Clinical trial NCT00423514
Conditions: Graft Versus Host Disease Leukemia Myelodysplastic Syndromes
Keywords: graft versus host disease adult acute lymphoblastic leukemia in remission adult acute myeloid leukemia in remission childhood acute lymphoblastic leukemia in remission childhood chronic myelogenous leukemia recurrent childhood acute myeloid leukemia accelerated phase chronic myelogenous leukemia acute undifferentiated leukemia adult acute myeloid leukemia with 11q23 (MLL) abnormalities blastic phase chronic myelogenous leukemia juvenile myelomonocytic leukemia previously treated myelodysplastic syndromes recurrent adult acute lymphoblastic leukemia recurrent adult acute myeloid leukemia relapsing chronic myelogenous leukemia secondary acute myeloid leukemia secondary myelodysplastic syndromes childhood acute myeloid leukemia in remission de novo myelodysplastic syndromes recurrent childhood acute lymphoblastic leukemia chronic phase chronic myelogenous leukemia adult acute myeloid leukemia with inv(16)(p13;q22) adult acute myeloid leukemia with t(15;17)(q22;q12) adult acute myeloid leukemia with t(16;16)(p13;q22) adult acute myeloid leukemia with t(8;21)(q22;q22) childhood myelodysplastic syndromes
Sponsor: Memorial Sloan Kettering Cancer Center
Start date: 2006-11-20; Completion date: 2021-06-18
Enrollment: 38 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Giving chemotherapy, such as clofarabine, melphalan, and thiotepa, before a donor stem cell transplant helps stop the growth of cancer or abnormal cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving tacrolimus and mycophenolate mofetil before the transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects and best dose of clofarabine when given together with melphalan and thiotepa, followed by a donor stem cell transplant and to see how well it works in treating patients with high-risk and/or advanced hematologic cancer or other disease.

Detailed description:
OBJECTIVES:

Primary

* Determine the maximum tolerated dose of clofarabine when administered with melphalan and thiotepa followed by allogeneic stem cell transplantation in patients with high-risk and/or advanced hematologic malignancies. (Phase I)
* Determine the 1-year disease-free survival of patients treated with this regimen. (Phase II)
* Determine the efficacy of this regimen, in terms of antileukemic potential and relapse rate, in these patients.

Secondary

* Evaluate the incidence and severity of nonhematologic toxicity of this regimen in these patients.
* Evaluate the incidence and severity of graft-versus-host disease in patients treated with this regimen.

OUTLINE: This is a phase I, dose-escalation study of clofarabine followed by an open-label, phase II study. Patients are stratified according to HLA-compatible donor type (related vs unrelated).

* Cytoreductive therapy: Patients receive clofarabine IV over 2 hours once daily on days -9 to -5, thiotepa IV over 4 hours on day -4, and melphalan IV over 30 minutes once daily on days -3 and -2.

Cohorts of 3-6 patients receive escalating doses of clofarabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

* Graft-versus-host disease (GVHD) prophylaxis: Patients who undergo bone marrow or peripheral blood stem cell transplantation receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -3 and methotrexate IV on days 1, 3, 6, and 11. Patients who undergo UCB transplantation receive tacrolimus IV continuously over 24 hours or orally every 8-12 hours beginning on day -3 and mycophenolate mofetil (MMF) IV or orally 2 or 3 times daily on days -3 to 45 followed by a taper until day 100 (unless there are signs of acute GVHD). Patients who undergo UCB transplantation without GVHD continue tacrolimus for 6 months followed by a taper and discontinued 1 year after transplantation.
* Allogeneic hematopoietic stem cell transplantation (HSCT) or allogeneic umbilical cord blood (UCB) transplantation: Patients undergo allogeneic HSCT (bone marrow or peripheral blood stem cells) or double UCB transplantation on day 0. Patients also receive filgrastim (G-CSF) IV or subcutaneously beginning on day 7 and continuing until blood counts recover.
* Maintenance therapy: Approximately 2 months after transplantation patients with ALL, M4 or M5 AML, and those transplanted with AML in bone marrow relapse receive cytarabine intrathecally (IT) monthly for up to 5 doses. Patients with a history of CNS leukemia receive cytarabine IT once monthly during months 2-12 after HSCT.

After completion of study therapy, patients are followed periodically for at least 4 years.

PROJECTED ACCRUAL: A total of 42 patients will be accrued for this study.

Arms: arm 1: This is a single arm phase I/II clinical trial to assess efficacy (the antileukemic potential and relapse rate), and safety (peri-transplant morbidity and mortality) of a novel cytoreduction regimen in preparation for allogeneic hematopoietic stem cell transplantation (HSCT).
Interventions: intervention 1: filgrastim intervention 2: clofarabine intervention 3: melphalan intervention 4: mycophenolate mofetil intervention 5: tacrolimus intervention 6: thiotepa intervention 7: allogeneic bone marrow transplantation intervention 8: allogeneic hematopoietic stem cell transplantation intervention 9: peripheral blood stem cell transplantation
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None

Protocol documents:
Prot_SAP_000.pdf: 
Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
Amended: 11/06/12 
 
 
A PHASE I/II DOSE ESCALATION TRIAL OF CLOFARABINE, IN ADDITION TO 
MELPHALAN AND THIOTEPA AS MYELOABLATIVE REGIMEN FOLLOWED BY AN 
ALLOGENEIC UNMODIFIED HEMATOPOIETIC STEM CELL TRANSPLANT FROM 
HLA-COMPATIBLE RELATED OR UNRELATED DONORS FOR THE TREATMENT 
OF HIGH RISK AND/OR ADVANCED HEMATOLOGIC MALIGNANCIES. 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL 
 
 
Principal Investigator: 
Farid Boulad, M.D 
Co-Principal 
Investigator(s): 
Esperanza B. Papadopoulos, M.D. 
Andromachi Scaradavou, M.D. 
Investigator(s): 
Juliet Barker, M.B.B.S. 
Hugo R. Castro-Malaspina, M.D. 
David Chung, M.D., Ph. D 
Kevin Curran, M.D. 
Sergio A. Giralt, MD. 
Jenna Goldberg, M.D. 
Alan M. Hanash, MD 
Aisha Hasan, M.D. 
Katharine C. Hsu, M.D., Ph.D. 
Ann A. Jakubowski, M.D. 
Robert Jenq, M.D. 
Heather Landau, M.D. 
Richard J. O’Reilly, M.D. 
Miguel-Angel Perales, M.D. 
Doris Ponce, M.D. 
Craig Sauter, M.D. 
Marcel R. M. Van den Brink, M.D., Ph.D. 
James W. Young, M.D. 
Nancy A. Kernan, M.D. 
Rachel Kobos, M.D. 
Susan E. Prockop, M.D. 
Trudy N. Small, M.D. 
Glenn Heller, Ph.D. 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
Amended: 11/06/12 
 
 
Consenting 
Professional(s): 
Juliet Barker, M.B.B.S. 
Hugo R. Castro-Malaspina, M.D 
Kevin Curran, M.D. 
David Chung, M.D., Ph. D 
Sergio A. Giralt, MD. 
Jenna Goldberg, M.D Alan 
M. Hanash, MD Aisha 
Hasan, M.D. 
Katharine C. Hsu, M.D., Ph.D. 
Ann A. Jakubowski, M.D. 
Robert Jenq, M.D. 
Heather Landau, M.D. 
Richard J. O’Reilly, M.D. 
Esperanza B. Papadopoulos, M.D. 
Miguel-Angel Perales, M.D. 
Doris Ponce, M.D. 
Craig Sauter, M.D. 
Marcel R. M. Van den Brink, M.D., Ph.D. 
James W. Young, M.D. 
Farid Boulad, M.D. 
Nancy A. Kernan, M.D. 
Rachel Kobos, M.D. 
Susan E. Prockop, M.D. 
Andromachi Scaradavou, M.D. 
Trudy N. Small, M.D. 
 
 
Please Note: A Consenting Professional must have completed the mandatory 
Human Subjects Education and Certification Program. 
 
 
 
 
 
 
 
 
 
 
 
 
 
Memorial Sloan-Kettering Cancer Center 
1275 York Ave. 
New York, NY 10021 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
Amended: 11/06/12 
 
 
 
 
 
 
Table of Contents 
 
 
MSKCC THERAPEUTIC/DIAGNOSTIC PROTOCOL ..................................................... 0 
1.0 
PROTOCOL SUMMARY AND/OR SCHEMA ....................................................... 3 
2.0 
OBJECTIVES AND SCIENTIFIC AIMS................................................................. 4 
3.0 
BACKGROUND AND RATIONALE ...................................................................... 4 
4.0 
OVERVIEW OF STUDY DESIGN/INTERVENTION ........................................... 14 
5.0 
THERAPEUTIC/DIAGNOSTIC AGENTS ............................................................ 15 
6.0 
CRITERIA FOR SUBJECT ELIGIBILITY ............................................................ 18 
7.0 
RECRUITMENT PLAN ....................................................................................... 20 
8.0 
PRETREATMENT EVALUATION ....................................................................... 20 
9.0 
TREATMENT/INTERVENTION PLAN ................................................................ 22 
10.0 EVALUATION DURING TREATMENT/INTERVENTION .................................... 27 
11.0 TOXICITIES/SIDE EFFECTS ............................................................................. 30 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT ....... 32 
13.0 CRITERIA FOR REMOVAL FROM STUDY ........................................................ 35 
14.0 BIOSTATISTICS ................................................................................................. 35 
15.0 SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES .............. 37 
16.0 DATA MANAGEMENT ISSUES ........................................................................ 38 
17.0 PROTECTION OF HUMAN SUBJECTS ............................................................. 39 
18.0 INFORMED CONSENT PROCEDURES ............................................................ 40 
19.0 REFERENCE(S) ................................................................................................. 42 
20.0 APPENDICES..................................................................................................... 49 


Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
Amended: 11/06/12 
- 3 - 
 
 
1.0     PROTOCOL SUMMARY AND/OR SCHEMA 
 
This is a single arm phase I/II clinical trial to assess efficacy (the antileukemic potential and 
relapse rate), and safety (peri-transplant morbidity and mortality) of a novel cytoreduction 
regimen in preparation for allogeneic hematopoietic stem cell transplantation (HSCT). Patients 
with high risk or advanced hematologic malignancies will receive cytoreduction with a novel 
agent, Clofarabine, in addition to Thiotepa and Melphalan as preparation for an allogeneic 
HSCT. Tacrolimus and Methotrexate (MTX) will be given to bone marrow transplant (BMT) and 
peripheral blood stem cell transplant (PBSCT) recipients for graft versus host disease (GvHD) 
prophylaxis. For umbilical cord blood transplant (UCBT) recipients, Tacrolimus and 
Mycophenolate mofetil (MMF) will be given for GvHD prophylaxis. 
 
Candidates for this trial will include patients with high risk or advanced forms of acute 
lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic myelogenous 
leukemia (CML), acute biphenotypic or undifferentiated leukemia, infant leukemia or 
myelodysplastic syndrome (MDS) for whom an allogeneic marrow transplant is indicated. 
 
Stem cell grafts will be unmodified marrow, peripheral blood stem cells derived from HLA- 
matched related donors or HLA-compatible unrelated donors, or umbilical cord blood from 
unrelated donors. Cord blood grafts will consist of two cord blood units. Candidates for 
transplant will be stratified according to their donor  types. Patients will be  monitored for 
engraftment, chimerism, incidence and severity of acute and chronic GvHD, regimen-related 
toxicity, characteristics of hematopoietic and immune reconstitution, as well as overall and 
disease-free survival. 
 
The first component of this trial is a phase I dose escalation study to determine the maximum 
tolerated dose (MTD) of Clofarabine, a novel agent included in the cytoreductive regimen. A 
total of 3 dose levels will be explored in this study. A standard 3 + 3 dose escalation design will 
be employed with 6 patients at each dose level. All patients will be conditioned for 
transplantation with Clofarabine at a dose of 20, 30 or 40 mg/m2/dose x 5, followed by standard 
transplant doses of thiotepa (10 mg/kg x 1 dose) and melphalan (70 mg/m2/dose x 2 doses). All 
patients will also receive Tacrolimus and MTX (for BMT and PBSCT recipients) or Tacrolimus 
and MMF (for cord blood transplant recipients) as GvHD prophylaxis. 
 
Following the dose escalation portion of the trial, the second phase of this trial will be the 
treatment of the subsequent patients with clofarabine at the MTD level if achieved early, or at 
the third and highest dose level if not. Six patients treated at the maximum tolerated dose and 
24 additional patients will be evaluated for the phase 2 component of the trial. 
 
A total of 30 patients will be accrued on the phase 2 portion of the trial. This will include six 
patients treated at the MTD during the phase I portion of the trial and an additional 24 patients 
treated at the MTD dose level. It is anticipated that the accrual will last 3 years. At the 
conclusion of the study, the 1-year disease-free survival probability can be estimated to within 
+/- 0.20 for the 30 patients on this study. 
 
In order to reduce patient risk, the study design includes early termination of any trial group in 
the event of excessive regimen related toxicity and grade 4 acute graft-versus-host disease. 


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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
 
 
PROTOCOL SCHEMA 
 
Phase 1 
 
The dose of Clofarabine will be escalated with 3 Dose Levels: 
- Dose Level 1: 
20 mg/m2/dose x 5 
- Dose Level 2: 
30 mg/m2/dose x 5 
- Dose Level 3: 
40 mg/m2/dose x 5 
Dose level 1: Clofarabine at 20 mg/m2/dose x 5 + THIO-MEL 
6 patients 
- 
If 0 or 1 of 6 patients experience dose limiting toxicity, proceed to dose level 
2. 
- 
If > 2 patients experience a dose limiting toxicity, re-evaluate the protocol. 
 
Dose level 2: Clofarabine at 30 mg/m2/dose x 5 + THIO-MEL 
6 patients 
- 
If 0 or 1 of 6 patients experience dose limiting toxicity, proceed to dose level 
3. 
- 
If > 2 patients experience a dose limiting toxicity, the MTD will be Dose Level 
1. 
 
Dose level 3: Clofarabine at 40 mg/m2/dose x 5 + THIO-MEL 
6 patients 
- 
If 0 or 1 of 6 patients experience dose limiting toxicity, this will be the dose 
level to be used for the rest of the trial. 
- 
If > 2 patients experience dose limiting toxicity, the MTD will be Dose Level 2. 
 
Phase 2 
6 patients treated at Dose Level of MTD (or dose Level 3 if MTD not reached) + 24 additional 
patients 
 
ROAD MAP 
 
 
 
MMF 
OR MTX 
Tacrolimus 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
DAYS 
-1 
0 
 
AGENT 
Clofarabine (CLO)* 
DOSE 
20, 30 or 40 mg/m2/dose x 5 
DAYS 
-9 to -5 
Thiotepa (THIO) 
Melphalan (MEL) 
10 mg/kg/dose x 1 
70 mg/m2/dose x 2 
-4 
-3 and -2 
+ 
Tacrolimus 
Dose per levels 
Start -3 
C 
L 
O 
C 
L 
O 
C 
L 
O 
C 
L 
O 
C 
L 
O
T 
H 
I 
O
M
E 
L 
M
E 
L 
UNMODIFIED 
SCT 


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IRB Protocol 
IRB#: 06-125 A(10) 
 
 
AND 
 
UCBT: 
 
For Adults and Children >12 yrs and > 50 kgs: 
 
Mycophenolate mofetil (MMF) 
1 gram IV bid 
Start -3 
 
 
For Adults and Teens >12 yrs but <50 kgs: 
 
Mycophenolate mofetil (MMF) 
For less than 12 yrs: 
Mycophenolate mofetil (MMF) 
15 mg/kg/dose po/IV bid 
20 mg/kg/dose po/IV bid to maximum 
Start -3 
Start -3 
of 1 gram IV bid 
OR 
BMT/PBSCT: 
Methotrexate (MTX) 
15 mg/m2/dose 
Day +1 
10 mg/m2/dose 
Days +3, +6, +11 
*All  patients  will  receive  hydrocortisone  prior  to  Clofarabine  in  an  attempt  to  prevent 
inflammation-induced liver enzyme elevation 
 
EXAMPLE OF ROAD MAP OF PREPARATION FOR BONE MARROW OR PERIPHERAL BLOOD 
STEM CELL TRANSPLANT 
 
SUNDAY 
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
-9 
hydrocortisone 
Clofarabine 
-8 
hydrocortisone 
Clofarabine 
-7 
hydrocortisone 
Clofarabine 
-6 
hydrocortisone 
Clofarabine 
-5 
hydrocortisone 
Clofarabine 
-4 
Thiotepa 
-3 
Melphalan 
Tacrolimus 
-2 
Melphalan 
-1 
0 
Unmodified 
Stem cell 
transplant 
1 
Methotrexate 
2 
3 
Methotrexate 
4 
5 
6 
Methotrexate 
7 
8 
9 
10 
11 
Methotrexate 


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IRB Protocol 
IRB#: 06-125 A(10) 
 
 
EXAMPLE OF ROAD MAP OF PREPARATION FOR UMBILICAL CORD BLOOD TRANSPLANT 
 
SUNDAY 
MONDAY 
TUESDAY 
WEDNESDAY 
THURSDAY 
FRIDAY 
SATURDAY 
-9 
hydrocortisone 
Clofarabine 
-8 
hydrocortisone 
Clofarabine 
-7 
hydrocortisone 
Clofarabine 
-6 
hydrocortisone 
Clofarabine 
-5 
hydrocortisone 
Clofarabine 
-4 
Thiotepa 
-3 
Melphalan 
Tacrolimus 
Mycophenolate 
-2 
Melphalan 
-1 
0 
Double unit 
cord blood 
transplant 
1 
2 
 
 
2.1 
OBJECTIVES AND SCIENTIFIC AIMS 
 
Primary Objectives: 
 
1. Phase I: To determine the MTD of clofarabine used in combination with melphalan and 
thiotepa as a conditioning regimen 
 
2. Phase II: To determine the 1 year disease-free survival (DFS) rate using this regimen. 
Secondary Objectives 
3. To evaluate the incidence and severity of non-hematologic toxicity and GvHD using this 
regimen. 
 
 
3.1 
BACKGROUND AND RATIONALE 
 
Myeloablative therapy followed by allogeneic HSCT is potentially curative therapy in high risk 
hematologic malignancies including: very high risk acute lymphoblastic leukemia (ALL) in first 
remission (slow response to induction therapy and/or Philadelphia Chromosome positivity),1-7 
ALL in second or greater remission,4,8-10 acute myeloblastic leukemia in first and second 
remission,11-15 chronic myelogenous leukemia,16-20 and myelodysplasia.21-28 Hematologic 
malignancies associated with a lower risk of relapse following allogeneic HSCT include AML in 
first complete remission (CR1), ALL-CR1, ALL-CR2, and CML in first chronic phase. Allogeneic 
HSCT in these diseases are associated with a disease-free survival (DFS) rate as high as 
70%1,2,8-10,16-19 
 
Standard cytoreduction prior to allogeneic HSCT for hematologic malignancies includes 
cyclophosphamide in combination with either total body irradiation (TBI) or busulfan. DFS rates 
of 40 to 70% are reported in patients with good risk malignancies (AML CR1, ALL CR1 or CR2, 
or CML in first chronic phase) using these combinations.1,2,8,10-12,16-19,29,30 The addition of 
thiotepa to standard cytoreduction with TBI and cyclophosphamide has resulted in disease-free 
survival rates of >70% in both children and adults with AML in CR1.11 Patients with advanced 
disease  have  a  significantly  higher  rate  of  recurrence  and    transplant-related  toxicity(10- 


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40%).8,31-35 At this center from 2000 to the present, 33 patients with advanced disease received 
unmodified stem cells following busulfan and melphalan for myeloablation.   The disease-free 
survival among these very high-risk patients is 39% (median follow up is 12 months). With 
advances in supportive care, post transplant relapse remains the major barrier to cure in the 
advanced leukemias. Accordingly, transplant conditioning regimens for the advanced 
leukemias should include agents with anti-leukemic as well as myeloablative and/or 
immunosuppressive properties. 
 
In 2003, Lacerda et. al36. reported a 50% overall survival rate in 14 patients with advanced 
hematologic malignancies transplanted with T-cell depleted bone marrow from haploidentical 
donors following cytoreduction with thiotepa, melphalan and fludarabine. Fludarabine is 
employed for its immunosuppressive effects to allow for the engraftment of a haplo-disparate 
graft. It is unlikely to add additional anti-leukemic activity. In the setting of a better-matched 
donor, this regimen may be improved upon by utilizing the potential anti-leukemic effect of a 
conventional graft and by replacing the fludarabine with a compound with more anti-leukemia 
activity. 
 
Studies of clofarabine as a single agent demonstrate significant anti-leukemic activity when 
administered in 5 daily doses. The primary toxicity of both clofarabine and thiotepa is 
hepatotoxicity.  The thiotepa will be given as a single 10mg/kg/dose, rather than the more 
common 5 mg/kg/dose x 2 doses in order to keep cytoreduction to a reasonable length without 
administering the drugs on the same day. The Italian group has used the single 10 mg/kg dose 
without any significant problems 37, 38.  The thiotepa will be followed by two daily doses of 
melphalan. 
 
3.2 Overview of Clofarabine 
 
Clofarabine 
([2-chloro-9-(2-deoxy-2-fluoro--D-arabinofuranosyl) 
adenine]; 
Cl-F-ara-A; 
CAFdA) is a rationally designed, second-generation purine nucleoside analogue. 
Clofarabine was designed as a hybrid molecule to overcome the limitations and incorporate 
the best qualities of both fludarabine (F-ara-A) and cladribine (2-CdA, CdA) both of which 
are currently approved by the FDA for treatment of hematologic malignancies.  Because 
clofarabine has a chloro group at the 2-position of adenine, its chemical structure is more 
closely related to CdA than to F-ara-A. Halogenation at the 2-position of adenine renders 
this class of compounds resistant to cellular degradation by the enzyme adenosine 
deaminase. Substitution of a fluorine at the C-2’-position of the arabinofuranosyl moiety of 
clofarabine increases its  stability in gastric  acid39,40 and decreases its susceptibility to 
phosphorolytic cleavage by the bacterial enzyme Escherichia coli purine nucleoside 
phosphorylase in the gastrointestinal tract.39 Both of these factors may lead to enhanced 
oral bioavailability. 
 
 
3.3 Clofarabine Mechanism of Action and Antitumor Activity 
 
Like most other deaminase-resistant nucleoside analogues (see Figure 1), clofarabine 
requires intracellular phosphorylation by deoxycytidine kinase (dCK) to its  active 
triphosphate form for cytotoxic and therapeutic activity.40,41 The cellular distribution and 
substrate specificity of the nucleoside-activating enzyme, dCK, are highly species-specific. 
The activity of dCK has been reported to be 10-fold greater in human bone marrow than in 


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IRB#: 06-125 A(10) 
 
 
mice.42    Thus, the toxicity of these nucleoside analogues is qualitatively the same among 
the various species, but the maximum tolerated dose (MTD) and dose level required to 
produce toxicity in a particular target organ may vary greatly. 
 
Figure 1: 
Structure of 2 Nucleoside Analogues and Clofarabine 
 
Clofarabine is a more efficient substrate for deoxycytidine kinase than CdA and the 
natural substrate deoxycytidine.43 Similar to the other purine nucleosides, clofarabine 
potently inhibits DNA synthesis by inhibiting both DNA polymerase  and ribonucleotide 
reductase.44 Clofarabine and CdA have demonstrated the unique ability to disrupt 
mitochondrial integrity, resulting in the release of pro-apoptotic proteins—cytochrome C 
and apoptosis-inducing factor.45 This may be a factor in the cytotoxic effects of 
clofarabine towards non-dividing lymphocytes. 
 
The precise mechanism of clofarabine, CdA, and F-ara-A on dividing and non-dividing 
cells is unknown. In dividing cells, the incorporation of the phosphorylated form of the 
halogenated nucleosides into DNA appears to be an important part of their activity in 
arresting cell division. Inhibition of DNA polymerase  and ribonucleotide reductase has 
been associated with their mechanism of cytotoxicity as well. Clofarabine has shown 
potent cytotoxic activity in a range of cell lines including CEM, K562, Hep2, and murine 
leukemia L1210.46 Therapeutic activity has also been shown in murine tumor models 
(P388 leukemia, colon 36, and mammary 16/c).47 Curative activity was noted in both 
advanced and early colon cancer in the tumor model colon 36.47 The compound has 
also shown potential in the treatment of solid tumors41,47  and nanomolar concentrations 
are cytotoxic to normal lymphocytes and macrophages, making it potentially useful in the 
treatment of autoimmune diseases.40 
 
3.4 Clinical Studies of Clofarabine 
 
In 1999, investigators at The University of Texas MD Anderson Cancer Center (MDACC) 
initiated the first Phase I, dose-escalation study (DM93-036) to evaluate safety, 
tolerability and maximum tolerated dose of clofarabine when administered to highly 
refractory and/ or relapsed adult patients with solid or hematologic malignancies. Doses 
ranged from 1.5 mg/m2 to 55 mg/m2 daily and were administered as a short intravenous 
infusion daily x 5 every 3 to 4 weeks up to a maximum of 12 cycles. According to the 
results published by MDACC, the dose limiting toxicity (DLT) in solid tumor patients was 
myelosuppression and the MTD was 2 mg/m2. For patients with acute leukemia, the 
DLT was hepatotoxicity and the MTD 40 mg/m2. Among 32 patients treated for acute 
leukemia, 2 achieved a complete response and 3 had a marrow complete response 
without platelet recovery, for an overall response rate of 16%.48 
 
A phase I study (ID99-383) of clofarabine in pediatric patients with hematologic 
malignancies was performed by MDACC. MDACC observed the DLT to be reversible 
hepatotoxicity (hyperbilirubinemia, and elevated transaminases) and skin rash observed 
at the 70 mg/m2 dose level. The MTD was determined to be 52 mg/m2/day x 5 days for 
pediatric patients with relapsed or refractory acute leukemia. This  was  the 
recommended dose for Phase II studies. The higher MTD observed in pediatric patients 
compared to adult patients was attributed to better renal and hepatic function in pediatric 


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patients. A total of 25 patients were treated. Five patients achieved  a  complete 
remission and 3 achieved a partial remission, for an overall response rate of 32%.49 
 
As of October 1, 2004, a total of 377 patients (245 adult and 132 pediatric patients) have 
been treated with clofarabine. Three hundred twenty one patients were treated for 
hematologic malignancies and 56 for solid tumors (including 17 patients that received 
the oral formulation). A summary of clinical studies conducted with clofarabine is listed 
in the table below.50 


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IRB#: 06-125 A(10) 
 
 
 
Protocol/ 
Status 
Sponsor 
Date 
Initiated 
Patient 
Population/ 
# Patients 
Treated 
Phase 
of Study 
Disease 
Description 
DM93-036 
Completed 
MDACC 
Feb 1999 
Adult 
51 patients 
Phase I 
Solid and 
hematologic 
Malignancies
DM99-25 
Completed 
MDACC 
Sep 1999 
Adult 
11patients 
Phase II 
CLL 
ID99-383 
Completed 
MDACC 
Aug 2000 
Pediatric 
25 patients 
Phase I 
Hematologic 
Malignancies 
ID00-038 
Completed 
MDACC 
May 2001 
Adult 
64 patients 
enrolled 
(62 treated) 
Phase II 
Acute Leukemia 
and 
Myelodysplastic 
Syndrome 
CLO-221 
Completed 
Genzyme 
Nov 2001 
Adult 
40 patients 
Phase II 
AML 
CLO-212 
Closed to 
accrual 
Genzyme 
Apr 2002 
Pediatric 
49 patients 
Phase II 
ALL 
CLO-222 
Closed to 
accrual 
Genzyme 
Jan 2002 
Pediatric 
35 patients 
Phase II 
AML 
CLO-151 
Ongoing 
Genzyme 
May 2002 
Adult 
26 patients 
Phase I 
Solid Tumors 
CLO-152 
Ongoing 
Genzyme 
July 2003 
Adult 
17 patients 
Phase I 
Oral formulation 
in Solid Tumors 
CLO-141 
Completed 
Genzyme 
June 2002 
Adult 
32 patients 
Phase 
I/II 
Clofarabine in 
combination 
with ara-C in 
AML, ALL, high 
risk MDS, CML 
blastic phase 
Expanded 
Access 
Genzyme 
Jan 2002 
Adult/Pediatric 
29 patients 
-- 
AML and ALL 


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IRB Protocol 
IRB#: 06-125 A(10) 
 
 
 
Efficacy and safety in pediatric patients with ALL were demonstrated in a single multi- 
center Phase II trial that enrolled 49 patients, CLO-212. Most patients had received 2 to 
4 prior regimens and 15/49 (31%) had undergone at least one transplant. The median 
age was 12 years. Clofarabine was given at a dose of 52 mg/m2, intravenously, over 2 
hours daily x 5 repeated every 2 to 6 weeks following recovery or return to baseline 
organ function. The study endpoints were the rate of complete response (CR) and the 
rate of complete response without platelet recovery (CRp).  Six patients (12%) achieved 
a CR and 4 patients (8%) achieved a CRp, and 5 patients (10%) achieved a PR. Of the 
15 responding patients, 6 had post-clofarabine bone marrow transplantation. Hence, 
response durations could not be determined. In the patients who were not transplanted, 
the response durations for CR were 43, 50, 82, 93+, and 160+ days; for CRp the 
response duration was 32 days.50 Twelve (24%) of the patients were treated here at 
MSKCC. 
 
 
CLO-222 was an identical Phase II trial in for pediatric patients with relapsed or 
refractory AML. Clofarabine was given at a dose of 52 mg/m2, intravenously, over 2 
hours daily x 5 repeated every 2 to 6 weeks following recovery or return to baseline 
organ function. The study endpoints were the rate of complete response (CR) and the 
rate of complete response without platelet recovery (CRp). A total of 35 patients were 
treated. No patient achieved a CR, 1 patient (2.9%) achieved a CRp, and 8 patients 
(22.9%) achieved a PR. Twelve of the 35 patients (34%) had post-clofarabine bone 
marrow transplantation. The responses of these 12 patients included 1 CRp, 6PR, 3 as 
not evaluable and 2 treatment failures. Time to transplant after clofarabine was 21 to 75 
days, indicating these patients proceeded to transplant very rapidly. Seven of the 12 
patients that underwent bone marrow transplant were still alive at last followup. Survival 
from treatment with clofarabine ranges from 16.4+ weeks to 93.6+ weeks and survival 
post transplant ranged from 0+ weeks to 64.4+ weeks.50 Ten of the 35 patients (28%) 
were treated here at MSKCC. 
 
 
The principal clofarabine toxicities were nausea, vomiting, hematologic toxicity, febrile 
neutropenia, hepatobiliary toxicity, infections and renal toxicity. Clofarabine can rarely 
produce systemic inflammatory response syndrome/capillary leak syndrome (SIRS), 
manifested by the rapid development of tachypnea, tachycardia, hypotension, shock, 
and multi-organ failure. Cardiac toxicity was characterized as transient left ventricular 
systolic dysfunction.50 
 
 
Clofarabine was approved by the Food and Drug Administration on December 28, 2004 
for use in children with relapsed and refractory acute lymphoblastic leukemia. 
 
The highest dose to be used in this trial is to be 40 mg/m2/dose, which is the MTD in 
adults with acute leukemia as defined by the Phase I study of clofarabine.  In this study, 
5 patients had a response. The doses received by these responders ranged from 11.25 
to 55 mg/m2/dose, with only one patient receiving more than 40 mg/m2/dose. 48 


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IRB#: 06-125 A(10) 
 
 
A Phase II trial of clofarabine at 40 mg/m2/dose was conducted in adults with refractory 
or relapsed leukemia.  Thirty two percent of patients achieved a CR, 2% achieved a PR 
and 15% achieved complete response with incomplete platelet recovery, for an overall 
response rate of 49%.49 
 
The phase I Study in pediatric patients used doses ranging from 11.25 to 70 mg/m2/dose. 
The MTD was defined as 52 mg/m2/dose. Five patients achieved a complete response at 
doses of 30 (n=1), 40 (n=2), and 52 mg/m2/dose (n=2). Seven other patients had a partial 
response or hematologic improvement; two patients received 40 mg/m2/dose, four patients 
received 52 mg/m2/dose and one patient received 72 mg/m2/dose.50 
 
GVHD Prophylaxis 
 
In the current trial, Tacrolimus and MTX (for BMT and PBSCT recipients) or Tacrolimus 
and MMF (for cord blood transplant recipients) will be utilized as GVHD prophylaxis. The 
gold standard of GVHD prophylaxis is cyclosporine (CSA) and methotrexate (MTX), which 
has been shown to reduce the incidence and severity of acute GVHD.52 The combination 
of tacrolimus and methotrexate has also demonstrated a reduction in the incidence and 
severity of acute GvHD in matched related and unrelated BMT recipients 53-54. In 1998, a 
multi-institutional study demonstrated that the incidence of grade II-IV acute GvHD was 
significantly lower in patients who received methotrexate in combination with tacrolimus 
compared to those given methotrexate in combination with CSA (31.9%  and 44.4%, 
respectively; p = .01). Grade III-IV acute GvHD was similar regardless of the prophylactic 
regimen (CSA: 17.1%; Tacrolimus: 13.3%) The incidence of chronic GvHD between the 
two groups was comparable (Tacrolimus: 55.9% and CSA: 49.4%; p = .8); however, a 
significantly higher proportion of patients in the CSA group had extensive chronic GVHD (p 
= . 03). Przepiorka et al55, reported grade II-IV acute GvHD in 34% (95% CI, 17% to 52%) 
of patients and grade III-IV acute GVHD in 17% (95% CI, 3% to 31%) following tacrolimus 
and methotrexate for unrelated unmodified HSCT. These results are consistent with other 
studies utilizing CSA and methotrexate in similar unrelated patient populations. 
 
 
A pilot study by Bornhauser et al56 treated 14 patients with MMF (1g po bid from day 1 to 
14) and CSA (started on day -1 to obtain levels of 200-300 ng/ml). They were followed for 
14 days after allogeneic stem cell transplantation from an HLA-compatible sibling. These 
14 patients were compared to a control group of 15 patients receiving MTX and CSA. 
Conditioning regimens consisted of busulfan and cyclophosphamide with or without 
etoposide. One patient’s conditioning regimen included TBI. There were no significant 
differences in engraftment, toxicity, or acute GVHD. 
 
A study by Niederwieser et al 57 used MMF in combination with cyclosporine to prevent 
rejection and GVHD in recipients of unrelated donor hematopoietic cell transplant after 
nonmyeloablative conditioning with low dose TBI and fludarabine. MMF was dosed at 
15mg/kg twice daily; MPA levels were not monitored. CSA was dosed to obtain levels of 
500ng/ml. It was tapered and then stopped on day 180 . There was a 12% rejection rate, 
which occurred primarily in MDS patients and those with low T cell counts in the graft. The 
21% rate of Grade II-IV acute GVHD and 30% rate of chronic GVHD were acceptable. 


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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
 
 
A prospective randomized trial by Bolwell et al 58 compared CSA and short course 
methotrexate  with  CSA  and  MMF  for  GVHD  prophylaxis.    The  preparative  regimen 
consisted of oral busulfan and cyclophosphamide. The group receiving MMF had 
significantly less mucositis and a shorter median time to neutrophil engraftment. The 
incidence of acute GVHD was similar in both groups, as was overall and relapse-free 
survival.   This study is limited by its small sample size. 
 
A second study has compared CSA + MTX and CSA+ MMF after myeloablative allogeneic 
stem cell transplant from an HLA-identical sibling 59. The preparative regimens consisted 
of high dose chemotherapy alone or in combination with TBI. Again, shorter time to 
neutrophil engraftment was demonstrated. There was no difference in overall survival, 
relapse rate, treatment-related mortality and acute or chronic GVHD. This study was 
retrospective and was limited by the lack of balance of parameters between the 2 groups. 
 
The combination of tacrolimus and MMF to be used in this study has been shown to be an 
effective salvage therapy for steroid-resistant GVHD.  60-61 
 
Also, preliminary data from Pavletic et al 62 suggest the combination of tacrolimus and 
MMF possesses a superior safety profile, is associated with a lower incidence of acute 
GVHD and earlier myeloid and platelet engraftment compared with a CSA and low dose 
MTX 
regimen. Twenty-three 
adults 
with 
hematologic 
malignancies 
underwent 
myeloablative matched related donor allogeneic stem cell transplant. Tacrolimus was 
given via continuous infusion of 0.03 mg/kg/day until day +60. MMF was started on day +1 
at a dose of 15mg/kg/dose po or IV twice daily until day +28. Outcomes were compared 
to 23 matched historical controls who received CSA/low dose methotrexate. The 
cumulative incidence of grades II to IV and grades III to IV acute GVHD in tacro/MMF vs 
CSA/MTX at 100 days post transplantation was 15% versus 62% (p=0.0003) and 6% 
versus 25% (p=0.025), respectively. The median time to neutrophil and platelet 
engraftment in study patients versus controls was 10 versus 15 days (p=0.001) and 13 
versus 19 days (p=0.11) respectively. There was no difference in overall survival or 6 
month cumulative incidence of relapse between the 2 groups. 
 
A pilot study of tacrolimus and MMF for GVHD prophylaxis by Osunkwo et al 63  was well 
tolerated and may be an effective alternative to methotrexate and corticosteroids. 
Tacrolimus was administered via continuous infusion of 0.03 mg/kg/day. MMF was started 
on day +1 at a dose of 15mg/kg/dose po or IV twice daily.  A total of 34 patients were 
enrolled, with age ranging from 0.5 to 21 years. Twenty-two patients had a malignant 
diagnosis. The donor of hematopoietic stem cells were umbilical cord blood (n=22), 
related bone marrow (n=6) and related peripheral blood stem cells (n=9). Conditioning 
regimens were diverse; 57% received myeloablative regimens, 43% received fludarabine- 
based reduced intensity regimens. Eleven patients (31%) received TBI. 
 
Twelve of 27 patients developed grade > II acute GVHD; 8 patients were grade III or IV. 
The probability of developing grade > II acute GVHD and grade III to IV acute GVHD was 
higher in patients receiving related PBSC compared to cord blood or related bone marrow. 
Failure to achieve target MPA levels before day 30 was associated with a higher 
probability of developing moderate to severe acute GVHD (100% vs 16.7% + 15.2%, 
p=0.02).   The probability of developing chronic GVHD was 38.1 + 19.7%.   Four of 21 


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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
 
 
patients developed limited chronic GVHD and no patients developed extensive chronic 
GVHD. 
 
Tacrolimus and MMF were well tolerated overall. Three patients (9%) had grade III to IV 
neurotoxicity (disorientation and leukoencephalopathy). Four patients (12%) developed 
grade III to IV nephrotoxicity; however, all were receiving concomitant nephrotoxins. 
 
STEM CELL GRAFT 
 
In the present study the stem cell graft can be obtained from one of three tissues: bone 
marrow, peripheral blood or cord blood. 
 
Bone marrow or peripheral blood stem cells can be collected directly from related or 
unrelated donor and infused directly to the patient. 
 
Cord blood is collected from healthy newborn babies and is being frozen. One cord 
blood collection is called a “cord blood unit.” Multiple reports 64-70 have documented that 
cord blood stem cells are capable of reconstituting hematopoiesis after intensive 
myeloablative therapy. However, the cell content of a single cord blood collection may 
be low for adult or larger patients. To overcome this limitation, double unit cord blood 
transplants were pioneered at the University of Minnesota.71 The results demonstrated 
that double unit UCBT can be performed safely in adults with improved engraftment and 
reduced TRM as compared to historical controls of single unit cord blood transplants. 
Interestingly, preliminary data also suggest that double unit UCBT may be associated 
with protection against relapse as  compared to single unit UCBT.72-73 Currently, all 
MSKCC protocols use double unit cord blood grafts, with the exception of 07-056, which 
is the BMT-CTN (0501) randomized study of single versus double cord blood unit grafts 
in pediatric patients with acute malignancies. 
 
4.1 
OVERVIEW OF STUDY DESIGN/INTERVENTION 
 
4.2 
Design 
 
This is a single arm phase I/II clinical trial to assess the antileukemic potential and 
relapse rate (efficacy), and peri-transplant morbidity and mortality (safety) in patients 
with high risk  or advanced hematologic malignancies following cytoreduction with a 
novel agent, clofarabine, in addition to thiotepa and melphalan as preparation for an 
allogeneic hematopoietic stem cell transplant. Tacrolimus and MTX (for BMT and 
PBSCT recipients) or Tacrolimus and MMF (for cord blood transplant recipients) will be 
given for GvHD prophylaxis. 
 
Candidates for this trial will include patients with high risk or advanced forms of ALL, 
AML, CML, acute biphenotypic or undifferentiated leukemia, infant leukemia or 
myelodysplastic syndrome for whom an allogeneic marrow transplant is clearly 
indicated. 
 
Stem cell grafts will be unmodified marrow, peripheral blood, or cord blood stem cells 
derived from HLA-matched related donors or HLA-compatible unrelated donors. 
Candidates for transplant will be stratified according to their donor types. 


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IRB#: 06-125 A(10) 
 
 
 
4.3 
Intervention 
 
The first component of this trial is a phase I dose escalation study to determine the 
maximum tolerated dose (MTD) of Clofarabine. A total of 3 dose levels will be explored 
in this study. A standard 3+3 dose escalation design will be employed with 6 patients at 
each dose level. All patients will be conditioned for transplantation with Clofarabine at a 
dose of 20, 30 or 40 mg/m2/dose x 5, followed by thiotepa (10 mg/kg x 1 dose) and 
melphalan (70 mg/m2/dose x 2 doses). All patients will also receive Tacrolimus and MTX 
(for BMT and PBSCT recipients) or Tacrolimus and MMF for cord blood transplant 
recipients)  as GvHD prophylaxis. 
 
The second component of this trial will be the treatment of the subsequent patients with 
clofarabine at the MTD level if achieved early, or at the third and highest dose level if the 
MTD is not reached. Six patients treated at the maximum tolerated dose and 24 
additional patients will be evaluated for the phase 2 component of the trial, for a total of 
30 patients. 
 
5.1 
THERAPEUTIC/DIAGNOSTIC AGENTS 
 
5.2 
Clofarabine (Clolar™) 
 
FORMULATION 
Clofarabine is formulated at a concentration of 1 mg/mL in sodium chloride (9 mg/mL), United 
States Pharmacopeia (USP) and water for injection, USP, qs to 1 mL. Clofarabine is supplied in 
a 1 mg/ml, 20 mL vial. The pH range of the solution is 4.0 to 7.0. The solution is clear with color 
ranging from colorless to yellow and is free from visible particulate matter. 
DOSE, ADMINISTRATION, AND STORAGE 
Vials containing undiluted Clofarabine for injection should be stored at controlled room 
temperature (15 to 30°C). Shelf-life studies of intact vials are currently ongoing. Clofarabine for 
injection should be filtered through a sterile 0.2 µm syringe filter and then further diluted with 5% 
dextrose injection USP or European Pharmacopoeia (EP) (D5W) or 0.9% sodium chloride 
injection USP or EP (normal saline [NS]) prior to IV infusion. The resulting admixture may be 
stored at room temperature, but must be used within 24 hours of preparation. Clofarabine will be 
administered by IV infusion over 2 hours daily for 5 consecutive days. Dosage of clofarabine will 
be based on a dose escalation format with cohorts of 3 to 6 patients.  The starting dose will be 
20  mg/m2/day  of  Clofarabine.      Dosage  will  escalate  to  30  mg/m2/day  and  finally  to  40 
mg/m2/day. To prevent drug incompatibilities, no other medications should be administered 
through the same IV line. 
 
TOXICITY 
 
1. Reversible hepatotoxicity is the major dose-limiting toxicity.  This is most commonly 
demonstrated by a transient elevation of transaminases.  Hyperbilirubinemia was less 
common. 
2. Myelosuppression 
3. acral erythema, dermatitis, pruritus 
4. capillary leak syndrome, systemic inflammatory response syndrome 
5. nausea, vomiting , diarrhea, abdominal pain 


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IRB#: 06-125 A(10) 
 
 
6. headache, fatigue, dizziness, somnolence,  tremor 
7. fever, rigors 
8. myalgias,  arthralgias 
9. anorexia, weight loss 
10. infection 
11. shortness of breath 
 
5.2 
Thiotepa (Thioplex®) 
 
FORMULATION: 
15 mg vial lyophilized powder; must be diluted prior to infusion. 
 
RECONSTITUTION DIRECTIONS: 
Add 1.5ml of Sterile Water for Injection to 15mg vial to yield 10mg/ml. Solutions, which are 
grossly opaque or contain a precipitate, should not be used. In order to eliminate haze, solutions 
should be filtered through a 0.22-micron filter prior to administration. 
 
STORAGE AND STABILITY: 
1. Store vials in refrigerator and PROTECT FROM LIGHT. 
2. Refrigerated: Prepare Infusion in NSS; stable for 14 days. 
3. Room temperature: Prepare Infusion in NSS; stable for 7 days 
 
PREPARATION: 
1. Standard IV fluid: NSS 
2. Final concentration range up to: 5mg/ml. 
3. IV piggyback volume: 500 cc 
4. Spike infusion bag with IMED 2200 tubing, primed with non-chemo containing fluid (ie; NSS). 
 
CLINICAL CONSIDERATIONS: 
Hydration: NA 
TOXICITY 
1. Myelosuppression is the major dose-limiting toxicity 
2. Nausea, vomiting, diarrhea, anorexia, abdominal pain 
3. Cutaneous erythema and bronzing 
4. CNS toxicity manifested by headache, mild cognitive dysfunction, disorientation, 
confusion, irritability, and bizarre behavior. 
5. Fever 
6. Mucositis 
7. Transient hepatic transaminase elevations are occasionally seen, but rarely severe. 
8. Amenorrhea and impaired spermatogenesis 
9. Anaphylaxis 
10. Interstitial pneumonitis 
11. Alopecia 
 
INCOMPATIBILITIES: cisplatin, filgrastim (G-CSF), vinorelbine 


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IRB#: 06-125 A(10) 
 
 
5.3 
Melphalan (Alkeran™) 
 
FORMULATION:  Melphalan is supplied as a freeze-dried powder containing 50 mg melphalan 
and 20 mg povidone per vial. A sterile diluent is provided for reconstitution. 
 
RECONSTITUTION DIRECTIONS:  The sterile diluent contains sodium citrate 0.2 g, propylene 
glycol 6 ml, ethanol (96%) 0.52 ml, and water for Injection for a total of 10 ml. 
 
STORAGE AND STABILITY: 
• 
Store vials at room temperature. 
• 
Protect from light. 
• 
Do not refrigerate the reconstituted product; a precipitate forms if  the reconstituted 
solution is stored below 410 F. 
• 
Reconstituted solutions must be further diluted immediately, discard unused portion. 
• 
Drug administration must be completed within 60 minutes of initial reconstitution. 
 
PREPARATION: Reconstitute by rapidly injecting 10 ml of the supplied diluent into the vial to 
yield a final concentration of 5 mg/ml. Shake vigorously until the solution is clear. Immediately 
dilute the dose to be administered in 0.9% Sodium Chloride, USP, to a concentration no greater 
than 0.45 mg/ml. Refrigerated storage of the reconstituted product results in precipitation. 
 
CLINICAL CONSIDERATIONS: 
Hydration: 
Pre-Dose – 2x maintenance for 2 hours 
Post-Dose – 1.5x maintenance for 2 hours 
 
TOXICITY 
1. myelosuppression 
2. 
hemolytic anemia 
3. nausea, vomiting, diarrhea 
4. mucositis 
5. hepatotoxicity including veno-occlusive disease (rare) 
6. syndrome of inappropriate antidiuretic hormone (SIADH) induced hyponatremia 
7. pulmonary fibrosis, interstitial pneumonitis 
8. alopecia 
9. fever 
10. hypersensitivity reactions 
11. renal dysfunction 
12. sterility 
13. secondary leukemia 
14. seizures 


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IRB Protocol 
IRB#: 06-125 A(10) 
 
 
6.1 
CRITERIA FOR SUBJECT ELIGIBILITY 
 
6.2 
Subject Inclusion Criteria 
 
▪ Diagnosis and Status 
 
DISEASE 
DISEASE STATUS 
AML 
CR1 
Poor risk 
[not t(15,17), not inv 16, not 
t(8,21)] 
OR 
not candidates for TBI* 
OR 
Any Infant AML in CR1 
CR2 
All patients 
> CR2 or 
Relapse / 
Refractory 
All patients 
Blast percentage >5% and < 25% 
in BM at time of SCT 
ALL 
CR1 
Poor risk 
- t(9;22), t(4;11) 
- no CR after 7-28 days 
of induction* 
OR 
not candidates for TBI* 
OR 
Any Infant ALL in CR1 
CR2 
All patients 
> CR2 or 
Relapse / 
Refractory 
All patients 
Blast percentage >5% and < 25% 
in BM at time of SCT 
AUL OR ABIPL 
SAME as above 
CML 
>1stCP 
All patients 
MDS 
High Risk 
Primary MDS 
Stage: > RAEB1 
High Risk 
Secondary MDS 
Any stage 
All patients 
JMML 
All patients 
 
 
*The patients’ initial diagnostic material must be submitted and made available for the 
confirmation of the patients’ diagnosis and status at the time of transplant. 
 
 
▪ 
Patients must be less than 55 years of age. Patients over the age of 55 
years may be considered on a case-by-case basis. There is no lower age 
restriction. 
▪ 
Patients may be male or female and of any ethnic background. 


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IRB Protocol 
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▪ 
Patients  must  have  adequate  cardiac,  hepatic,  renal,  and  pulmonary 
function as defined below: 
• 
Cardiac: a left ventricular ejection fraction at rest of >50% or a 
fractional shortening of > 29% 
• 
Hepatic: SGOT of less than <2x upper limits of normal, and serum 
bilirubin < 1.5 m/dl unless the liver is involved with disease. 
• 
Renal: Serum creatinine within normal range for age or creatinine 
clearance of >60 ml/min/1.73 square meter 
• 
Pulmonary: asymptomatic with no prior risk factors or if 
symptomatic, diffusion capacity of >50% of predicted, corrected 
for hemoglobin. 
▪ 
Patients may have had a prior allogeneic or autologous stem cell 
transplant. Interval between primary and secondary transplant must be >6 
months. 
▪ 
Patients or their guardians must be able to understand the nature and risk 
of the proposed study, and be able to sign informed consent. 
 
 
6.3 
Donor Inclusion Criteria 
 
 
All donor and recipient pairs will be tested by DNA typing methods at high-resolution 
level for HLA – A, B, C, and DRB1. 
 
HLA-compatible Related donors 
• 
Patients who have an HLA-matched related donor are eligible for entry on 
this protocol. This will include a healthy related donor who is genotypically or 
phenotypically matched at least 7 or 8 of the A, B, C, and DRB1 alleles. 
 
HLA-compatible Unrelated donors 
• 
Patients who do not have an available healthy related HLA-matched donor as 
defined above but have an unrelated donor who is HLA-matched at 
o all  8 of 8 alleles matched 
o  FOR PATIENTS < 18 years only: 7 or 8 alleles matched with the 
mismatch at only one A, B, C, or DRB1 allele. 
 
HLA-compatible Unrelated Cord Blood Units 
• 
2 UCB units will be selected according to current MSKCC unit selection 
algorithm. HLA testing to be done using molecular techniques: A and B 
antigen to at least intermediate resolution and DRB1 allele at high-level 
resolution. 
• 
Each unit will be at least 4/6 HLA-A,B antigen and DRB1 allele matched 
with the recipient 
• 
In addition, each unit will have a cryopreserved dose of at least 1.5 x 107 
total nucleated cells/recipient body weight (TNC/kg). 
• 
Units with attached segments for confirmatory typing will be given 
preference. 


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Donors who are seropositive for HIV1/2 or HTLV I or II and female patients who are pregnant or 
breast-feeding will not be eligible for this study. 
 
 
6.4 
SubjectExclusion Criteria 
 
o Karnofsky/Lansky score <70% (APPENDIX A) 
o Female patients who are pregnant or breast-feeding 
o Active CNS disease 
o Active uncontrolled viral, bacterial, or fungal infection. 
o Use of hydroxyurea within 2 week prior to initiation of cytoreduction 
o Patients whose peripheral  blast count doubles in two  weeks 
o Patients seropositive for HIV1/2 or HTLV I or II 
o Patients who have undergone a prior allogeneic or autologous stem cell transplant within 
the previous 6 months 
 
7.0 
RECRUITMENT PLAN 
 
One of the BMT attendings will see the patient in consultation; typically, this is the outpatient 
BMT attending. As part of the consultation, the BMT attending will present the patient with 
the risks and benefits of different types of cytoreduction and transplants. The BMT attending 
will then recruit patients who fulfill the eligibility criteria as listed in Section 6.0 for this study. 
After confirmation of patient eligibility by the medical or pediatric clinical trials office, one of 
the participating investigators authorized to obtain consent will obtain informed consent. A 
copy of the signed informed consent will be placed in the chart, as well as in the adult and 
pediatric clinical trials office. 
 
 
8.1 
PRETREATMENT EVALUATION 
 
8.2 Pretreatment evaluation of the patient 
 
In general, the following tests must be performed within 30 days of initiating cytoreduction: 
 
1. Complete history, review of systems, and physical exam. 
2. Bone marrow aspirate for morphology, surface markers (if warranted), cytogenetics, 
FISH and molecular studies (when warranted) for documentation of disease status. 
3. Spinal or intra-Ommaya tap in patients with acute leukemia at risk for CNS disease. 
4. Complete blood count and differential, comprehensive panel (as defined by HICFA), and 
for patients not in remission, LDH, serum uric acid and phosphorous 
5. Coagulation profile 
6. Type and Screen 
7. EKG 
8. Echocardiogram or MUGA (if clinically indicated) 
9. Chest x-ray (Chest x-ray need not be performed if the patient has had a chest CT scan 
to evaluate pulmonary disease and the location of the central line tip is evident.) 
10. Assessment of performance status 
11. Blood  will  be  tested  for  antibodies  for  CMV  (IgG  and  IgM),  HIV-1,2,  HTLV1,  2, 
toxoplasmosis, Hep B, Hepatitis C, Hepatitis B surface antigen, Herpes Simplex, Herpes 


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Zoster, Epstein-Barr Virus, syphilis, as well as pcr testing for HIV 1-2, hepatitis C, and 
West Nile Virus PCR 
12. Pregnancy test for females of childbearing age. 
 
The following tests may be performed within 90 days of initiating cytoreduction as long as 
there has been no interval therapy given for the underlying disease and there has been no 
change in the patient’s clinical status: 
 
1. Dental evaluation 
2. Pulmonary function testing when feasible 
 
Research Studies for UCBT recipients: 
1.  Within approximately 60 days preceding cytoreduction, 3 green top tubes should be sent 
to Dr. Katharine Hsu’s lab in Z745D. 
 
8.3 Pretreatment evaluation of the donor 
 
Family Donor 
 
Any consenting healthy family donor who is HLA compatible with the recipient will be given 
highest priority as a potential donor for marrow or PBSC transplant. The donor (or the donor’s 
parents for minors) must also provide signed informed consent for a marrow harvest under 
general anesthesia, or alternatively, to receive a 5-day course of G-CSF followed by  2-3 
leukaphereses. 
 
In preparation for the stem cell donation, the donor will provide informed consent and then 
undergo the following evaluation. In general, the following tests must be performed within 30 
days of initiating cytoreduction: 
 
1) Complete history, review of systems, and physical exam. 
2) Complete blood count and differential 
3) Comprehensive panel (as defined by HICFA) 
4) Coagulation profile 
5) Type and Screen 
6) EKG and chest x-ray (if clinically indicated) 
7) Serum will be tested for antibodies for CMV (IgG and IgM), HIV-1,2, HTLV1, 2, 
toxoplasmosis, Hep B, Hepatitis C, Hepatitis B surface antigen, Herpes Simplex, Herpes 
Zoster, Epstein-Barr Virus, VDRL 
8) West Nile Virus PCR, Hepatitis C PCR and HIV PCR 
9) Pregnancy test for females of childbearing age. 
 
Before admission for bone marrow harvest (only  in context of BMT and not PBSC), it is 
recommended that all donors at the discretion of the transplant physician, or at least all female 
donors be referred for autologous blood donation. The autologous blood product will be held in 
reserve for the donor, to be transfused in lieu of allogeneic blood products (unless emergency 
indications dictate otherwise) at the completion of the marrow harvest. Because of small donor 
size in many pediatric cases, autologous blood donation will be recommended at the discretion 
of the pediatric bone marrow transplant attending physician. 


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Memorial Sloan-Kettering Cancer Center 
IRB Protocol 
IRB#: 06-125 A(10) 
 
 
Unrelated donor 
 
Unrelated donors will undergo preparation for marrow or peripheral blood stem cell collection as 
per the standards of the National Marrow Donor Program (NMDP). The donor will undergo 
pretransplant work-up and will sign consent for either G-CSF administration followed by 
leukapheresis or for bone marrow harvest at the donor center, also according to standard 
procedure as dictated by the NMDP and institutional guidelines. 
 
Unrelated cord blood unit 
 
Units will be selected according to the current MSKCC unit selection criteria, under the direction 
of Dr. Juliet Barker and Dr. Andromachi Scaradavou. Infectious disease testing and eligibility 
assignment will be reviewed by the above physicians. 
 
 
9.0     TREATMENT/INTERVENTION PLAN 
 
Patients will be admitted the Pediatric or Adult Bone Marrow Transplant Service. Patients will be 
maintained in reverse isolation as per the BMT clinical care guidelines. Prior to the 
administration of the pretransplant cytoreductive regimen, a double or triple lumen central 
venous catheter will be inserted under general or local anesthesia. A separate consent form will 
be obtained for this procedure. 
 
9.1 
Cytoreductive regimen and transplant 
 
1. Clofarabine 
Clofarabine will be administered via a 2 hour intravenous infusion at a dose of 
20, 30 or 40mg/m2/day for 5 doses (days  -9, -8, -7, -6. -5). 
 
Clofarabine will be administered after premedication with hydrocortisone. 
Hydrocortisone was added to the amended protocol in an attempt to prevent hepatic 
inflammation and elevation of transaminases. 
 
Hydrocortisone will be dosed at 50 mg/m2 dose IV once daily pre-clofarabine 
(maximum 100 mg). 
 
2. Thiotepa 
Thiotepa will be administered via a 4 hour intravenous infusion at a dose of 
10mg/kg/day for 1 dose (day –4). Dose should be adjusted if patient is > 125% ideal 
body weight and should be calculated on adjusted ideal body weight per MSKCC 
standard of care guidelines. 
. 
3. Melphalan 
Melphalan will be administered via a 30 minutes infusion at a dose of 
70mg/m2/day for 2 doses (days -3, and -2). Dose should be adjusted if patient is > 125% 
ideal body weight and should be calculated on adjusted ideal body weight per MSKCC 
standard of care guidelines. 


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4.  Day 0: patients will receive a T-cell replete allogeneic BMT or PBSCT or an allogeneic 
double unit CB graft. 
 
 
Phase I 
 
The dose of Clofarabine will be escalated with 3 Dose Levels: 
- Dose Level 1: 
20 mg/m2/dose x 5 
- Dose Level 2: 
30 mg/m2/dose x 5 
- Dose Level 3: 
40 mg/m2/dose x 5 
Dose level 1: Clofarabine at 20 mg/m2/dose x 5 + THIO-MEL 
6 patients 
- 
If 0 or 1 of 6 patients experience dose limiting toxicity, proceed to dose level 
2. 
- 
If > 2 patients experience a dose limiting toxicity, re-evaluate the protocol. 
 
Dose level 2: Clofarabine at 30 mg/m2/dose x 5 + THIO-MEL 
6 patients 
- 
If 0 or 1 of 6 patients experience dose limiting toxicity, proceed to dose level 
3. 
- 
If > 2 patients experience a dose limiting toxicity, the MTD will be Dose Level 
1. 
 
Dose level 3: Clofarabine at 40 mg/m2/dose x 5 + THIO-MEL 
6 patients 
- 
If 0 or 1 of 6 patients experience dose limiting toxicity, this will be the dose 
level to be used for the rest of the trial. 
- 
If > 2 patients experience dose limiting toxicity, the MTD will be Dose Level 2. 
 
Phase II 
6 patients treated at Dose Level of MTD (or dose Level 3 if MTD not reached) + 24 additional 
patients 
 
 
9.2 Graft versus host disease prophylaxis 
 
BONE MARROW AND PERIPHERAL BLOOD STEM CELL TRANSPLANT 
RECIPIENTS 
 
1. Tacrolimus 
Tacrolimus will be started day –3 at an approximate dose of 0.03 mg/kg/24 hours as a 
continuous infusion. The dose of tacrolimus will be adjusted to achieve a level between 5 
and 15 ng/ml. Once oral medications are tolerated, patients may be converted to oral 
tacrolimus at 3-4 times the current IV dose divided every 8 to 12 hours. 
 
For recipients of matched related transplants without GvHD, tacrolimus will be continued 
for approximately 60 days and will then be tapered by approximately 10% per week. It 
will be discontinued at approximately 6 months post-transplant. 


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For recipients of unrelated or mismatched related transplants without GvHD, tacrolimus 
will be continued for approximately 6 months and will then be tapered by approximately 
5% per week.  It will be discontinued at approximately 1 year post-transplant. 
 
 
In case of major toxicity, such as CNS symptomatology, tacrolimus may be discontinued 
earlier and substituted with other immunosuppressive medications as per clinical care 
guidelines. 
 
The immunosuppressive regimens on this protocol may conform to current practice 
where additional agents may be introduced in addition to Tacrolimus. 
 
 
2. Methotrexate 
 
A. Methotrexate (MTX) Methotrexate will be given at a dose of 15 mg/m2/dose on day 
+1 post transplant and 10 mg/m2 intravenously on days +3, +6 and +11 to recipients of 
related or unrelated donor bone marrow or peripheral blood stem cell transplants BUT 
not to Cord Blood transplant recipients. 
 
Methotrexate dose adjustment will be as follows: 
 
a. Creatinine   < 1.5 
100% 
1.6-1.8 
50% 
1.9-2.0 
25% 
> 2.0 
hold 
 
b. Bilirubin 
< 2.0 
100% 
2.1-3.0 
50% 
3.1-5.0 
25% 
> 5.0 
hold 
 
c. For patients with severe mucositis > grade 3, decrease or hold Methotrexate as 
clinically indicated. 
 
B. Methotrexate will be given at a dose of 5 mg/m2/dose intravenously on day +1, days 
+3, +6 and +11 post transplant to all adult recipients of related or unrelated donor bone 
marrow or peripheral blood stem cell transplants BUT not to Cord Blood transplant 
recipients. 
 
If Methotrexate is to be modified or discontinued, GvHD prophylaxis may conform to current 
practice and additional agents can be introduced. 


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IRB Protocol 
IRB#: 06-125 A(10) 
 
 
CORD  BLOOD TRANSPLANT RECIPIENTS 
 
1. Tacrolimus 
Tacrolimus will be started day –3 at an approximate dose of 0.03 mg/kg/24 hours as a 
continuous infusion. The dose of tacrolimus will be adjusted to achieve a level between 5 
and 15 ng/ml. Once oral medications are tolerated, patients may be converted to oral 
tacrolimus at 3-4 times the current IV dose divided every 8 to 12 hours. 
 
For recipients of umbilical cord blood transplants without GvHD, tacrolimus will be 
continued for approximately 6 months and will then be tapered 5% per week. It will be 
discontinued at approximately 1 year post-transplant. 
 
 
In case of major toxicity, such as CNS symptomatology, tacrolimus may be discontinued 
earlier and substituted with other immunosuppressive medications as per clinical care 
guidelines. 
 
The immunosuppressive regimens on this protocol may conform to current practice 
where additional agents may be introduced in addition to Tacrolimus. 
 
2. Mycophenolate mofetil  (MMF) 
 
MMF will be started on day -3 to +45 then tapered. 
 
• 
Dose is 1 gram IV q8 hours for adults and children who are both >12 years and >50 kg. 
Adults and teens >12 years but <50 kgs, give 15 mg/kg IV q8 hours. If less than 12 
years, give 20mg/kg IV q8 hours to a maximum of 1 gram IV q8 hours. MMF from day -3 
to hospital discharge (must be at least day +14) should be IV. In preparation for 
discharge, switch to oral route (CellCept or generic mycophenolate mofetil and same 
dosing as IV) and round to tablet size. 
• 
No dose adjustments for renal or liver disease are needed routinely unless severe organ 
dysfunction. Measurements of serum blood levels of MMF should be done routinely as 
per current MSKCC guidelines to guide assessment of potential MMF toxicity in the 
event of unexpected myelosuppression. If patient > +28 days and slow engraftment, 
consideration can be made to reduce dosing to q12 after discussion with PI or co-PI. 
See MSKCC guidelines for further information about MMF levels. 
• 
Taper to 500 mg TID (or 7.5 mg/kg/dose if < 50 kg) on day +46 and continue to +70. 
Then taper to 250mg TID (3.75 mg/kg/dose) till day 100 and stop. 
• 
If the patient cannot tolerate therapeutic doses of CSA due to renal dysfunction, do not 
taper MMF on day +46. 
• 
If the patient has acute GVHD requiring systemic therapy, MMF should only be tapered 
on days 46 and 70, or stopped on days 100, if control of GVHD has been obtained (eg 
resolution of skin rash, vomiting, and diarrhea). 
• 
If persistent disease or disease progression occurs prior to day 100, early taper or 
cessation of MMF can be considered with close observation for acute GVHD. 
 
For patients with active GvHD, tacrolimus and MMF may be continued for longer periods 
of time according to clinical care guidelines. 


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IRB#: 06-125 A(10) 
 
 
9.3 
Stem Cell Transplant 
 
BMT 
Bone marrow is harvested from the donors in the Operating Room according to standard 
BMT guidelines. The marrow is delivered to the Cytotherapy Laboratory. In the Cytotherapy 
Laboratory, cell counts will be performed. Red cells or Plasma will be depleted in case of 
ABO mismatch according to standard BMT guidelines. Volume depletion will be performed in 
Pediatric patients to obtain a final volume of 10-12 ml/Kg of recipient’s weight. 
 
PBSCT 
Peripheral blood stem cells are collected from the donors in the Donor Room according to 
standard BMT guidelines. The peripheral blood is delivered to the Cytotherapy Laboratory. In 
the Cytotherapy Laboratory, cell counts will be performed. Red cells or Plasma will be 
depleted in case of ABO mismatch according to standard BMT guidelines. Volume depletion 
will be performed in Pediatric patients to obtain a final marrow volume of 10-12 ml/Kg of 
recipient’s weight. 
 
The goal of stem cell collection is > 2 x 106 CD34+ cells per kilogram patient weight. As this 
value cannot be obtained while the patient is in the OR, the harvesting physician will aim to 
collect at least 2 x 108 total nucleated cells per kilogram patient weight. 
 
UCBT 
• 
UCB grafts will be received at the MSKCC Cytotherapy Laboratory prior to the start of 
the preparative regimen. 
• 
Units will be thawed by and released from the Cytotherapy Laboratory according to 
current standards of practice (SOPs) and release criteria. Units will undergo albumin dilution, 
except in case of small children with wt less than 20 kg, when the cord blood units will be 
washed to remove the cryoprotectant, and the stem cells will be resuspended in appropriate 
volume (for the wt of the patient). As per standard practice, ABO blood group, total nucleated 
cells (TNC), CD34+ and CD3+ cell number and viability, sterility and colony-forming units 
(CFU) will be measured post-thaw. 
A small amount of cells (<5% of the post-thaw TNC of each unit) will be used for laboratory 
research studies. 
• 
Units should be administered immediately upon arrival to the patient care unit by IV 
infusion by the nursing staff under supervision of a BMT attending physician. UCB infusion 
nursing guidelines should be followed. 
• 
Units should be given consecutively as per nursing guidelines. 
• 
Pre-medication should include acetaminophen and diphenhydramine or hydroxyzine 
dosed as appropriate for patient age. Do not give Hydrocortisone. Anti-emetics may be 
necessary and can be given prn. 
• 
IV hydration equal to twice standard maintenance should be given for 6 hours prior to 
and at least 12 hours post UCB graft infusion with close monitoring of fluid balance, per 
MSKCC guidelines. 
• 
IV Hydralazine should be used to treat hypertension associated with UCB infusion, if 
necessary. 


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Following  infusion  the  bag  and  tubing  from  each  UCB  unit  must  be  submitted  to  the 
Microbiology Laboratory. Specimen for Diagnostic Molecular Pathology will be forwarded by 
the personnel in the Cytotherapy Laboratory. 
 
GROWTH FACTOR (G-CSF) AFTER SCT 
G-CSF will be given to all patients, regardless of transplant type, from day +7 if absolute 
neutrophil count (ANC) is < 500. Continue until ANC is >2000 for 3 consecutive days. GCSF 
may be given earlier post transplant if clinically indicated at the discretion of the Attending 
Physician. G-CSF doses will be rounded according to institutional guidelines. 
 
10.0 EVALUATION DURING TREATMENT/INTERVENTION 
 
10.1 
Prophylaxis against Infection 
Patients will be treated according to the allogeneic BMT standard of care guidelines and will be 
given prophylaxis against 1) Pneumocystis carinii, 2) Herpes simplex and Herpes Zoster, and 3) 
fungal infections. Patients  who are CMV sero-negative pre-transplant should receive CMV 
seronegative blood products, if possible. Patients with CMV viremia will be treated according to 
the allogeneic BMT standard of care guidelines with ganciclovir or foscarnet. 
 
10.2 
Prophylaxis against Graft versus Host Disease 
 
All patients will receive Tacrolimus and MTX (for BMT and PBSCT recipients) or Tacrolimus and 
MMF (for cord blood transplant recipients) as GvHD prophylaxis as follows: 
 
Tacrolimus will be started day –3 at a dose of 0.03 mg/kg/24 hours as a continuous infusion. 
Trough tacrolimus levels will be drawn 30 minutes prior to the dose in patients receiving divided 
doses. In patients receiving continuous infusion tacrolimus, steady state levels can be drawn at 
any time. Care must be given not to draw levels through IV tubing that has been exposed to 
tacrolimus. Plasma levels will be determined by whole blood assay. Tacrolimus dosing will be 
monitored as clinically appropriate. Trough levels or steady state levels will be adjusted to try to 
keep tacrolimus levels between 5-15 ng/ml. Adjustments of tacrolimus levels are to be approved 
by the supervising BMT  Attending.  Tacrolimus dose may be decreased in case of 
hyperbilirubinemia, unexplained elevation of BUN and creatinine, or other major toxicity felt to 
be related to this drug. Once the patient can tolerate oral medications, tacrolimus will be 
converted to an oral form at four times the current IV dose divided every 8 to 12 hours. In case 
of major toxicity (eg CNS neurotoxicity documented by MRI), tacrolimus should be discontinued. 
Patients may be re-challenged at a later date if thought clinically appropriate. Substitution with 
other immunosuppressive medications as prophylaxis must only be done in consultation with 
the Principle Investigator. 
 
The immunosuppressive regimens on this protocol may conform to current practice where 
additional agents may be introduced in addition to Tacrolimus. 
 
The duration of tacrolimus is dependent on the type of donor. Patients whose donors were 
HLA-matched related donors will continue tacrolimus until day approximately +60. As long as 
there are no signs or symptoms of GVHD, the dose will be tapered by approximately 10% per 
week and discontinued at approximately 6 months post-transplant 


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Patients whose donors were unrelated donors or mismatched related donors will continue 
tacrolimus until approximately day +180. As long as there are no signs or symptoms of GVHD, 
the dose will be tapered by approximately 5% per week and discontinued at approximately 1 
year post-transplant. 
 
Mycophenolate mofetil (MMF) will be started on day –3 and continued through day +45 then 
tapered. The dose is 1 gram IV q8 hours for adults and children who are both >12 years and 
>50 kg. Adults and teens >12 years but <50 kgs, give 15 mg/kg IV q8 hours. If less than 12 
years, give 20mg/kg IV q8 hours to a maximum of 1 gram IV q8 hours. Subsequently, MMF may 
be administered orally once other oral medications are tolerated. The dosing is the same as the 
IV formulation but will be rounded to the nearest tablet size. No dose adjustments for renal or 
liver disease are required. MMF will be tapered after day +45 by 50%, as long as there are no 
signs or symptoms of acute GVHD present. The aim is to be off MMF by day 100 in the 
absence of uncontrolled GVHD. If the patient has acute GVHD requiring systemic therapy by 
day +45, MMF may be stopped 7 days after control of GVHD (e.g. resolution of skin rash, 
vomiting, and diarrhea). 
 
 
Methotrexate (MTX) will be given at a dose of 15 mg/m2/dose on day +1 post transplant and 10 
mg/m2 intravenously on days +3, +6 and +11 to recipients of related or unrelated donor bone 
marrow or peripheral blood stem cell transplants BUT not to Cord Blood transplant recipients. 
 
 
10.2 
CNS leukemia 
Patients with ALL, those with M4/M5 AML, and those transplanted with AML in bone marrow 
relapse may receive intrathecal infusions of cytarabine at monthly intervals, beginning 
approximately 2 months posttransplant, and thereafter on a monthly basis for a total of 5 doses. 
Patients with a prior history of CNS leukemia may receive 11 doses of IT cytarabine from 
approximately 2 until 12 months post-transplant. Intrathecal Cytarabine will be dosed according 
to age: 
AGE 
DOSE 
<1 year 
20 mg 
1 to <2 years 
30 mg 
2 to <3 years 
50 mg 
> 3 years 
70 mg 
 
 
10.4 
Transfusions 
Following initiation of the pretransplant cytoreduction, all blood products for transfusion, with the 
exception of the stem cell graft, will be irradiated to 3,000 cGy to inactivate lymphocytes capable 
of initiating lethal GvHD. Blood products are irradiated in the blood bank, using a cesium 
gamma emitter. Patients who are Cytomegalovirus (CMV)-seronegative pretransplant will not be 
permitted to receive any CMV-seropositive blood products, except in an emergency. Platelets 
will be administered for clinical evidence of active hemorrhage. To minimize bleeding, platelets 
will be transfused prophylactically in order to maintain a platelet count greater than 20,000/mm3. 
Posttransplantation, the marrow donor or selected family donors will be utilized, whenever 
possible, as platelet donors. Packed irradiated red blood cells will be administered as clinically 
indicated. 


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10.5 
Prophylaxis against metrorrhagias 
All post-pubertal females will receive hormonal therapy to suppress menses. This therapy may 
include Ovral™ (Ethinyl estradiol + norgestrel) daily at a dose of one daily tablet orally, estrogen 
patch +/- oral progesterone, or another regimen which has been successful for the patient. 
Hormonal suppression will continue throughout the transplant until the platelet count is above 
50,000. The administration of hormonal therapy will be determined based on the patient’s 
clinical status. 
 
10.6 
Nutritional Support 
The physician will monitor nutritional status, and high-calorie parenteral alimentation will be 
introduced as needed. Vitamin supplements will be administered as clinically indicated. 
 
10.7 
Post transplant evaluation* 
During the first 100 days or 3 months post transplant: 
1. Regular physical examination as per standard of care until discharge, CBCs at least 3x 
per week until discharge. 
2. Acute GVHD will be assessed and graded according to MSKCC criteria. To determine 
the severity of acute GVHD data will be collected approximately every 2 weeks for the 
first 3 months (Appendix B). 
3. Blood chemistries, including liver function tests, will be performed at least twice weekly, 
until discharge after discharge, 
4. Physical examination, CBC, and blood chemistries, including liver function tests will be 
obtained every 2-4 weeks, or as clinically indicated. 
5. Bone marrow aspiration with cytogenetic analysis for chimerism and disease status (if 
indicated) will be performed at approximately 1 month and 3 months posttransplant. 
6. Recipients of cord blood grafts will undergo BM evaluation by aspirate, as well as 
evaluation of donor-host chimerism, on approximately day +21. Evaluation of PB 
chimerism will be performed on approximately days +28, +60, and +100. 
7. Cord blood transplant recipients will have research blood (approximately 20 cc) be 
obtained to assess the recovery of NK cells on approximately days +28, +60 and +100. 
8. Cord blood transplant recipients will be closely monitored for any infections that may be 
associated with delayed engraftment. 
 
*Tests may be held in case of severe toxicity or if patient is without counts. 
 
10.8 
Evaluation > 100 days post transplant* 
1. Physical examinations, CBC, blood chemistries and liver function test at a minimum of 
approximately every 6 weeks until 6 months, then at a minimum of approximately every 
three months for one year, then at approximately 3-6 month intervals until 2 years post 
transplant. The patient’s referring physician, in consultation with a bone marrow 
transplant physician, may perform follow-up. 
2. Chronic GVHD will be diagnosed and graded according to the criteria of Sullivan et al 67, 
(Appendix C). Assessments will be obtained at approximately day 100, 180 and 365. 
Patients who develop chronic GVHD will be treated according to current standard of 
care. 
3. Bone marrow aspiration with cytogenetic analysis for chimerism and disease status (if 
indicated) should be performed approximately every 3-6 months until one-year post 
transplant, and then as clinically indicated. 


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4. Recipients of cord blood grafts will undergo evaluation of PB chimerism at 6 months, 1 
year, and 2 years post-transplant. 
5. Lymphoid immunophenotyping and function will be evaluated as per BMT standard of 
care guidelines. 
6. For  cord  blood  transplant  recipients,  research  blood  (approximately  20  cc)  will  be 
obtained to assess the recovery of NK cells on days 180 and 1 year post-transplant. 
7. Cord blood transplant recipients will be closely monitored for any infections that may be 
associated with delayed engraftment. 
 
*Tests may be held in case of severe toxicity or if patient is without counts. 
 
11.1 TOXICITIES/SIDE EFFECTS 
 
11.2 
Clofarabine 
Likely 
• 
Reversible hepatotoxicity is the major dose-limiting toxicity.  This is most 
commonly demonstrated by a transient elevation of transaminases. 
Hyperbilirubinemia was less common. 
• 
Dermatitis and pruritus 
• 
nausea, vomiting , diarrhea, abdominal pain 
• 
myelosuppression and pancytopenia 
• 
headache 
• 
fever - chills or rigors 
 Less Likely 
• 
acrodermatitis 
• 
anorexia, weight loss myalgias, arthralgias 
• 
headache, fatigue, dizziness, somnolence,  tremor 
• 
shortness of breath 
• 
infections 
Rare but serious 
• 
Capillary leak syndrome 
• 
Systemic inflammatory response syndrome 
 
11.2 
Thiotepa 
Likely 
• 
alopecia 
• 
anorexia - nausea and vomiting – abdominal pain - diarrhea 
• 
myelosuppression and pancytopenia 
• 
sterility 
• 
fever 
• 
cutaneous erythema and bronzing 
 Less Likely 
• 
dizziness 
• 
transient hepatic transaminases elevation 
 
Rare but serious 
• 
CNS toxicity manifested by headache, mild cognitive dysfunction, disorientation, 
confusion, irritability, and bizarre behavior 


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IRB Protocol 
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• 
Anaphylaxis 
• 
interstitial pneumonitis 
• 
renal failure 
 
11.3 
Melphalan 
Likely 
• 
nausea and vomiting - Diarrhea 
• 
mucositis 
• 
myelosuppression and pancytopenia 
• 
elevated liver function tests 
• 
sterility 
• 
alopecia 
• 
fever 
 Less Likely 
• 
Syndrome of Inappropriate anti-diuretic hormone (SIADH) 
• 
Interstitial pneumonitis 
• 
Pulmonary fibrosis 
Rare but serious 
• 
secondary leukemia 
• 
anaphylaxis 
• 
seizures 
• 
kidney failure 
• 
veno-occlusive disease of the liver (VOD): 
 
11.4 
Tacrolimus (FK506, Prograf™) 
Likely 
• 
renal dysfunction and electrolyte abnormalities of potassium and magnesium 
• 
hypertension 
• 
hepatotoxicity 
• 
nausea and vomiting – constipation - anorexia 
• 
tremors 
• 
fatigue 
 Less Likely 
• 
hemolytic anemia 
• 
renal failure 
• 
unsteadiness 
• 
depression 
• 
peripheral neuropathy 
Rare but serious 
• 
Seizures 
• 
Ataxia – cortical blindness 
• 
hemolytic uremic syndrome – thrombotic thrombocytopenic purpura 
• 
post-transplant lymphoproliferative disorder 
• 
anaphylaxis 
• 
capillary leak syndrome 
 
11.5 
Mycophenolate mofetil  (MMF) 


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Likely 
• 
hypertension 
• 
nausea and vomiting - diarrhea 
• 
myelosuppression and pancytopenia 
 Less Likely 
• 
headache 
• 
insomnia 
• 
peripheral edema 
• 
confusion - tremor 
Rare but serious 
• 
skin cancer, not including melanoma 
• 
gastrointestinal bleeding 
• 
progressive multifocal leukoencephalopathy (PML), a progressive disease of the 
nervous system that can cause severe disability or death. A very small number of 
cases of PML have been reported in patients treated with MMF. 
 
11.6 
Methotrexate (MTX) 
Likely 
• 
Renal dysfunction: Decrease in creatinine clearance, renal wasting of magnesium 
and calcium, hypertension. Hypertension may be exacerbated by the concomitant use of 
corticosteroids. 
• 
Hepatic dysfunction: Elevation in serum bilirubin and occasionally in serum 
transaminases. 
• 
Mucositis: Mucositis secondary to the cytoreduction may be potentiated following the 
use of methotrexate post transplant. 
 
 
11.7 
G-CSF (Neupogen) 
• Side effects of G-CSF are generally mild, include bone pain, headaches, body aches, 
fatigue, edema and nausea and are managed with supportive care. Pleuro- or 
pericarditis are seen rarely and are managed by cessation of the medication and 
corticosteroids if necessary. 
 
 
11.8 
CORD BLOOD UNIT INFUSION 
Toxicities potentially associated with the infusion of the UCB graft include DMSO toxicity 
and side effects from red cells and may  include changes in heart rate or rhythm, 
changes in blood pressure, fever, chills, sweats, nausea/vomiting, diarrhea, abdominal 
cramping, headache, dyspnea, presence of DMSO taste and odor, hemoglobinuria, and 
acute renal failure. However, due to the dilution step and pre-medications,  these 
toxicities are unlikely. 
 
 
 
12.0 CRITERIA FOR THERAPEUTIC RESPONSE/OUTCOME ASSESSMENT 
 
Definition of events in the post-transplant course important for analysis and treatment 


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12.1. Leukemic Relapse 
 
Relapse of leukemia is the primary endpoint of this study. It will be analyzed as to type and 
genetic origin of the leukemic cells. These will be defined by an increasing number of blasts in 
the marrow over 5%, by the presence of circulating peripheral blasts, or by the presence of 
blasts in any extramedullary site. 
 
Cytogenetic analysis of the marrow and/or peripheral blood will also be obtained for the 
diagnosis of relapse. The presence of the original cytogenetic marker or molecular evidence of 
disease will be considered a relapse if the abnormality is present in two consecutive samples 
obtained 1 month apart or if treating physician initiates additional therapy for treatment of 
relapse. 
 
For high-risk patients with advanced disease, an estimated relapse probability is approximately 
50%. 
 
12.2. Early post-transplant severe morbidity and mortality 
 
Early severe post transplant regimen-related severe morbidity (grade IV non-hematologic 
toxicity) and/or mortality will be the second endpoint of this study. In the context of the agents or 
agent-combination used for cytoreduction, particular attention will be given to, and Dose Limiting 
Toxicity will be based on, grade IV toxicity involving (1) the liver, (2) the heart, (3) the oral 
mucosa and gastrointestinal tract, and (4) the skin. The grading for monitoring the morbidity and 
mortality will be based on the NCI/CTEP common toxicity criteria, CTCAE version 3.0. 
 
12.3. Graft Failure or Rejection 
 
Primary non-engraftment is diagnosed when the patient fails to achieve an ANC 500/l at any 
time in the first 28 days post-transplant. If the patient's leukemia recurs during this interval, the 
patient is scored as having refractory leukemia. In such a situation, the absence of donor 
hematopoiesis is not evaluable for graft failure or rejection.  If (1) after achievement of an ANC 
500/mm3, the ANC declines to <500/mm3 for more than 3 consecutive days in the absence of 
relapse, or, (2) there is absence of donor cells in the marrow and/or blood as demonstrated by 
chimerism assay in the absence of relapse, a diagnosis of secondary graft failure is made. If, 
however, recurrence of host leukemia is detected concurrently, the patient is not evaluable for 
graft failure or rejection. Patients with evidence of graft failure without evidence of recurrence of 
host leukemia will have additional studies drawn to ascertain cause and define relevant 
histoincompatibilities. 
 
These analyses may include (1) evaluation of bone marrow aspirates and biopsies for residual 
or recurrent leukemia, when indicated, (2) culture and/or molecular analyses of marrow and 
blood for viral pathogens potentially causing graft failure including CMV, HHV6 and parvovirus B 
19, and (3) immunophenotypic  and genetic  analysis  of circulating T-cells  and NK cells  to 
ascertain their origin and potential function. 
 
Patients who suffer graft failure will be considered for a secondary transplant. The need for 
additional immunosuppression or treatment for viral infection prior to the secondary transplant 
will be determined by the results obtained from chimeric and viral studies. 
 
12.4. Graft Versus Host Disease 


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Standard clinical criteria as defined by MSKCC criteria and histological grading of skin, liver or 
gastrointestinal pathology as defined by Glucksberg et al75, Slavin, et al 77 and Schulman et al. 
78 will be used to establish and grade acute GvHD (Appendix B). 
 
To determine the severity  of acute GvHD, data will be collected approximately  weekly  to 
characterize the severity of symptoms and signs caused by GvHD and to evaluate possible 
confounding factors. Real time data collection will include 
• 
descriptive characteristics of rash 
• 
estimated body surface area involved 
• 
extent of dermal/epidermal separation 
• 
identification of concomitant causes of increased bilirubin other than GvHD 
• 
presence   or   absence   of   nausea,   vomiting   or   anorexia   persistent   after 
engraftment 
• 
peak 
diarrhea volume with annotations concerning 
the presence 
after 
engraftment 
• 
peak diarrhea volume with annotations concerning the presence or absence of 
urinary mixing and estimates of true diarrhea volume 
• 
presence or absence of abdominal cramps 
• 
presence or absence of frank blood in the stool or melena 
• 
concomitant causes of GI symptoms other than GvHD 
• 
biopsy results 
• 
identification of any agents used for treatment 
• 
autopsy results. 
 
Patients will be observed for acute and/or chronic GvHD as long as they have not received 
donor derived leukocytes infusions (DLI) for the treatment of relapse or infections. If at any time, 
a patient receives DLI, that time will represent the end-time for evaluation of GvHD. Graft- 
versus-host disease occurring after DLI infusions will be analyzed separately. 
 
Patients with moderate to severe acute GvHD (grade II-IV) will be treated in standard fashion 
with high-dose IV methylprednisolone (2-20mg/kg/day). Patients failing to respond to steroids 
will be considered for treatment with a human monoclonal antibody directed against the IL-2 
receptor or with and/or experimental treatment available at the time of diagnosis of GvHD. 
 
Chronic GvHD will be diagnosed and graded according to the criteria of Sullivan76 (Appendix C) 
and treated with standard or experimental immunosuppressive therapy. Treatment will consist of 
corticosteroids, cyclosporin A, azathioprine, or combinations of these agents. Other novel 
treatments could be used if available, i.e. thalidomide, rituximab, psoralen/ultraviolet A 
phototherapy (PUVA). 
 
 
 
 
12.5. Immunologic Reconstitution 
 
Immunophenotyping of T-cells, B-cells, and NK cells, and T-cell proliferations in response to 
non-specific mitogens and specific antigens, will be performed at serial time points after 
transplant to measure immune recovery.   Cord blood transplant recipients will have research 


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blood  (  approximately  20  cc)  will  be  obtained  to  assess  the  recovery  of  NK  cells  on 
approximately days +28, +60, and +100. The studies will be performed at approximately 4 and 6 
months post transplant and then every 6-12 months until normal for all patients. Patients may 
receive supplemental IV immunoglobulin (Ig) to prevent infections as clinically indicated and 
based on IgG levels. Subsequently, Ig levels will be tested at approximately 6, 12, 18 and 24 
months post transplant to guide further IgG supplementation. Patients may be re-immunized as 
from 12 months post-transplant and the response to vaccination will be documented. 
 
12.6    Response to Therapy 
 
• 
A complete response (CR) will be defined as less than 5% bone marrow blasts in the 
setting of a neutrophil count of >1.0 K/ul and a platelet count of >75,000/ ul. 
• 
A complete response except platelets (CRp) will be defined as less than 5% bone marrow 
blasts in the setting of a neutrophil count of >1.0 K/ul and a platelet count of <75,000/ul. 
• 
A partial response (PR) will be defined as 5%-25% bone marrow blasts in the setting of a 
neutrophil count of >1.0 K/ul and a platelet count of >75,000/ul. 
• 
A partial response except platelets (PRp) will be defined as 5%-25% bone marrow blasts 
in the setting of a neutrophil count of >1.0 K/ul and a platelet count of <75,000/ul. 
 
 
13.0   CRITERIA FOR REMOVAL FROM STUDY 
 
Patients may be removed from the study at any point deemed appropriate by the principle 
investigator. However, once the melphalan is given on Day -4, patients will continue on study 
until after administration of the stem cells. Failure to rescue the patient with stem cells at this 
point in the cytoreduction would most likely be fatal. 
 
14.0   BIOSTATISTICS 
 
This is a phase1/2 clinical trial to determine the safety and efficacy of clofarabine, melphalan, 
and thiotepa followed by a hematopoietic stem cell transplant from HLA compatible related or 
unrelated donors for patients with advanced hematologic disorders. 
 
After the first 6 patients were enrolled on this study, it was decided by the transplant team to 
change (1) the stem cell sources and allow the use of cord blood transplants, (2) the indications 
for transplant and allow high risk acute leukemias in CR1, and (3) change the GvHD prophylaxis 
for recipients of marrow or peripheral blood stem cell grafts. 
Because of these changes, the protocol accrual for the study will restart from zero. 
 
 
 
 
This is an amendment for the phase 1 component of the study. Three dose levels will be 
explored in the study. To find the maximum tolerated dose (MTD), a dose escalation scheme 
will be employed with 6 patients per dose. Dose escalation is based on dose limiting toxicity 
(DLT), which is defined as grade IV toxicity involving (1) the liver, (2) the heart, (3) the oral 
mucosa and gastrointestinal tract, and (4) the skin (section 12.2) 


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If zero or one patient experiences a DLT at a given dose level, then dose assessment will 
proceed to the next dose level. If two or more patients experience a DLT at a dose level, the 
preceding dose will be declared the MTD. Escalation to the next dose level is probable if the 
risk of DLT is low, and the likelihood of escalation decreases as the risk of DLT increases. 
 
True Risk of Toxicity 
0.10 
0.20 
0.30 
0.40 
0.50 
Probability of Escalation 
0.89 
0.66 
0.42 
0.23 
0.11 
 
Given 3 dose levels, a maximum of 18 patients will be entered onto this component of the trial. 
 
The 6 patients treated at the MTD, plus an additional 24 patients (for a total of 30) will be 
evaluated for the phase 2 component of this trial. The primary objective is to estimate the 
probability of survival and disease free survival (DFS) in this patient population. We propose 
declaring the treatment active if the one year DFS in the population exceeds 0.50. A single 
stage design that differentiates between one-year DFS probabilities of 0.50 and 0.70 will be 
used to assess efficacy. The donor subgroups will be aggregated for the survival and disease 
free survival estimates. If nineteen or more patients survive free of disease for one year from 
the time of transplant, it is concluded that the transplant is sufficient effective to warrant further 
study. This design has power 0.89 for a one-year disease free survival probability of 0.70, using 
a one-sided test with size 0.10. 
 
At the conclusion of the study, the overall and disease free survival endpoint will be estimated 
using the product limit estimate. 
 
In order to reduce patient risk, the study design includes early termination of the trial in the 
event of excessive grade 4 non-hematologic toxicity and grade 2-4 acute graft versus host 
disease (aGvHD) during the accrual period. A constrained sequential probability ratio test, 
based on the binomial random variable, will be used to monitor the failure rates within each 
donor group. If the stopping boundary is met for one donor group, the study will continue 
accrual in the other donor group. At the conclusion of the study, these incidence rates will be 
summarized using the cumulative incidence function. 
 
Tables 1-3 describe the stopping boundaries for this study. A single sequential stopping 
boundary is developed for the endpoint grade 4 non-hematologic toxicity (Table 1). For grade 2- 
4 acute graft versus host disease, separate stopping boundaries are produced for patients with 
related donors and patients with unrelated donors (Tables 2 and 3). 
 
If the disease-free survival probability in this heterogeneous population is acceptable, and the 
trial is not terminated due to excessive levels of non-hematologic toxicity or graft versus host 
disease, then larger, potentially multi-institutional trials designed to ascertain the potential of this 
transplant approach for patients with advanced hematologic disorders would be indicated. 
 
We anticipate a per year accrual of approximately 10 patients and expect the study to run three 
to four years. 
 
Table 1 – stopping boundary for non-hematologic toxicity 
Boundary based on an expected toxicity rate of 0.10 and an unacceptable toxicity rate of 0.30. 
The constrained probability ratio test using this boundary has size 0.10 and power 0.90. 


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Stop if observe 
2 
toxicities within the first 
3 
patients 
3 
6 
4 
10 
5 
23 
6 
25 
7 
30 
 
Table 2 - stopping boundary for grade 2-4 acute GvHD – related donor 
Boundary based on an expected acute GvHD rate of 0.15 and an unacceptable acute GvHD 
rate of 0.35. The constrained probability ratio test using this boundary has size 0.10 and power 
0.90. 
 
Stop if observe 
2 
GvHDs within the first 2 
patients 
3 
5 
4 
8 
5 
12 
6 
26 
7 
30 
 
Table 3 - stopping boundary for grade 2-4 acute GvHD – unrelated donor 
Boundary based on an expected acute GvHD rate of 0.25 and an unacceptable acute GvHD 
rate of 0.50. The constrained probability ratio test using this boundary has size 0.10 and power 
0.90. 
 
Stop if observe 
11 
GvHDs at any time during the study 
 
 
15.1 SUBJECT REGISTRATION AND RANDOMIZATION PROCEDURES 
 
15.2 Research Participant Registration 
 
 
Confirm eligibility as defined in the section entitled Criteria for Patient/Subject Eligibility. 
 
Obtain informed consent, by following procedures defined in section entitled Informed 
Consent Procedures. 
 
During the registration process registering individuals will be required to complete a 
protocol specific Eligibility Checklist. 
 
All participants must be registered through the Protocol Participant Registration (PPR) 
Office at Memorial Sloan-Kettering Cancer Center. PPR is available Monday through 
Friday from 8:30am – 5:30pm at 646-735-8000. The PPR fax numbers are (646) 735- 
0008 and (646) 735-0003. Registrations can be phoned in or faxed. The completed 
signature page of the written consent/verbal script and a completed Eligibility Checklist 
must be faxed to PPR. 


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16.1 DATA MANAGEMENT ISSUES 
A Research Study Assistant (RSA) will be assigned to the study. The responsibilities of the RSA 
and principal investigator include project compliance, data collection, abstraction and entry, data 
reporting, regulatory monitoring, problem resolution and prioritization, and coordinate the 
activities of the protocol study team. The data collected for this study will be entered into a 
secure database. Source documentation will be available to support the computerized patient 
record. 
 
16.2 Quality Assurance 
 
Weekly registration reports will be generated to monitor patient accruals and completeness of 
registration data. Routine data quality reports will be generated to assess missing data and 
inconsistencies. Accrual rates and extent and accuracy of evaluations and follow-up will be 
monitored periodically throughout the study period and potential problems will be brought to the 
attention of the study team for discussion and action. 
 
Random-sample data quality and protocol compliance audits will be conducted by the study 
team, at a minimum of  two times per year, more frequently if indicated. 
 
16.3 Data and Safety Monitoring 
 
The Data and Safety Monitoring (DSM) Plans at Memorial Sloan-Kettering Cancer Center were 
approved by the National Cancer Institute in September 2001. 
The plans address the new 
policies set forth by the NCI in the document entitled “Policy of the National Cancer Institute for 
Data 
and 
Safety 
Monitoring 
of 
Clinical 
Trials”  which 
can 
be 
found 
at:  
http://cancertrials.nci.nih.gov/researchers/dsm/index.html. 
The DSM Plans at MSKCC were 
established and are monitored by the Office of Clinical Research.  The MSKCC Data and Safety 
Monitoring Plans can be found on the MSKCC Intranet at:  
http://mskweb2.mskcc.org/irb/index.htm 
 
There are several different mechanisms by which clinical trials are monitored for data, safety 
and quality. There are institutional processes in place for quality assurance (e.g., protocol 
monitoring, compliance and data verification audits, therapeutic response, and staff education 
on clinical research QA) and departmental procedures for quality control, plus there are two 
institutional committees that are responsible for monitoring the activities of our clinical trials 
programs. The committees: Data and Safety Monitoring Committee (DSMC) for Phase I and II 
clinical trials, and the Data and Safety Monitoring Board (DSMB) for Phase III clinical trials, 
report to the Center’s Research Council and Institutional Review Board. 
 
During the protocol development and review process, each protocol will be assessed for it’s 
level of risk and degree of monitoring required. Every type of protocol (e.g., NIH sponsored, in- 
house sponsored, industrial sponsored, NCI cooperative group, etc.) Will be addressed and the 
monitoring procedures will be established at the time of protocol activation 


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17.1 PROTECTION OF HUMAN SUBJECTS 
 
17.2 Privacy 
 
MSKCC’s Privacy Office may allow the use and disclosure of protected health information 
pursuant to a completed and signed Research Authorization form. The use and disclosure of 
protected health information will be limited to the individuals described in the Research 
Authorization form. A Research Authorization form must be completed by the Principal 
Investigator and approved by the IRB and Privacy Board. 
 
17.3 Serious Adverse Event (SAE) Reporting 
 
Any SAE must be reported to the IRB/PB as soon as possible but no later than 5 calendar days. The 
IRB/PB requires a Clinical Research Database (CRDB) SAE report be submitted electronically to the SAE 
Office at sae@mskcc.org containing the following information: 
Fields populated from the CRDB: 
• 
Subject’s name 
• 
Medical record number 
• 
Disease/histology (if applicable) 
• 
Protocol number 
Data needing to be entered: 
• 
The date the adverse event occurred 
• 
The adverse event 
• 
Relationship of the adverse event to the treatment (drug, device, or intervention) 
• 
If the AE was expected 
• 
The severity of the AE 
• 
The intervention 
• 
Detailed text that includes the following information: 
o A explanation of how the AE was handled 
o A description of the subject's condition 
o Indication if the subject remains on the study 
o If an amendment will need to be made to the protocol and/or consent form 
The PI’s signature and the date it was signed are required on the completed report. 
17.2.1 Definition of SAE 
 
An SAE is an undesirable experience that meets one of the following criteria: 
 
• 
Is fatal or life-threatening 
• 
Is disabling 
• 
Results in hospitalization or prolongation of hospitalization 
• 
Results in a congenital anomaly or occurrence of malignancy 
• 
Important medical event that jeopardizes the participant AND requires medical or 
surgical intervention to prevent one of the outcomes above Note: Hospital admission 
for a planned procedure/disease treatment is not considered an SAE. 
 
Attribution: 


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• 
Unrelated: The AE is clearly NOT related to the intervention 
• 
Unlikely: The AE is doubtfully related to the intervention 
• 
Possible: The AE may be related to the intervention 
• 
Probable: The AE is likely related to the intervention 
• 
Definite: The AE is clearly related to the intervention 
Expected and Unexpected Event: 
• 
Expected: Any experience previously reported (in nature, severity, or incidence) in 
the current Investigator’s Brochure or general investigational plan 
• 
Unexpected: Any experience not previously reported (in nature, severity, or 
incidence) in the current Investigator’s Brochure or general investigational plan 
 
 
UNEXPECTED EVENT: 
 
• 
Grades 1-2: Adverse Event Reporting NOT required. 
• 
Grades 3: Possible, Probable or Definite attribution to the drug and/or device. 
• 
Grades 4 and 5: Regardless of Attribution. This includes all deaths within 30 days of the 
last dose of treatment with an investigational agent regardless of attribution. 
EXPECTED EVENT 
 
• 
Grades 1 – 3: Adverse Event Reporting NOT required. 
 
• 
Grades 4 and 5: Regardless of Attribution. This includes all deaths within 30 days of the 
last dose of treatment with an investigational agent regardless of attribution. 
 
*Reportable events are those  which occur within 30 days from the last day of treatment on 
protocol. Events beyond 30 days will be reported at the discretion of the PI. 
 
18.1 INFORMED CONSENT PROCEDURES 
 
The individual listed as consenting professionals have completed the mandatory Human 
Subjects Education and Certification Program. The consulting BMT attending will obtain consent 
from the patient or the patient’s guardian. The patient will sign three copies of the consent. One 
copy will be given to the patient to keep, one will be scanned into the patient’s medical record 
and one copy will be stored in the patient’s research file. 
 
 
 
Before protocol-specified procedures are carried out, consenting professionals will 
explain full details of the protocol and study procedures as well as the risks involved to 
participants prior to their inclusion in the study. Participants will also be informed that 
they are free to withdraw from the study at any time. All participants must sign an 
IRB/PB-approved consent form indicating their consent to participate. This consent form 


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meets the requirements of the Code of Federal Regulations and the Institutional Review 
Board/Privacy Board of this Center. The consent form will include the following: 
1. The nature and objectives, potential risks and benefits of the intended study. 
2. The length of study and the likely follow-up required. 
3. Alternatives to the proposed study. (This will include available standard and 
investigational therapies. In addition, patients will be offered an option of 
supportive care for therapeutic studies.) 
4. The name of the investigator(s) responsible for the protocol. 
5. The right of the participant to accept or refuse study interventions/interactions 
and to withdraw from participation at any time. 
 
Before any protocol-specific procedures can be carried out, the consenting professional 
will fully explain the aspects of patient privacy concerning research specific information. 
In addition to signing the IRB Informed Consent, all patients must agree to the Research 
Authorization component of the informed consent form. 
Each participant and consenting professional will sign the consent form. The participant 
must receive a copy of the signed informed consent form. 


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19.0 REFERENCE(S) 
 
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Nedellec G, Pico J, et al. Consolidation treatment of adult acute lymphoblastic leukemia: a 
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Sutton L, Kuentz M, Cordonnier C, et al: Allogeneic bone marrow transplantation for adult 
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4. 
De la Camara R, Figuera A, Steegmann JL, et al: Allogeneic bone marrow transplantation 
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5. 
De Witte T, Awwad B, Boezeman J, et al: Role of allogeneic bone marrow transplantation 
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Niederwieser D, Granena A, Hermans J, et al: Slow response to induction chemotherapy 
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Brochstein JA, Kernan NA, Groshen S, Cirrincione C, Shank B, Emanuel D, Laver J, 
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12. Michel G, Gluckman E, Esperou-Bourdeau H, Reiffers J, Pico JL, Bordigoni P, Thuret I, 
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Plouvier, E., Gratecos, N., Bernaudin, F., Lioure, B., Bergeron, C., Jouet, J. P., 
Gardembas-Pain, Belanger, C., Gouvernet, J., Perrimound, H. and Maranchini, D. 
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16. Horowitz MM, Rowlings PA, Passweg JR. Allogeneic Bone marrow transplantation for 
CML: a report from the International Bone Marrow Transplant Registry. Bone Marrow 
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17. Clift RA, Anasetti C. Allografting for chronic Myelogenous Leukemia. Bailleres Clin 
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19. Balduzzi A, Gooley T, Anasetti C, et al. Unrelated donor marrow transplantation in 
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20. Clift RA, Buckner CD, Thomas ED, Bryant E, Anasetti C, Bensinger WI, Bowden R, Deeg 
HJ, Doney, KC, Fisher LD, et al. Marrow transplantation for patients in accelerated phase 
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21. O'Donnell MR, Nademanee A, Snyder DS, Schmidt GM, Parker PM, Bierman PJ et al. 
Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes. J Clin 
Oncol 1987; 5: 1822-1826.Longmore G, Guinan EC, Weinstein HJ, Gelber RD, Rappeport 
JM, Antin JH. Bone marrow transplantation for myelodysplasia and secondary acute 
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22. De Witte T, Zwaan F, Hermans J, Vernant J, Kolb H, Vossen J et al. Allogeneic bone 
marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey 
by the Leukemia Working Party of the European Bone Marrow Transplantation Group 
(EBMTG). Br J Haematol 1990; 74: 151-155 


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23. Sutton L, Chastang C, Ribaud P, Jouet JP, Kuentz M, Attal M, Reiffers J et al. Factors 
influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone 
marrow transplantation: a long-term study of 71 patients. Blood 1996; 88: 358-365 
24. Nevill TJ, Shepherd JD, Reece DE, Barnett MJ, Nantel SH, Klingeman HG et al. 
Treatment of myelodysplastic syndrome with busulfan-cyclophosphamide conditioning 
followed by allogeneic BMT. Bone Marrow Transplantation 1992; 10: 445-450 
25. Anderson JE, Appelbaum FR, Fisher LD, Schoch G, Shulman H, Anasetti C et al. 
Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome. 
Blood 1993; 82: 677-681 
26. Anderson JE, Appelbaum FR, Storb R. An update on allogeneic marrow transplantation for 
myelodysplastic syndrome. Leukemia Lymphoma 1995; 17: 95-99 
27. Anderson JE, Appelbaum FR, Schoch G, Gooley T, Anasetti C, Bensinger WI et al. 
Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative 
regimen and analysis of prognostic factors. Blood 1996; 87: 51-58 
28. Runde V, de Witte T, Arnold R, Gratwohl A, Hermans J, van Biezen A et al. On behalf of 
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APPENDICES 
A. Karnofsky and Lansky Performance Scales 
B. Clinical staging and Grading of Acute Graft versus Host Disease 
C. International Bone Marrow Transplant Registry Severity Scoring of Chronic 
GVHD 
APPENDIX A   
 
KARNOFSKY SCALE (>16 y.o.) 
 
The score is defined by the phrase which best describes the activity status of the recipient. 
 
. Able to carry on normal activity; no special care is needed. 
100 
Normal; no complaints; no evidence of disease 
90 
Able to carry on normal activity 
80 
Normal activity with effort 
 
. Unable to work; able to live at home, care for most personal needs; a varying amount of 
assistance is needed. 
70 
Cares for self; unable to carry on normal activity or to do active work 
60 
Requires occasional assistance but is able to care for most needs 
50 
Requires considerable assistance and frequent medical care 
 
. Unable to care for self; requires equivalent of institutional or hospital care; disease may be 
progressing rapidly. 
40 
Disabled; requires special care and assistance 
30 
Severely disabled; hospitalization indicated, although death not imminent 
20 
Very sick; hospitalization necessary 
10 
Moribund; fatal process progressing rapidly. 
 
*********** 
LANSKY SCALE (<16 y.o.) 
 
The score is defined by the phrase which best describes the activity status of the recipient. 
 
. Able to carry on normal activity; no special care is needed. 
100 
Fully active 
90 
Minor restriction in physically strenuous play 
80 
Restricted in strenuous play, tires more easily, otherwise active 
. Mild to moderate restriction 
70 
Both greater restrictions of, and less time spent in, active play 
60 
Ambulatory up to 50% of time, limited active play with assistance/supervision 
50 
Considerable assistance required for any active play; fully able to engage in quiet 
play 
. Moderate to severe restriction 
40 
Able to initiate quiet activities. 
30 
Needs considerable assistance for quiet activity 
20 
Limited to very passive activity initiated by others (e.g. TV) 
10 
Completely disabled; not even passive play 


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APPENDIX B 
 
CLINICAL STAGING AND GRADING OF ACUTE GRAFT VERSUS HOST DISEASE 
 
ORGAN INVOLVEMENT 
STAGE 
Skin 
Liver 
Gut 
1 
maculopapular rash 
<25% body surface 
Bili 2.0 – 3.0 mg/dl 
Diarrhea 
500-1000 ml/d 
(children: 280-555 ml/m2/d) 
OR persistent nausea 
2 
maculopapular rash 
25-50 % of body 
surface 
Bili 3.1 – 6.0 mg/dl 
Diarrhea 
>1000 but < 1500 ml/d 
(children: 556-833 ml/m2/d) 
3 
maculopapular rash 
>50 % of body 
surface 
Bili 6.1 - 15 mg/dl 
Diarrhea 
>1500 ml/d 
(children: >834 ml/m2/d) 
4 
generalized 
erythroderma 
with bullous 
formation 
Bili > 15 mg/dl 
Severe abdominal pain + Ileus 
GRADING 
GRADE 
Skin 
Liver 
Gut 
0 
NONE 
None AND 
NONE 
I 
Stage 1-2 AND 
None AND 
NONE 
II 
Stage 3 AND/OR 
Stage 1 AND/OR 
Stage 1 
III 
None OR Stage 3 AND 
Stage 2-3 OR 
Stage 2-4 
IV 
Stage 4 OR 
Stage 4 
NA 
STAGING 
- For skin GvHD: 
- Use “Rule of Nines or burn chart to determine extent of rash 
- For liver GvHD: 
- Range of bilirubin given as total bilirubin. 
- Downgrade one stage if an additional cause of hyperbilirubinemia is documented 
- For gut GvHD:  - Downgrade one stage if an additional cause of diarrhea is documented 
- St 1: 
Persistent nausea, vomiting and anorexia in the absence of other known cause 
Unless histology is negative 
GRADING- Criteria for grading given as minimum degree of organ involvement required to confer that grade 


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Appendix C 
 
 
 
International Bone Marrow Transplant Registry (IBMTR) Severity Scoring of 
Chronic GVHD 
 
KPS at diagnosis 
of cGVHD 
Mild 
(low risk) 
Moderate 
(intermediate 
risk) 
Severe 
(high risk) 
>80 
No weight loss 
No diarrhea 
Either weight loss or 
diarrhea 
Both weight loss 
and diarrhea 
< 80 
No weight loss, no 
skin involvement 
(or) one or two of 
above with oral 
involvement 
Diarrhea, weight loss 
and or skin 
involvement (one or 
two of above) 
Weight loss, 
diarrhea and skin 
involvment (or) 
one or two of the 
above with oral 
involvement