomiting can usually be controlled with standard antiemetic therapy. 
Gastrointestinal toxicities are slightly more frequent after oral administration than after 
intravenous infusion. 
10.8.3.3 Hypotension 
Transient hypotension following rapid intravenous administration has been reported in 1% to 


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2% of patients. It has not been associated with cardiac toxicity or electrocardiographic changes. 
No delayed hypotension has been noted. To prevent this rare occurrence, it is recommended 
that Etoposide Injection be administered by slow intravenous infusion over a 30 to 60 minute 
period. If hypotension occurs, it usually responds to cessation of the infusion and administration 
of fluids or other supportive therapy as appropriate. When restarting the infusion, a slower 
administration rate should be used. 
10.8.3.4 Allergic Reactions 
Anaphylactic-like reactions characterized by chills, fever, tachycardia, bronchospasm, dyspnea, 
and/or hypotension have been reported to occur in 0.7% to 2% of patients receiving intravenous 
etoposide and in less than 1% of the patients treated with the oral capsules. These reactions 
have usually responded promptly to the cessation of the infusion and administration of pressor 
agents, corticosteroids, antihistamines, or volume expanders as appropriate; however, the 
reactions can be fatal. Hypertension and/or flushing have also been reported. Blood pressure 
usually normalizes within a few hours after cessation of the infusion. Anaphylactic-like 
reactions have occurred during the initial infusion of etoposide. Facial/tongue swelling, 
coughing, diaphoresis, cyanosis, tightness in throat, laryngospasm, back pain, and/or loss of 
consciousness have sometimes occurred in association with the above reactions. In addition, an 
apparent hypersensitivity-associated apnea has been reported rarely. Rash, urticaria, and/or 
pruritus have infrequently been reported at recommended doses. At investigational doses, a 
generalized pruritic erythematosus, maculopapular rash, consistent with perivasculitis, has been 
reported. 
10.8.3.5 Alopecia 
Reversible alopecia, sometimes progressing to total baldness was observed in up to 66% of 
patients. 
10.8.3.6 Other Toxicities 
The following adverse reactions have been infrequently reported: aftertaste, fever, 
pigmentation, abdominal pain, constipation, dysphagia, transient cortical blindness, optic 
neuritis, and a single report of radiation recall dermatitis. Hepatic toxicity, generally in patients 
receiving higher doses of the drug than those recommended, has been reported with etoposide. 
Metabolic acidosis also has been reported in patients receiving higher doses. 
10.8.4 Storage and Stability 
Unopened vials of Etoposide Injection are stable for 24 months at room temperature (25°C). Vials 
diluted as recommended to a concentration of 0.2 to 0.4 mg/mL are stable for 96 and 24 hours, 
respectively, at room temperature (25°C) under normal room fluorescent light in both glass and 
plastic containers. 
10.9 
CYTARABINE (ARA-C, CYTOSINE ARABINOSIDE) 
Cytarabine is an antineoplastic that acts through the inhibition of DNA polymerase. 
10.9.1 Formulation and Preparation 
Cytarabine is an odorless, white to off-white, crystalline powder that is freely soluble in water and 
slightly soluble in alcohol and in chloroform. Molecular weight: 243.22. Molecular formula: 
C9H13N3O5. 


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Figure 10. Structural formula of cytarabine. 
10.9.2 Human Pharmacology 
Cytarabine is rapidly metabolized. Following rapid intravenous injection of cytarabine labeled 
with tritium, the disappearance from plasma is biphasic. There is an initial distributive phase with 
a half-life of about 10 minutes, followed by a second elimination phase with a half-life of about 1 
to 3 hours. After the distributive phase, more than 80% of plasma radioactivity can be accounted 
for by the inactive metabolite 1-ß-D-arabinofuranosyluracil (Ara-U). Within 24 hours about 80% 
of the administered radioactivity can be recovered in the urine, approximately 90% of which is 
excreted as Ara-U. Relatively constant plasma levels can be achieved by continuous intravenous 
infusion. 
10.9.3 Toxicity 
10.9.3.1 Expected Reactions 
Because cytarabine is a bone-marrow suppressant, anemia, leukopenia, thrombocytopenia, 
megaloblastosis and reduced reticulocytes can be expected as a result of administration with 
Cytarabine. Cellular changes in the morphology of bone marrow and peripheral smears can be 
expected.  Following 5-day constant infusions or acute injections of 50 mg/m2 to 600 mg/m2, 
white cell depression follows a biphasic course. Regardless of initial count, dosage level, or 
schedule, there is an initial fall starting the first 24 hours with a nadir at days 7-9. This is 
followed by a brief rise that peaks around the twelfth day. A second and deeper fall reaches 
nadir at days 15-24. Then there is rapid rise to above baseline in the next 10 days. Platelet 
depression is noticeable at 5 days with a peak depression occurring between days 12-15. 
Thereupon, a rapid rise to above baseline occurs in the next 10 days. 
10.9.3.2 Infectious Complications 
Viral, bacterial, fungal, parasitic, or saprophytic infections, in any location in the body may be 
associated with the use of Cytarabine for Injection, USP alone or in combination with other 
immunosuppressive agents following immunosuppressant doses that affect cellular or humoral 
immunity. These infections may be mild, but can be severe and at times fatal. 
10.9.3.3 Cytarabine (Ara-C) Syndrome 
A cytarabine syndrome has been described. It is characterized by fever, myalgia, bone pain, 
occasionally chest pain, maculopapular rash, conjunctivitis and malaise. It usually occurs 6 to 
12 hours following drug administration. Corticosteroids have been shown to be beneficial in 


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treating or preventing this syndrome. If the symptoms of the syndrome are deemed treatable, 
corticosteroids should be contemplated as well as continuation of therapy with cytarabine. 
10.9.3.4 Most Frequent Adverse Reactions 
Most frequent adverse reactions include anorexia, oral and anal inflammation or ulceration, 
rash, nausea, thrombophlebitis, vomiting, hepatic dysfunction, bleeding (all sites), diarrhea, and 
fever.  Nausea and vomiting are most frequent following rapid intravenous injection. 
10.9.3.5 Less Frequent Adverse Reactions 
Less frequent adverse reactions include sepsis, esophageal ulceration, conjunctivitis (may occur 
with rash), pneumonia, esophagitis, dizziness, cellulitis at injection site, chest pain, alopecia, 
skin ulceration, pericarditis, anaphylaxis, urinary retention, bowel necrosis, allergic edema, 
renal dysfunction, abdominal pain, pruritus, neuritis, pancreatitis, shortness of breath, neural 
toxicity, freckling, urticaria, sore throat, jaundice, and headache. 
10.9.4 Storage and Stability 
Store the product at controlled room temperature 15° to 30° C (59° to 86° F). 
When reconstituted Cytarabine was added to Sterile Water for Injection, 5% Dextrose Injection or 
Sodium Chloride Injection, 94 to 96 percent of the cytarabine was present after 192 hours storage 
at room temperature. Parenteral drugs should be inspected visually for particulate matter and 
discoloration, prior to administration, whenever solution and container permit. 
10.10 MELPHALAN 
Melphalan, also known as L-phenylalanine mustard, phenylalanine mustard, L-PAM, or L-
sarcolysin, is a phenylalanine derivative of nitrogen mustard and is a bifunctional alkylating agent 
whose cytotoxicity appears to be related to the extent of its interstrand cross-linking with DNA. 
10.10.1Formulation and Preparation 
Melphalan for Injection is supplied as a sterile, nonpyrogenic, freeze-dried powder.  Each single-
use vial contains melphalan hydrochloride equivalent to 50 mg melphalan and 20 mg povidone.  It 
is reconstituted using the sterile diluent provided and administered intravenously. The molecular 
formula is C13H18Cl2N2O2, and the molecular weight is 305.20. 
 
 
Figure 11. Structural formula of melphalan (L-phenylalanine mustard). 
10.10.2  Pharmacokinetics 
Drug plasma concentrations of melphalan decline rapidly in a biexponential manner with 
distribution phase and terminal elimination phase half-lives of approximately 10 and 75 minutes, 
respectively. The extent of melphalan binding to plasma proteins ranges from 60% to 90%. 
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melphalan and dihydroxymelphalan.  Aside from these hydrolysis products, no other melphalan 
metabolites have been observed in humans.  
10.10.3  Toxicity 
The following information on adverse reactions is based on data from both oral and I.V. 
administration of melphalan as a single agent, using several different dose schedules for treatment 
of a wide variety of malignancies. 
10.10.3.1 Hematological 
The most common side effect is bone-marrow suppression. White blood cell count and platelet 
count nadirs usually occur 2 to 3 weeks after treatment, with recovery in 4 to 5 weeks after 
treatment. Irreversible bone-marrow failure has been reported. 
10.10.3.2 Gastrointestinal 
Gastrointestinal disturbances such as nausea and vomiting, diarrhea, and oral ulceration occur 
infrequently. Hepatic disorders ranging from abnormal liver function tests to clinical 
manifestations such as hepatitis and jaundice have been reported. Hepatic veno-occlusive disease 
has been reported. 
10.10.3.3 Hypersensitivity 
Acute hypersensitivity reactions including anaphylaxis were reported in 2.4% of 425 patients 
receiving melphalan for Injection for myeloma. These reactions were characterized by urticaria, 
pruritus, edema, and in some patients, tachycardia, bronchospasm, dyspnea, and hypotension. 
These patients appeared to respond to antihistamine and corticosteroid therapy. If a 
hypersensitivity reaction occurs, IV or oral melphalan should not be re-administered since 
hypersensitivity reactions have also been reported with oral melphalan. 
10.10.3.4 Miscellaneous 
Other reported adverse reactions include skin hypersensitivity, skin ulceration at injection site, 
skin necrosis rarely requiring skin grafting, vasculitis, alopecia, hemolytic anemia, allergic 
reaction, pulmonary fibrosis, and interstitial pneumonitis. 
10.10.3.5 Secondary malignancies 
Secondary malignancies including acute nonlymphocytic leukemia, myeloproliferative 
syndrome, and carcinoma, have been reported in patients with cancer treated with alkylating 
agents (including melphalan). Some patients also received other chemotherapeutic agents or 
radiation therapy. Precise quantitation of the risk of acute leukemia, myeloproliferative 
syndrome, or carcinoma is not possible. Published reports of leukemia in patients who have 
received melphalan (and other alkylating agents) suggest that the risk of leukemogenesis 
increases with chronicity of treatment and with cumulative dose. 
10.11 ADMINISTRATION 
Melphalan for Injection must be reconstituted by rapidly injecting 10 mL of the supplied diluent 
directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger needle 
diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. This 
provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent followed by immediate 
vigorous shaking is important for proper dissolution.  Immediately dilute the dose to be 
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mg/mL. Administer the diluted product over a minimum of 15 minutes. Complete administration 
should be accomplished within 60 minutes of reconstitution.  The time between 
reconstitution/dilution and administration of melphalan should be kept to a minimum because 
reconstituted and diluted solutions of melphalan are unstable. 
10.12 STORAGE AND STABILITY 
 Store at controlled room temperature 15° to 30°C (59° to 86°F) and protect from light 
10.13   PALIFERMIN (KEPIVANCE) 
Palifermin is a human recombinant keratinocyte growth factor (KGF) used to reduce the incidence 
and duration of severe oral mucositis. 
Palifermin is commercially available and will be purchased by the Clinical Center Pharmacy. 
10.13.1  Formulation storage 
 intravenous powder for solution: 6.25 mg 
 add sterile water for injection to vial for a final concentration of 5 mg/mL, gently swirl,     
 do not shake or vigorously agitate vial 
 destroy reconstituted solution after 1 hour if left at room temperature or 24 hours if    
 refrigerated 
10.13.2  Administration 
add sterile water for injection to vial for a final concentration of 5 mg/mL, gently swirl, do not 
shake or vigorously agitate vial 
give reconstituted solution immediately or destroy after 1 hour if left at room temperature or 24 
hours if refrigerated 
do not filter reconstituted solution during preparation or administration  
if heparin is used to maintain the i.v. line, flush with saline prior to and after the dose to prevent 
binding to heparin 
palifermin should not be used during or within 24 hours preceding or following myelotoxic 
therapy administration 
10.13.3  Dose and schedule 
-  60 g/kg intravenously push 
-  daily for three days starting day -9 pre-ASCT (i.e. days -9, -8 and -7) 
-  then for three additional daily doses on days +1, +2 and +3 of ASCT 
10.13.4  Drug interaction 
In vitro and in vivo data suggest that palifermin binds to unfractionated as well as low-molecular- 
weight heparins, and licensed product information therefore recommends that such combinations 
should be used with care, although the clinical relevance is unclear. 
10.13.5  Toxicity 


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The following adverse events were found in excess in the palifermin group over the control group 
in randomized studies and may be related to palifermin administration: 
Rash, pruritus, erythema, cough, edema, taste changes or taste loss, coating of the tongue, 
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15. 
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CD20) antibody. N Engl J Med, 1993. 329(7): p. 459-65. 
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stem cell transplantation for relapsed B cell lymphomas. Lancet, 1995. 346(8971): p. 336-40. 
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labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol, 1998. 16(10): p. 3270-
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cyclophosphamide, and autologous stem cell transplantation for relapsed B-cell lymphomas. 
Blood, 2000. 96(9): p. 2934-42. 
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reinfusion: an outpatient preparative regimen for autologous hematopoietic cell transplantation. J 
Clin Oncol, 2008. 26(32): p. 5175-82. 
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tiuxetan and high-dose chemotherapy in patients with non-Hodgkin's lymphoma. J Clin Oncol, 
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2) in patients with hematologic malignancies. J Clin Oncol, 2000. 18(8): p. 1622-36. 
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45. 
Education, O.R.I.f.S.a., Calcium DTPA Informational Material Package Insert 2002. 
46. 
Dudley, H.R., et al., Pathologic changes associated with the use of sodium ethylene 
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12 APPENDICES 
12.1 
APPENDIX A:  WORLD HEALTH ORGANIZATION (WHO) CLASSIFICATION OF LYMPHOID 
TUMORS. 
 


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12.2 
APPENDIX B:  REVISED RESPONSE CRITERIA FOR MALIGNANT LYMPHOMA40 
 
 
 
 
 
 


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12.3 
APPENDIX C:  ECOG PERFORMANCE STATUS SCALE 
 
 
 
ECOG Performance Status Scale 
 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time.  Ambulatory and capable of all self-
care, but unable to carry out any work activities.  Up and about 
more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, 
confined to bed or chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair. 
5 
Dead. 
 
 
 


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12.4 
APPENDIX D:  ABNORMALITIES ENCOUNTERED IN MDS THAT CAN CONTRIBUTE TO THE 
DIAGNOSIS 
 
The diagnosis of Myelodysplasia will be made by an independent investigator of the Laboratory of 
Pathology, NCI taking into consideration the totality of the clinical, pathological, flow cytometric 
and cytogenetic information described below and present in a particular individual’s evaluation 
 
The following is derived from the “WHO Classification of tumours of Haematopoietic and 
lymphoid tissues” 4th Edition. International Agency for Research on cancer 


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12.5 
APPENDIX E: PROTOCOL FOR AUTOLOGOUS PBSC COLLECTION BY APHERESIS 
FOLLOWING MOBILIZATION WITH FILGRASTIM AND PLERIXAFOR 
Mobilization of CD34 cells with G-CSF and Plerixafor 
Patients will undergo mobilization with filgrastim (Neupogen, Amgen) and plerixafor 
(Mozobil, Genzyme). The filgrastim will be administered as a single daily dose in a dose range of 
10-15.9 ug/kg/day subcutaneously for 5-6 days (see Table below for sliding-scale filgrastim dose 
schedule). The filgrastim doses for days 1-4 may be given between 8:00A.M. to 5:00 P.M.  The 
filgrastim that is administered on day 5, and if necessary day 6, will be combined with a 
concurrent dose of plerixafor 240 mcg/kg subcutaneously.  On days 5 and 6, both drugs must be 
given approximately six hours prior to starting apheresis. Predictable side effects of filgrastim, 
including headache, bone pain, and myalgia, will be treated as appropriate. 
Filgrastim administration 
Filgrastim will be administered according to a vial-based algorithm to reduce wastage and 
increase the total filgrastim dose given to lighter weight donors in order to improve CD34 yields.1   
 
CD34 cell yield per liter processed as a function of pre-apheresis CD34 cell count in 220 NMDP 
donors. 
1Vasu S, Leitman SF, Tisdale JF, et al. Donor demographic and laboratory predictors of allogeneic 
peripheral blood stem cell mobilization in an ethnically diverse population. Blood 2008; 112:2092-100 
 
 


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Subject Weight        
Total Filgrastim Dose  
Dose /kg (range)              
  
38 - 48 kg 
 
 
600 mcg   
 
(12.5 to 15.8 mcg/kg)     
 
49 - 56 kg       
 
780 mcg   
 
(13.9 to 15.9 mcg/kg)  
57 - 60 kg  
 
 
900 mcg   
 
(15.0 to 15.8 mcg/kg)  
61 - 67 kg        
 
960 mcg   
 
(14.3 to 15.7 mcg/kg)  
68 - 108 kg     
 
1080 mcg  
 
(10.0 to 15.9 mcg/kg)   
 > 109 kg  
     
 
1200 mcg  
 
(11.0 or less)  
 
Plerixafor Administration 
Subject Weight 
Total Plerixafor Dose 
< 90 kg  
 
calculate dose at 240 mcg/kg 
> 90 kg 
 
24,000 mcg (flat dose, equal to one full 1.2-mL vial) 
 
Stem cell collection by apheresis 
Peripheral blood stem cell (PBSC) collection will be performed in the Dowling Apheresis Clinic of 
the Department of Transfusion Medicine (DTM).  A DTM physician is within the immediate 
vicinity of the procedure or available within one minute by pager. The minimum CD34 dose that 
must be collected in order to proceed with a single autologous transplantation is 2 x 106/kg.  When 
feasible, based on the mobilization response of the donor, a higher dose of >4 x106 CD34 cells/kg 
will be targeted, to permit more than one cycle of high dose chemotherapy with autologous stem 
cell rescue.   
The volume processed per apheresis procedure will be determined by DTM medical staff on the 
day of apheresis, based on peak CD34 cell mobilization response to filgrastim and optimum and 
minimum CD34 cell dose needed (see graph below). Volume processed will range from 12 to 25 
liters per procedure for 1 to 3 consecutive daily procedures, not to exceed a total of 75 liters over 3 
days.   
Collections will be performed with use of a dual-access continuous-flow apheresis device (Spectra 
Apheresis System, Caridian). Most donors will require a central double lumen apheresis catheter. 
Donors will receive continuous intravenous calcium prophylaxis to prevent citrate toxicity during 
apheresis, in accordance with standard DTM policies. 
 

ICF_001.pdf: 
MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
INSTITUTE: 
National Cancer Institute 
STUDY NUMBER: 
12-C-0003 
PRINCIPAL INVESTIGATOR: 
Thomas A. Waldmann, M.D. 
STUDY TITLE:  
Phase I/II Trial of Yttrium-90-labeled Daclizumab (anti-CD25) Radioimmunotherapy 
with High-dose BEAM Chemotherapy and Autologous Hematopoietic Stem Cell Rescue 
in Recurrent and Refractory Hodgkin’s Lymphoma 
Continuing Review Approved by the IRB on 12/03/18 
Amendment Approved by the IRB on 03/07/18 (F) 
                            Date posted to web: 12/13/18  
Standard 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In 
either case, you will not lose any benefits to which you are otherwise entitled.  However, 
to receive care at the NIH, you must be taking part in a study or be under evaluation for 
study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that 
may help people in the future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your NIH doctors or research team before you agree 
to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with anyone at NIH, or with family, 
friends or your personal physician or other health professional.   
Why is this study being done?  
Hodgkin’s lymphoma (HL) is a highly treatable cancer; however, in persons that have HL that 
either does not respond to chemotherapy or has responded in the past but has reoccurred, the 
success in treating HL is greatly lessened. Only 30 – 65% of individuals with HL that has 
relapsed and been treated with high dose chemotherapy and their own transplanted stem cells 
(cells that can develop into many different cell types) remain disease free in the long term.  Some 
of the cells within the lymphoma and the surrounding tissue have a molecule called CD25 on the 
surface. Daclizumab is a monoclonal antibody, a purified protein that attaches to foreign 
substances in the body or to body tissues.  Daclizumab attaches specifically to CD25.  Most 


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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 2 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
monoclonal antibodies are produced from mouse tumor cells, but are the same type of protein 
that your body produces to fight infection. Basiliximab is a drug that is similar to daclizumab. 
You may receive basiliximab if unlabeled daclizumab becomes unavailable. 
In a study where persons with HL that did not respond to chemotherapy or had relapsed were 
given daclizumab attached to a radioactive atom called Yttrium 90 on the theory that the 
radiation would kill the CD25 bearing tumor cells, 63% had their tumors either shrink or 
disappear completely.  In this phase 1/phase 2 study we plan to combine 90Yttrium labeled 
daclizumab (90Ydaclizumab) with standard high dose chemotherapy consisting of BCNU 
(carmustine), etoposide, Ara-C (cytarabine) and melphalan (also called the BEAM regimen) and 
stem cell transplant.  
Stem cells are a type of cell that has the potential to develop into several different cell types.  We 
are interested in stem cells that will develop into cell types that fight infection.  In this study, we 
will collect stem cells from your blood before starting the regimen and return them to your body 
after you have completed chemotherapy.  We will attempt to determine: 
• the effect of this combination on tumor response and the amount of time participants 
remain disease free 
• the side effects associated with this combination 
• the highest dose of 90Y daclizumab that can be given without causing intolerable side 
effects 
Why are you being asked to take part in this study? 
You are being asked to participate in this study because you have Hodgkin’s lymphoma that has 
either not responded to chemotherapy or has responded in the past, but has now relapsed. 
How many people will take part in this study?  
Up to 95 subjects may be enrolled in the study. 
Description of Research Study 
What will happen if you take part in this research study?  
Before you begin the study 
All research studies have specific criteria for entry to allow for valid interpretation of the study 
results and safety of participants, known as eligibility criteria.  Before you begin this study, you 
will need to have some exams and tests to make sure you are eligible for this study.  Your 
doctors and nurses will explain which exams and tests you will have. The exams and tests are 
part of regular cancer care and may be done even if you do not join the study.  You will probably 
have these tests done while you are on the NCI Screening Protocol.  If you recently had some of 
the tests, they may not need to be repeated. Studies must be completed within 28 days prior to 
study entry with the exception of the bone-marrow aspirate and biopsy with cytogenetic studies 
which must be completed within 60 days prior to study entry. 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 3 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
During the study 
If you are eligible to participate and agree, you will spend an estimated 6 - 12 weeks in the 
treatment portion of the study depending on your dose level on the study regimen. 
You will receive the following tests to establish a baseline prior to receiving the study regimen: 
• Scans and x-rays to measure your disease and an FDG-PET scan  
• Routine blood and urine tests 
• Pregnancy test if you are a woman that can have children 
• Blood test for cytomegalovirus (CMV) infection 
• Blood test for to measure your CD25 levels 
• Electrocardiogram (EKG) 
After you enroll in the study, you will start the preparation of treatment according to the 
following schedule:  
1. You will be given an injection called filgrastim (also called GCSF or neupogen) every day 
for five to six days in a row.   
a. Filgrastim is used to stimulate the bone marrow to make the stem cells that eventually 
produce a subgroup of white blood cells called granulocytes.   
2. On or about 5 days after filgrastim starts, you will be given an injection of plerixafor.  
a. Plerixafor will help the new stem cells move from the bone marrow into your blood 
stream so that they may be collected.   
3. On or about 6 or 7 days after filgrastim starts, the stem cells will be collected in a procedure 
called apheresis.   
a. The apheresis procedure involves inserting a catheter (tube) into your vein to allow your 
blood to be collected.  Stem cells will be separated from the rest of your blood and stored 
until the time they are returned to your body through an IV infusion; and the rest of the blood 
will be returned to you through the same catheter it came out of.  If we are unable to collect 
enough stem cells during this procedure, you will receive an additional dose of filgrastim and 
another dose of plerixafor.  The apheresis procedure will be repeated. If we are unable to 
collect enough cells after two apheresis procedures in a row, we will wait a minimum of 
three weeks then repeat the process once more.  If there are still not enough stem cells after 
this second cycle, you will be removed from the study. 
4. Four weeks after your stem cells have been collected and stored, you will be given the 
radioactive antibody 90Y Daclizumab through an IV (a plastic tube in your vein) over the 
course of two hours.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 4 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
5. At the same time, you will receive a low dose Indium 111 labeled daclizumab and unlabeled 
daclizumab/basiliximab.  The Indium 111 labeled daclizumab is used to help us see where 
the antibodies are binding on CT scan.  The unlabeled daclizumab/basiliximab helps to 
ensure that more the 90Y daclizumab binds to the CD25 target.  
6. If you have been assigned to dose level 1 of the Phase 1 portion of the study, you will start 
BEAM chemotherapy 9 days after you receive the antibody.   
7. If you are assigned to dose level 2-7 on the Phase 1 portion, you will receive a second dose of 
90Y daclizumab 6 weeks after the first dose.  
a. This will help us determine the amount of 90Y daclizumab to be given as the second dose in 
the Phase 2 portion of the study---this is called the Maximum Tolerated Dose or MTD 
(highest dose of a drug that will produce the desired effect without unacceptable side effects).   
8. If you are assigned to Phase 2, you will receive a dose of 90Y Daclizumab for the first 
infusion; and then 6 weeks later you will receive a second dose of 90 Y Daclizumab. 
9. With each dose of 90Y daclizumab and for two days after (three days total), you will receive 
an IV dose of Ca-DTPA given over 5 hours to help your body to eliminate the radioactive 
atom 90Yttrium. 
10. After each daclizumab (Indium 111, Yttrium 90 and unlabeled), you will undergo three 
SPECT scans (CT scans based on the detection of radioactivity) of your chest & abdomen.   
a. The first will be taken 2- 8 hours after the infusion 
b. The second will be done between 1 and three days after the infusion 
c. The third will be taken between 4 and 7 days after the infusion.   
d. These images will tell us where the daclizumab is located in your body at these times and 
help us make sure the 90 Y Daclizumab is going to all the sites of your disease.   
e. If you are assigned to Phase 1 Dose Level 2-7 or Phase 2, we will also perform a CT scan 
and FDG PET scan on the day of your second infusion to help us measure any changes in 
your tumor that may have occurred after the first infusion. 
f. Furthermore, we will draw 12mL of your blood prior to the infusion to test for radiation 
levels and 8mL of blood at the following intervals: ½ hour, 1 hour, 2 hours, 6 hours, 12 
hours, 24 hours and daily up to seven days after the infusion. 
11. During this part of the study, starting one week before you receive 90Y daclizumab, you will 
have weekly physical examinations and blood tests to help us know how you are doing on the 
medication. 
12. Nine days after you have been given the second dose of daclizumab, if you have not 
experienced intolerable side effects or other problems, you will begin BEAM chemotherapy.   
13. Chemotherapy will be given intravenously over the course of 6 days.   


MEDICAL RECORD 
CONTINUATION SHEET for either: 
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 5 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
a. On the first day, you will receive BCNU (Carmustine) over the course of approximately 
two hours.   
b. On the 2nd through the 5th days of the BEAM protocol you will receive IV infusions of 
cytarabine (Ara-C) for approximately 30 minutes every 12 hours.   
c. On the 2nd through the 5th days of the BEAM protocol, you will also receive etoposide 
infusions daily over 2-4 hours per day.  It is possible that this infusion may take longer.   
d. Melphalan will be given by IV on the 6th day of the BEAM regimen over a course of 
about 30 minutes. 
14. In order to prevent dehydration, you will receive IV fluids during BEAM therapy; you will 
also receive medication to help prevent nausea and vomiting. 
15. On the day following the last day of chemotherapy, the stem cells we collected and stored 
will be returned to you through an IV infusion.   
16. During your treatment, you will receive several medications to prevent or treat side effects of 
the stem cell transplantation regimen, including: 
a.  medication to help prevent the infections that can result from bone marrow depletion.   
b. medication to help prevent or treat fungal and viral infections starting with the first dose 
of 90Y daclizumab.   
c. medication to help prevent mouth sores.   
d. If needed, you will be given antibiotics to treat bacterial infections. 
17. Five days after the stem cell transplant, you will be given daily injections of filgrastim to 
help stimulate the growth of cells in your bone marrow.   
a. You will continue to receive these injections until the number of a certain type of white 
blood cell, granulocytes, reaches an acceptable level. 
18. You will have daily physical examinations and your blood will be sampled for testing twice 
daily to help us assess your health during the chemotherapy and transplantation portion of the 
study.  This assessment schedule will continue until your granulocyte count is adequate. 
When you are finished taking the drugs (treatment) 
Following completion of the study regimen and recovery of your neutrophil count, we will assess 
your condition with physical examinations and blood tests at a minimum of every week for one 
month, then at a minimum of every 2 weeks for one month.   
One hundred (100) days after the stem cell transplant:  
• We will measure the size of your tumor using a CT scan of your chest, abdomen and 
pelvis and an 18FDG-PET scan.   
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 6 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
• We will take a sample of your bone marrow (bone marrow biopsy).   
• We will perform tests for lung function (PFTs). 
After Day 100, you will come to the NIH Clinical Center at the following times: 4, 6, 9, 12, 16, 
20, 24 (± 14 days) months after the end of treatment. During the 3rd, 4th and 5th year, you will 
return to the NIH clinic every 6 months (± 28 days) and then yearly for regular physical and 
laboratory examinations. 
Birth Control 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how this medicine would affect your baby or your unborn child. If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice an effective form of birth control before starting study treatment, during 
study treatment, and for four months after you finish study treatment.  If you think that you or 
your partner is pregnant, you should tell your study doctor or nurse at once.   
Effective forms of birth control include: 
• abstinence  
• intrauterine device (IUD) 
• hormonal [birth control pills, injections, or implants] 
• tubal ligation 
• vasectomy 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
The main risks of this study come from the side effects of the drugs you will be given, some of 
the procedures you will undergo and from radiation exposure.   
Listed below are the side effects of the agents used in this study: 
Filgrastim 
Likely 
Less Likely 
Rare but Serious 
• 
Itching 
• 
Joint pain 
• 
Muscle pain 
• 
Bone pain 
• 
Rash 
• 
Headache 
• 
Increase in white blood cells 
• 
Pain and bleeding at injection 
site 
• 
Bleeding from the lungs 
• 
Coughing up blood 
• 
Enlarged or ruptured spleen 
Plerixafor 
Likely 
Less Likely 
Rare but Serious 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 7 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Likely 
Less Likely 
Rare but Serious 
• 
Joint pain 
• 
Dizziness 
• 
Trouble sleeping 
• 
Low energy 
• 
Nausea 
• 
Vomiting 
• 
Gas 
• 
Diarrhea 
• 
Pain and bleeding at injection 
site 
• 
Headache 
• 
Dry mouth 
• 
Indigestion 
• 
Constipation 
• 
Redness of skin 
• 
Muscle pain 
• 
Excessive sweating 
• 
Numbness 
• 
Swelling of the abdomen 
• 
Not feeling well 
• 
Abdominal pain 
• 
Hives 
• 
Trouble breathing 
• 
Decreased platelets 
• 
Low oxygen levels in blood or 
tissues 
• 
Increased white blood cells 
• 
Fainting 
• 
Low blood pressure 
BCNU 
Likely 
Less Likely 
Rare but Serious 
• 
Nausea 
• 
Vomiting 
• 
Flushing 
• 
Pain and burning at the injection 
site 
• 
Low white blood cells count 
with increased risk of infection 
• 
Low platelet count with 
increased risk of bleeding 
• 
Diarrhea 
• 
Loss of appetite 
• 
Headache 
• 
Fetal abnormalities if pregnancy 
occurs while on drug 
• 
Scarring of lung tissue, with 
cough and shortness of breath, 
which can happen years after 
treatment  
• 
Flushing of skin  
• 
Redness of the eyes (just after 
infusion) 
• 
Low energy 
• 
Loss or thinning of hair  
• 
Low red blood cell counts 
(anemia) causing tiredness and 
other symptoms 
• 
Temporary kidney damage 
• 
Hardening of the vein used for 
injection 
• 
Death due to lung damage or 
other problems 
• 
Temporary decrease in liver 
function 
 
Etoposide 
Likely 
Less Likely 
Rare but Serious 
• 
Low white blood cell count with 
increased risk of infection 
• 
Low blood platelet count with 
increased risk of bleeding  
• 
Low red blood cell count 
(anemia) causing tiredness and 
other symptoms  
• 
Nausea 
• 
Vomiting 
• 
Loss of appetite  
• 
Hair loss 
• 
Constipation  
• 
Diarrhea 
• 
Fever and chills 
• 
Sores in mouth and throat 
• 
Rash, which can become 
serious  
• 
Itching  
• 
Numbness and tingling in 
hands and/or feet  
• 
Allergic reactions (may 
include chills, fever, rapid 
heart rate, trouble breathing, 
dizziness) 
• 
Increased risk of a second  
• 
cancer 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 8 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
Cytarabine 
Likely 
Less Likely 
Rare but Serious 
• 
Low white blood cell count with 
increased risk of infection  
• 
Low platelet count with 
increased risk of bleeding  
• 
Low red blood cell count 
(anemia) with symptoms like 
weakness, tiredness, shortness of 
breath 
• 
Nausea 
• 
Vomiting 
• 
Stomach pain  
• 
Tiredness  
• 
Sores in mouth or on lips 
• 
Diarrhea  
• 
Loss of appetite  
• 
Rash  
• 
Hair loss or thinning  
• 
Fever 
• 
Muscle and bone aches  
• 
Liver damage  
• 
Blood clots and inflammation of 
the vein where the drug was 
given  
• 
Kidney damage  
• 
Fetal changes that may lead to 
birth defects, prematurity, or 
serious illness in the newborn 
if you become pregnant while 
taking this drug  
• 
Allergic reaction with itching, 
dizziness, trouble breathing, 
or swelling of the face, mouth, 
or throat 
• 
Death due to infection, 
bleeding, or other causes 
Melphalan 
Likely 
Less Likely 
Rare but Serious 
• 
Nausea  
• 
Vomiting  
• 
Low white blood cell count with 
increased risk of infection  
• 
Low platelet count with 
increased risk of bleeding 
• 
Anemia (low red blood cell 
count) with symptoms like 
tiredness, paleness, or trouble 
catching your breath 
• 
Weakness 
• 
Inability to have children 
• 
Severe allergic reaction 
• 
Scarring or inflammation of 
lungs 
• 
Second type of cancer (may 
happen years after treatment) 
• 
Death from lung damage or 
other causes 
Daclizumab/Basiliximab 
Likely 
Less Likely 
Rare but Serious 
 
• 
High blood pressure 
• 
Low blood pressure 
• 
Fluid in the lungs 
• 
Fever 
• 
Increased heart rate 
• 
Trouble breathing 
• 
Chest pain 
• 
Nausea 
• 
Vomiting 
• 
Diarrhea 
• 
Fluid retention in the legs, feet, 
arms or hands 
• 
Abnormal heart rhythm – 
which can lead to complete 
stoppage  
• 
Swelling of vocal cords 
• 
Loss of consciousness  
• 
Increased blood sugar 
• 
Decreased oxygen in blood or 
other tissues 
• 
Allergic reaction 
• 
Kidney damage 
 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 9 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
CaDTPA: 
Side effects of CaDTPA include nausea, vomiting, diarrhea, chills, fever, itching and muscle 
cramps.  These side effects are observed in fewer than 10% of persons using this drug. 
Other: 
Other side effects seen with the chemotherapy treatment may include ovarian function changes 
in women, including hormonal changes with menopausal symptoms (such as hot flushes) or early 
permanent menopause (also known as ovarian failure).   
Procedure Risks: 
Bone Marrow Biopsy:  This procedure is performed to collect cells from your bone marrow.  
Your hipbone will be numbed with a small needle containing a local anesthesia, and then a 
needle will be put into the hipbone, and about two tablespoons of bone marrow will be taken out 
through the needle. This procedure usually causes some pain.  Very rarely, infection or bleeding 
may occur at the needle site. 
Lymph node biopsy: This test involves taking a small tissue sample from one or more of your 
lymph nodes. The lymph nodes are small, oval-shaped glands found throughout the body, 
interconnected by lymph vessels.  To obtain the sample, a local anesthetic is injected under the 
skin over the lymph node.  A biopsy needle is placed through the skin and into the lymph node. 
A small tissue sample is removed when the needle is withdrawn. Tissue can also be drawn up 
into the needle by suction; this is called fine needle aspiration (FNA).  The risks of the biopsy 
procedure include pain at the biopsy site, bleeding from the skin, bruising, and infection of the 
biopsy site. 
ECG: The ECG (electrocardiogram) is a procedure that requires you to lie still for a few minutes 
while adhesive pads are attached to your chest to record the activity of your heart.  The ECG 
leads may cause slight discomfort during their placement on and removal from your skin.   
Echocardiogram: The echocardiogram is an ultrasound of your heart.  Sticky patches or 
electrodes are attached to the chest and shoulders and connected to electrodes or wires. These 
help to record the electrocardiogram (ECG) during the echocardiography test. The ECG helps in 
the timing of various cardiac events (filling and emptying of chambers). A colorless gel is then 
applied to the chest and the echo transducer is placed on top of it. There may be slight discomfort 
in the application of the gel and during the placement and removal of electrodes. 
Pulmonary Function Tests (PFTs): These tests, performed to test your lung function, involve 
inhaling and exhaling forcefully through your mouth and into a tube.  There is relatively little 
discomfort associated with this test; however, the tests may be tiring. 
Blood sampling: Local pain, bruising, bleeding, blood clot formation, and, in rare instances, an 
infection might occur at the site where blood is drawn.  There is also the possibility of dizziness 
or fainting while your blood is being drawn.  The decision to use a catheter (a thin tube) for 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 10 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
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NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
blood collecting is made by the study staff.  The study staff will explain the catheter to you if its 
use is necessary. 
FDG-PET and CT scans: Though the scanning itself causes no pain, there may be some 
discomfort from having to remain still for several minutes.  If you have a hard time staying still, 
are claustrophobic or have chronic pain, you may find scanning procedures somewhat 
uncomfortable.  You will also be exposed to radiation during the scan. 
Radiation Risk from Research Procedures: 
This research study involves exposure to radiation from 90Y daclizumab and 111Ind daclizumab 
as well as the SPECT scans you will undergo. Please note that this radiation exposure is not 
necessary for your medical care and is for research purposes only. The total amount of radiation 
you will receive in this study is from 2 injections (scans or repetitions) of 5 millicuries 111Ind 
daclizumab and 15 - 90 millicuries of 90Y daclizumab in addition to two series of 3 SPECT 
scans. The NIH Radiation Safety Committee has reviewed the use of radiation in this research 
study and has approved this use as involving acceptable risk and necessary to obtain the research 
information desired. 
Using the standard way of describing radiation dose, from participating in this study, you will 
receive a total of 1600 rad to your liver, 1000 rad to your red bone marrow, and 710 rad to your 
bone surfaces. All other organs will receive smaller amounts of radiation (whole body dose of 
200 rad). The amount of radiation received in this study exceeds the dose guideline established 
by the NIH Radiation Safety Committee for research subjects (this radiation is therapeutic so it is 
deemed reasonable). The guideline is an effective dose of 5 rad (or 5,000 mrad) received per 
year. 
The possible side-effects from the exposure to radiation are:  
• Low white blood cell count with increased risk of infection  
• Low platelet count with increased risk of bleeding 
• Anemia (low red blood cell count) with symptoms like tiredness, paleness, or trouble 
catching your breath 
• Damage to the bone marrow which may cause myelodysplastic syndrome (a group of 
disorders caused by poorly formed or dysfunctional blood cells)   
The average person in the United States receives a radiation exposure of 0.3 rad per year from 
natural sources, such as the sun, outer space, and the earth's air and soil.   
If you would like more information about radiation and examples of exposure levels from other 
sources, please ask the investigator for a copy of the pamphlet called, An Introduction to 
Radiation for NIH Research Subjects.  Please tell your doctor if you have taken part in other 
research studies or received any medical care at the NIH or other places/hospitals that used 
radiation. This way we can make sure that you will not receive too much radiation. Consider x-
rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear 
medicine scans in which radioactive materials were injected into your body. 


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CONTINUATION SHEET for either: 
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NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 11 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
If you are pregnant or breast feeding, you will not be permitted to participate in this research 
study. It is best to avoid radiation exposure to unborn or nursing children since they are more 
sensitive to radiation than adults. 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
The aims of this study are to find the highest dose of 90Y daclizumab that can be given with 
BEAM chemotherapy and stem cell transplant and to determine if this experimental treatment 
will cause your tumors to shrink.  We do not know if you will receive personal, medical benefit 
from taking part in this study. These potential benefits could include shrinking of your tumor or 
lessening of your symptoms, such as pain, that are caused by the cancer.  Because there is not 
much information about the drug’s effect on your cancer, we do not know if you will benefit 
from taking part in this study, although the knowledge gained from this study may help others in 
the future who have cancer.   
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options: 
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
Please talk to your doctor about these and other options. 
Stopping Therapy  
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
In this case, you will be informed of the reason therapy is being stopped. 
You can stop taking part in the study at any time. However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first. 
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you. However, according to FDA guidelines, 
information collected on you up to that point may still be provided to Hoffmann-La Roche, the 
manufacturer or designated representatives. If you withdraw your consent and leave the trial, any 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 12 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
samples of yours that have been obtained for the study and stored at the NCI can be destroyed 
upon request. However, any samples and data generated from the samples that have already been 
distributed to other researchers or placed in the research databases cannot be recalled and 
destroyed. 
Research Subject’s Rights 
What are the costs of taking part in this study?  
If you choose to take part in the study, the following will apply, in keeping with the NIH policy: 
• You will receive study treatment at no charge to you. This may include 
surgery, medicines, laboratory testing, x-rays or scans done at the Clinical 
Center, National Institutes of Health (NIH), or arranged for you by the 
research team to be done outside the Clinical Center, NIH if the study related 
treatment is not available at the NIH.  
• There are limited funds available to cover the cost of some tests and 
procedures performed outside the Clinical Center, NIH.  You may have to 
pay for these costs if they are not covered by your insurance company. 
• Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH. 
• Once you have completed taking part in the study, medical care will no 
longer be provided by the Clinical Center, NIH. 
Will your medical information be kept private?  
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Organizations that may look at 
and/or copy your medical records for research, quality assurance, and data analysis include: 
• The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), which are involved in keeping research safe for people. 
• National Cancer Institute Institutional Review Board. 
• Qualified representatives from Hoffmann-La Roche, the pharmaceutical company who 
produced daclizumab. 
A description of this clinical trial will be available on http://www.Clinicaltrials.gov, as required 
by U.S. Law.  This Web site will not include information that can identify you.  At most the Web 
site will include a summary of the results.  You can search this Web site at any time. 
Certificate of Confidentiality  
To help us protect your privacy, we have obtained a Certificate of Confidentiality. The 
researchers can use this Certificate to legally refuse to disclose information that may identify you 
in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 13 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
example, if there is a court subpoena. The researchers will use the Certificate to resist any 
demands for information that would identify you, except as explained below. 
You should also know that there are several circumstances in which the Certificate does not 
provide coverage. These include when information:  
• will be used for auditing or program evaluation internally by the NIH; or  
• must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA).  
• is necessary for your medical treatment and you have consented to this disclosure;  
• is for other research.  
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible 
as evidence or used for any purpose in any action, suit, or proceeding without your consent.  
You should understand that a Certificate of Confidentiality does not prevent you or a member of 
your family from voluntarily releasing information about yourself or your involvement in this 
research. If an insurer, employer, or other person obtains your written consent to receive research 
information, then the researchers will not use the Certificate to withhold that information. 
The Certificate of Confidentiality will not protect against the required reporting by hospital staff 
of information on suspected child abuse, reportable communicable diseases, and/or possible 
threat of harm to self or others. 
Conflict of Interest 
The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts 
of interest.  This process is detailed in a Protocol Review Guide. You may ask your research 
team for a copy of the Protocol Review Guide or for more information.  Members of the research 
team who do not work for NIH are expected to follow these guidelines but they do not need to 
report their personal finances to the NIH. 
Members of the research team working on this study may have up to $15,000 of stock in the 
companies that make products used in this study.  This is allowed under federal rules and is not a 
conflict of interest.  
The National Institutes of Health and the research team for this study have developed a method 
for joining radioactive atoms and molecules to daclizumab.  Two agents developed in this 
process, 90Y daclizumab and 111Ind daclizumab are being used in this study.  This means it is 
possible that the results of this study could lead to payments to NIH scientists and to the NIH. By 
law, government scientists are required to receive such payments for their inventions. You will 
not receive any money from the development of 90Y daclizumab and 111Ind daclizumab.  
Use of Specimens and Data for Future Research   
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. A researcher who wants to study the 


MEDICAL RECORD 
CONTINUATION SHEET for either: 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 14 of 16 pages 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
NIH-2514-1 (07-09) 
NIH-2514-2 (10-84) 
P.A.:  09-25-0099 
File in Section 4:  Protocol Consent 
 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect, use them for future research 
and share them with other researchers. We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for 
research purposes.  Your specimens and data will be used for research purposes only and will not 
benefit you.  It is also possible that the stored specimens and data may never be used.   
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
If you do not want your stored specimens and data used for future research, please contact us in 
writing and let us know that you do not want us to use your specimens and/or data.  Then any 
specimens that have not already been used or shared will be destroyed and your data will not be 
used for future research. However, it may not be possible to withdraw or delete materials or data 
once they have been shared with other researchers. 
 
 
 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 15 of 16 pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
OTHER PERTINENT INFORMATION 
1. 
Confidentiality.  When results of an NIH research study are reported in medical journals 
or at scientific meetings, the people who take part are not named and identified.  In most cases, 
the NIH will not release any information about your research involvement without your written 
permission.  However, if you sign a release of information form, for example, for an insurance 
company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance 
company to sell you insurance. 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you 
should know that the Act allows release of some information from your medical record without 
your permission, for example, if it is required by the Food and Drug Administration (FDA), 
members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
2. 
Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-
term medical care for any injury resulting from your participation in research here.  In general, 
no long-term medical care or financial compensation for research-related injuries will be 
provided by the National Institutes of Health, the Clinical Center, or the Federal Government.  
However, you have the right to pursue legal remedy if you believe that your injury justifies such 
action. 
3. 
Payments.  The amount of payment to research volunteers is guided by the National 
Institutes of Health policies.  In general, patients are not paid for taking part in research studies at 
the National Institutes of Health.  Reimbursement of travel and subsistence will be offered 
consistent with NIH guidelines. 
4. 
Problems or Questions.  If you have any problems or questions about this study, or 
about your rights as a research participant, or about any research-related injury, contact the 
Principal Investigator, Dr. Thomas Waldmann, M.D., Building 10, Room 4N115, Telephone: 
240-760-6091. You may also call the Clinical Center Patient Representative at 301-496-2626. If 
you have any questions about the use of your specimens or data for future research studies, you 
may also contact the Office of the Clinical Director, Telephone:  240-760-6070.  
5. 
Consent Document.  Please keep a copy of this document in case you want to read it 
again. 


MEDICAL RECORD 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
• 
Adult Patient or 
• Parent, for Minor Patient 
STUDY NUMBER: 12-C-0003 
CONTINUATION: page 16 of 16 pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH 
STUDY (Continuation Sheet) 
• 
Adult Patient or 
• Parent, for Minor Patient 
NIH-2514-1 (07-09) 
P.A.:  09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby consent to 
take part in this study. 
I have read the explanation about this study 
and have been given the opportunity to discuss 
it and to ask questions.  I hereby give 
permission for my child to take part in this 
study.   
(Attach NIH 2514-2, Minor’s Assent, if 
applicable.) 
 
  
  
 
 
 
Signature of Adult Patient/ 
Legal Representative 
Date 
Signature of Parent(s)/ Guardian Date 
 
 
Print Name 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to 
participate in the study. 
 
  
  
 
Signature of Parent(s)/Guardian 
Date 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM DECEMBER 03, 2018 THROUGH DECEMBER 17, 2019.  
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 
Print Name 
 
 
Print Name