Clinical trial NCT00303719
Conditions: Kidney Cancer Leukemia Lymphoma Multiple Myeloma Plasma Cell Neoplasm Myelodysplastic Syndromes
Keywords: leukemia lymphoma myeloma
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 2002-03-26; Completion date: 2019-05-08
Enrollment: 342 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
RATIONALE: A peripheral stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy and radiation therapy, or that have become cancer. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving cyclophosphamide and fludarabine together with total-body irradiation followed by cyclosporine and mycophenolate mofetil before the transplant may stop this from happening.

PURPOSE: This clinical trial is studying how well giving combination chemotherapy together with radiation therapy followed by cyclosporine and mycophenolate mofetil works in treating patients who are undergoing a donor stem cell transplant for hematologic cancer, metastatic breast cancer, or kidney cancer.

Detailed description:
OBJECTIVES:

* Determine if a nonmyeloablative regimen comprising cyclophosphamide, fludarabine, and radiotherapy followed by cyclosporine and mycophenolate mofetil provides a prompt and durable donor engraftment in patients with hematologic malignancies or kidney cancer who are undergoing allogeneic stem cell transplantation.
* Determine the safety of this nonmyeloablative transplantation regimen in these patients.
* Determine the risk of graft-versus-host-disease in patients treated with this regimen.
* Determine the antineoplastic potency of nonmyeloablative stem cell transplantation in patients treated with this regimen.
* Determine the effect of lower doses of daily fludarabine on treatment-related mortality (TRM) OUTLINE: Patients are stratified according to risk (standard vs high).
* Preparative regimen\*: Patients receive cyclophosphamide intravenously (IV) over 2 hours on day -6 and fludarabine IV over 1 hour on days -6 to -2. Patients undergo total body irradiation on day -1. Some patients also receive anti-thymocyte globulin (ATG)\*\* IV every 12 hours on days -6 to -4. Patients who receive ATG\* include the following:

  * Related donor recipients who have not received combination chemotherapy within the past 6 months
  * Unrelated donor recipients who have not received combination chemotherapy within the past 3 months
  * Unrelated donor recipients who have received only 1 induction course for the treatment of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or blastic phase chronic myelogenous leukemia (CML) NOTE: \*\*Patients who underwent prior autologous stem cell transplantation in the past year do not receive ATG.
* Allogeneic peripheral blood stem cell transplantation (PBSCT): Patients undergo allogeneic PBSCT on day 0.
* Graft-versus-host-disease prophylaxis: Patients receive cyclosporine IV over 2 hours beginning on day -3 and continuing until at least day 100. Patients also receive mycophenolate mofetil IV or orally twice daily on days -3 to 30.
* Donor lymphocyte infusion (DLI): Patients without active GVHD but deteriorating donor chimerism may receive DLI IV over 2 hours.

After completion of study treatment, patients are followed periodically for 2 years.

PROJECTED ACCRUAL: A total of 300 patients will be accrued for this study.

Arms: arm 1: Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim. arm 2: Nonmyeloablative conditioning using fludarabine, cyclophosphamide and low dose Total Body Irradiation with or without anti-thymocyte globulin followed by allogeneic hematopoietic stem cell transplantation, immunosuppressive cyclosporine and mycophenolate mofetil and post-transplant use of bone marrow-stimulating filgrastim.
Interventions: intervention 1: anti-thymocyte globulin intervention 2: cyclophosphamide intervention 3: cyclosporine intervention 4: fludarabine intervention 5: mycophenolate mofetil intervention 6: stem cell transplantation intervention 7: total body irradiation intervention 8: filgrastim
Intervention descriptions: intervention 1: ATG dose is 15 mg/kg intravenous (IV) every 12 hours for 6 doses on days -6, -5, and -4.

Those that should/will receive ATG in the preparative regimen:

* Related donor recipients who have not had exposure to combination chemotherapy in the 6 months preceding transplant should
* Unrelated donor recipients who have not had exposure to combination chemotherapy in the 3 months preceding transplant will
* Unrelated donor recipients who have had only a single induction cycle for the treatment of ALL/AML or MDS or CML blast crisis should
* Recipients with a prior autologous transplant in the year prior to second transplant do not require ATG. intervention 2: Cyclophosphamide will be given in a two hour infusion, total dose 50 mg/kg on day -6. intervention 3: Patients will receive cyclosporine A (CSA) therapy beginning on day -3 maintaining a level of \>200. For adults the initial dose will be 2.5 mg/kg IV over 2 hours every 12 hours. For children \< 40 kg the initial dose will be 2.5 mg/kg IV over 2 hours every 8 hours. Patients will receive CSA until day +100. intervention 4: Fludarabine 30 mg/m\^2/day intravenous (IV) on day -6 through day -2., total dose 150 mg/m\^2 for 5 days. intervention 5: Mycophenolate mofetil (MMF) 1.5 gram twice a day (BID) or if \< 50 kg will be given 15 mg/kg orally(po) BID,beginning on day -3, and discontinue at day +30 or 7 days after engraftment (3 consecutive days of absolute neutrophil count (ANC) \> 0.5 x 109 /L). intervention 6: On day 0, if related donor, stem cells are infused via central line. If unrelated donor, marrow/PBSC is infused after arrival and processing on day 0. intervention 7: The dose of TBI will be 200 cGy given in a single fraction on day -1. intervention 8: Patients with white blood cell (WBC) counts \< 2500 any time after stem cell infusion will be started on G-CSF support at Day +5 at a dose of 5 mcg/kg intravenously or subcutaneously (IV/SQ) daily rounded to vial size until absolute neutrophil count (ANC) \> 2500 for 2 consecutive days.

Protocol documents:
Prot_SAP_000.pdf: 
UNIVERSITY OF MINNESOTA BONE MARROW TRANSPLANTATION PROGRAM
ALLOGENEIC BONE MARROW TRANSPLANTATION
USING LESS INTENSIVE THERAPY
MT 2001-10
CPRC # 2001LS058
Study Committee
Erica Warlick, M.D., Chair
Daniel Weisdorf, M.D.
Bruce Blazar, M.D.
Kathryn Dusenbery, M.D.
Jeffrey Miller, M.D.
John Wagner, Jr. M.D.
Todd Defor, M.S.
Version Date
November 12, 2013
This document contains confidential information that is the property of the Blood and Marrow
Transplant Program. Do not copy, disclose, or circulate without written authorization from the
University of Minnesota, Fairview Blood and Marrow Transplant Services Medical Director.


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PROTOCOL CHANGES
DATE
CHANGE
11/12/2013
Add appendix III and create a separate consent form as a mechanism to enroll 10 patients using a related
donor from select diseases (AML, ALL, CML. HL, NHL, and MDS) to act as controls for MT2012-06 -
Inducible Regulatory T Cells (iTreg) study
Section 3 – add a paragraph regarding optional sub-study
Update Section 9.3 to current DSMC reporting requirements and new email address
03/21/2011
Update to current Cancer Center and IRB format – remove references to MT2004-03 as study has closed to
enrollment; update MMF dose to 1.5 grams
03/08/2010
3.1.1 and 3.1.2: Age limit changed to 75 years or less
5.12 Starting date of G-CSF post transplant changed to Day +5
10/12/09
2.0 Background and Rationale: Updated data regarding fludarabine dosing changes and interim analysis of
MT 2001-10 subjects enrolled to date added
3.2.6 Updates to MDS disease criteria
3.2.7 Remove breast cancer as a disease entity treated by allogeneic transplant
3.5.8 Updated Myeloma disease response exclusion criteria
5.0 Treatment Schema: Fludarabine dose changed to 30mg/m2 daily
13.1 and 13.2: Updates to statistical analysis and stopping rules to include expansion to enroll an additional
150 patients.
6/18/2009
Dr. Erica Warlick replaces Dr. Marcie Tomblyn as PI
4/22/2009
Added an arm to co-enroll subjects from MT2004-03;
2/24/2006
Data and Safety Monitoring plan updated to reflect phase 2 status of study (section 13.5).
6/10/2005
Section 4.0 (Donor Eligibility) If donor is unable to undergo apheresis, marrow harvest will be acceptable.
Section 4.2. Clarified that the target dose is for both unrelated and related donors.
Section 13.2 (stopping rules). Clarified that if any of the stopping rules in arms 1-6 are reached, the study
will be stopped
2/8/2005
Dr. Marcie Tomblyn takes over as Principal Investigator
11/12/2003
--Clarified that either marrow or PBSC will be transplanted (section 3.1, 5.6)
--Added Chronic myeloprolifterative disorder to the eligibility
--Replaced Anne Goldman, Ph.D. with Todd Defor, M.S., on the study committee.
1/30/2004
Section 3 Eligibility – minor edits for clarification and consistency throughout protocols; Metastic
Melanoma and Small Cell lung cancer removed from list of eligible diseases
Section 5.3 GVHD prophylaxis revised for consistency with program policy
Section 6 Required observations. Blood draw for RFLP day 35 removed; KLH and tetanus vaccines
removed.
Section 8.0 Reporting of adverse events. Revised to be consistent with program policy
Section 9.1.1 DLI eligibility revised for clarity
Section 12 Endpoints. Minor revisions to clarify post transplant clinical evaluation dates
Section 13 Experimental Design and Statistical considerations section revised to include an increase in
target subjects to 80 (and rationale); added Data Safety and monitoring plan.
10/28/04
Section 3.2.9 Eligibility. Added Marrow Aplasia (as a consequence of AHN-12 therapy) to the eligibility of
this study.
11/16/2004
Introduction of a new arm to this study labeled Arm 7 which will cater to high-risk patients transplanted
with marrow aplasia after chemotherapy or radio-labeled antibody.
Separate stopping rules have been
added to the protocol to allow for appropriate patient monitoring and safety of these patients. Standard risk
patients will continue to be transplanted as previously on and have been labeled as Arms 1-6 by our
database. The high risk patients will be analyzed as Arm 7.
As we have recently modified the way we select unrelated volunteer donors (must be 7-8/8 allele HLA-
match unless the patient less than 18 years), the wording of the graft selection section has been changed
accordingly.
The definition of leukemic remission for standard risk patients has been clarified to resolve some
confusion for borderline patients as to whether they are eligible or not.
Adequate organ function has been further defined to reflect the necessity for satisfactory renal function
to be transplanted on this protocol safely.
Patients that are severely malnourished have been excluded from the protocol due to the risk of high


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DATE
CHANGE
transplant related mortality in this group.
High grade lymphomas or Hodgkin’s disease that are progressive on salvage therapy have been excluded
as these patients are unlikely to benefit from the transplant procedure.
Clarification of the current accepted practice re dosing of G-CSF for donors has been made and
volunteer donors can give a product consisting of either BM or PB.
Which patients require the addition of ATG to their conditioning regimen has been clarified.
The days that the ATG is administered have been changed from days -3, 2, 1 to days -6, 5, 4.
Clarification of the cyclosporine and mycophenolate dosing to insure the wording in the protocol is
consistent with current accepted clinical practice.
In an effort to identify occult fungal infection in patients at high risk for this complication pre-transplant
a mandated chest CT has been added to the work-up studies for high-risk patients.
Clarification of the wording of who should receive donor lymphocyte infusions so its consistent with
current accepted practice has been included.
The statistical section has been modified appropriately to incorporate the new stopping rules for the
high-risk patients now labeled as Arm 7.


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Table of Contents
1
PURPOSE........................................................................................................................................5
2
BACKGROUND AND RATIONALE ...........................................................................................5
3
PATIENT/DONOR SELECTION AND REGISTRATION...........................................................8
4
DONOR ELIGIBILITY ..................................................................................................................9
5
TREATMENT PLAN/DONOR PROCEDURES .........................................................................10
6
REQUIRED OBSERVATIONS....................................................................................................13
7
EXPECTED TOXICITIES AND COMPLICATIONS -- see Appendix I....................................14
8
MANAGEMENT OF SELECTED RISKS...................................................................................14
9
ADVERSE EVENT REPORTING ...............................................................................................14
10
STUDY DATA COLLECTION AND MONITORING PLAN ................................................16
11
ENDPOINTS .............................................................................................................................18
12
EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS..............................18
13
ETHICAL CONSIDERATIONS...............................................................................................19
14
REFERENCES ..........................................................................................................................20
APPENDIX I: TOXICITIES AND COMPLICATIONS .....................................................................22
APPENDIX II: CHEMOTHERAPY DRUG INFORMATION..........................................................25
APPENDIX III: RESEARCH RELATED CONTROL COHORT FOR ITREG STUDY (MT2012-
06) .........................................................................................................................................................26


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1
PURPOSE
This treatment protocol will study the efficacy of a nonmyeloablative preparative regimen consisting
of fludarabine, cyclophosphamide, and low dose TBI to promote engraftment after allogeneic
hematopoietic stem cell transplant. Based on the initial favorable outcomes with day 100 treatment
related mortality far below the stopping rule of 30%, the study was amended in October 2009 to
enroll an additional 150 patients with a lower fludarabine dose of 30mg/m2 Day -6 through -2.
Objectives:

To evaluate the nonmyeloablative regimen for prompt and durable donor engraftment.

To determine if nonmyeloablative transplantation using this regimen has an acceptable safety
profile

To evaluate the risks of Graft versus Host Disease (GVHD)

To evaluate the anti-neoplastic potency of nonmyeloablative hematopoietic stem cell
transplantation

To evaluate the effect of lower doses of daily fludarabine on treatment related mortality
(TRM)
2
BACKGROUND AND RATIONALE
High dose conditioning regimens followed by allogeneic bone marrow transplantation can provide
durable remissions in a number of malignant diseases. The efficacy of such therapy is partly due to
the conditioning and partly due to the immunological effect of the graft on the malignant cells of the
recipient, the graft-versus-malignancy effect (GVM). However, such therapy is suitable only for a
minority of patients due to the toxicity of the high dose preparative regimens and time of
pancytopenia accompanying traditional transplantation. Thus, older patients and patients with certain
end organ toxicity and/or co-morbidities are not eligible for such therapy.
It was previously thought that intensive marrow ablative regimens were required to establish
allogeneic engraftment. Several recent studies have shown that that is not the case [1-6]. These early
reports of nonmyeloablitive or "mini" transplants suggest that immunosuppression without
myeloablation can be associated with allogeneic engraftment and that these regimens are less toxic.
This allows investigation of the GVM effect in patients not previously eligible for transplantation.
Our goal is to find non-toxic regimens that provide sufficient immunosuppression for engraftment
and that permit a graft versus malignancy (GVM) effect without increased GVHD [1,7,8]. Indeed we
may think of this type of allogeneic transplant not as a "stem cell rescue" following ablative cancer
therapy but primarily as an immunologic intervention [5,6,9-12]. Using a novel conditioning
regimen based on fludarabine, cyclophosphamide and low dose TBI as a preparatory regimen may
result in full donor chimerism. If mixed chimerism is not achieved, further manipulation of
immunosuppressive medications and if necessary donor lymphocyte infusions can lead to complete
chimerism with the potential for GVM effects [5,6].
The preceding study, MT1999-17, tested two moderate intensity, but still non-myeloablative (NMA)
conditioning regimens for allotransplantation. This trial compared Buslfan, Cladribine and low dose
total body irradiation to Busulfan, Fludarabine, and low dose total body irradiation. No unexpected


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adverse events were seen. Engraftment was prompt although three graft failures in the Cladribine
arm were observed out of 16 treated. As these results suggested no possibility that the Cladribine
arm could be superior, and, in fact might be inferior, this arm was closed. The trial continued to
enroll a total of 47 patients to date. Of these, 33 received sibling and 14 unrelated donor stem cells.
Generally, they achieved prompt engraftment with only 3 of 47 having graft failure. Overall 26 of 47
patients survive, 7 of 14 receiving unrelated donor grafts and 19 of 33 receiving related donor
transplants.
Because prolonged neutropenia and moderate mucositis was seen with Busulfan, Fludarabine and low
dose total body irradiation despite the lesser intensity, in MT2001-10, a further modification in the
conditioning regimen intensity is being investigated. A substitution of the busulfan with a single
dose of cyclophosphamide (CY/FLU/TBI) was felt likely to be considerably less myelosuppressive.
This has already been demonstrated in the sister protocol MT2000-15 (using umbilical cord blood)
which was changed to CY/FLU/TBI in September 2001 (N=11).
Fludarabine has a very acceptable toxicity profile, with the major side effect being myelosuppression
and immunosuppression [15]. Cyclophosphamide has been used in preparatory regimens for stem
cell transplant for decades and the toxicity and side effect profiles are well known. As patients
without prior combination chemotherapy are at greater risk for graft failure, those that have not had
any combination chemotherapy in the six months prior to transplant will receive three days of ATG,
the toxicity of which is relatively mild and well-known.
While fludarabine has shown a generally acceptable toxicity profile, dosing by creatinine clearance
alone lacks ideal precision. In a separate study, independent work by Pamala Jacobson, Pharm D in
the Deparment of Experimental and Clinical Pharmacology at the U of MN evaluated the role of
fludarabine pharmacokinetic-pharmacodynamics in outcomes of engraftment, treatment related
mortality (TRM), and overall survival (OS) in a subset of patients undergoing NMA allogeneic
transplants.
Eighty-seven patients were evaluated and received the standard cytoxan 50mg/kg/day IV Day -6, plus
fludarabine 40mg/m2/d IV days -6 to -2 and TBI 200cGy on day -1 used in MT 2001-10.
Pharmacokinetic sampling was performed after the first dose of fludarabine and analysis was
completed using standard noncompartmental methods with calculation of area-under-the curve
(AUC). The primary objective was to determine the relationship between fludarabine metabolite (F-
ara-A) exposure and neutrophil engraftment with secondary objectives evaluating the relationship
between F-ara-A exposure and incidence of GVHD, TRM, and OS. The results revealed no impact of
F-ara-A pharmacokinetic parameters on engraftment. Rates of grade II-IV aGVHD were lower in
patients with an AUC >6.5 ug*hr/ml at 14% (95% CI: 0-32%) versus 52% (95% CI: 39-65%) in
those with AUC < 6.5 ug*hr/ml (p=0.04). TRM was also significantly impacted by F-ara-A
concentrations. Overall TRM was 21% at 6 months (95% CI, 12-29%). However, in univariate
analysis, patients with F-ara-A AUC > 6.5 ug*hr/ml had 6 month TRM of 50% (95% CI: 23-77%)
while those with an AUC < 6.5 ug*hr/ml had a TRM of 15% (95% CI: 7-23). In multivariate
analysis, the only independent predictor of TRM was F-ara-A AUC > 6.5 ug*hr/ml with a RR of 4.56
(95% CI:1.22-17.12) (p=0.02). Overall survival was also impacted by higher F-ara-A AUC. Within
this study, those patients with renal dysfunction as measured by creatinine clearance estimates, had
fludarabine dose reduction of 20-25%. Despite this, these patients still had higher plasma


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concentrations then expected, had reduced clearance of F-ara-A and prolonged drug half-life. (Data
not yet published) Given the data of higher TRM seen with higher F-ara-A AUC, we will be
adjusting the daily fludarabine dosing from 40mg/m2 daily Day -6 through -2 to 30mg/m2 daily Day
-6 through -2. Study regarding possible individualized patient specific fludarabine dosing will likely
be incorporated into future trial amendments in order to provide a dosing approach superior to
creatinine clearance calculations.
Cyclosporine A (CsA) and MMF (mycophenolate mofetil) will be used exactly as in 1999-17. CsA
inhibits T cell lymphokine production, but is not effective as a single agent [16,17]. MMF is an
inhibitor of purine nucleoside metabolism and has been shown to provide an anti-GVHD effect as a
single agent and has synergistic anti-GVHD effect when combined with CsA in dogs [18].
In preparation for upcoming renewal of MT 2001-01, the outcomes of the first 123 patients enrolled
on MT 2001-10 were analyzed. The median age was 57 (range 23-70) and median comorbidity score
3 (range 0-10). A median of 709 days elapsed from diagnosis to transplant (range 76-4614) and
median follow-up of survivors was 919 days (range 100-2422). Sixty-five percent (n=80) of patients
were male and 78% (n=96) had a Karnofsky performance status of ≥ 90 at time of transplant. Eighty-
six percent (n=106) of patients had no prior HCT. Numerous hematologic malignancy diagnoses
were transplanted under this protocol: AML (27%, n=33), NHL (28%, n=35), MDS (11%, n=12),
Hodgkins (8%, n=10), multiple myeloma (8%, n=10), Other leukemia (8%, n=10), myeloproliferative
diseases (5%, n=6), CML (3%, n=4), and ALL (2%, n=3). Fifty percent (n=61) of the patients had
advanced disease at time of transplant.
All patients achieved engraftment by Day 42. Acute GVHD grades II-IV at 100 days developed in
37% of patients (95% CI, 28-46%). Severe aGVHD grades III-IV at 100 days developed in only 20%
(95% CI: 13-27%) of patients. At 2 years, the incidence of cGVHD was 50% (95% CI: 41-60%).
TRM at 100 Days was 14% (95% CI: 8-20%) and 1 year was 22% (95% CI, 14-29%). Four year
overall survival (OS) for the entire group was 47% (95% CI: 37-57%). Disease subtype impacted 4
year OS: indolent NHL: 73% (95% CI: 28-93%), aggressive NHL: 59% (95% CI: 34-77%), and
AML + MDS: 35% (95% CI: 19-52%). Progression free survival (PFS) at 4 years was 33% (95% CI:
24-43%) for the entire group. By disease subtype 4 year PFS was: indolent NHL: 73% (95% CI: 28-
93%), aggressive NHL: 55% (95% CI: 32-73%), and AML + MDS: 31% (95% CI: 16-48%)(p=0.04).
Relapse at 4 years was 32% (95% CI: 23-42%) for the entire group. Patients transplanted for AML +
MDS had the highest relapse rates of 36% (95% CI 18 – 54%), those with aggressive NHL had
relapse rates of 21% (95% CI, 3-40%) and those with indolent NHL rates of 0%.
Based on the above favorable outcomes thus far with MT 2001-10 with 100 Day TRM far below the
stopping rule of 30%, we plan to enroll an additional 150 patients with the new, lower fludarabine
dosing.


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3
PATIENT/DONOR SELECTION AND REGISTRATION
Study entry is open to patients ≤ 75 years of age regardless of gender or ethnic background.  While 
there will be every effort to seek out and include women and minority patients, the patient population
is expected to be no different than that of other transplant studies at the University Of Minnesota.
Effective with the November 2013 revision adult patients (≥ 18 years) with a diagnosis of AML, 
ALL, CML, NHL, HL or MDS and who are using a related donor will be invited to participate in an
optional sub-study to act as controls for MT2012-06 “Dose Escalation Study with Extension of
Inducible Regulatory T Cells (iTregs) in Adult Patients Undergoing Non-Myeloablative HLA
Identical Sibling Donor Peripheral Blood Stem Cell Transplantation.” A separate consent form will
request permission to collect additional blood for research related testing prior to transplant and at up
to 7 time points over the 1st 100 days post-transplant. Once 10 patients have been successfully
recruited and samples are collected, this sub-study will end. Please refer to appendix III for details.
Registration in OnCore will occur after the patient has signed the subject consent and eligibility is
confirmed, but before any treatment has been administered.
3.1
Age and Graft criteria (all patients)
Patient’s < 75 years old with a 5/6 or 6/6 related donor match or a 7-8/8 HLA-A,B,C,DRB1
allele matched unrelated donor marrow and/or PBSC donor match
3.2
Disease Criteria (standard risk patients)
Acute myelogenous leukemia— high risk CR1 (as evidenced by preceding MDS, high
risk cytogenetics such as those associated with MDS or complex karyotype, or > 2 cycles to
obtain CR); second or greater CR. Must be in remission by morphology. Patients in
morphologic relapse/ persistent disease defined as > 5% blasts in normocellular bone
marrow OR any % blasts if blasts have unique morphologic markers (eg auer rods) or
associated cytogenetic markers that allows morphologic relapse to be distinguished are not
eligible for arms 2 or 3. Note cytogenetic evidence of disease alone without morphologic
relapse is acceptable. Also a small percentage of blasts that is equivocal between marrow
regeneration vs early relapse is acceptable provided there are no associated cytogenetic
markers consistent with relapse.
Acute lymphocytic leukemia-- high risk CR1 as evidenced by high risk cytogenetics (eg
t(9;22) or complex cytogenetic abnormalities) or > 1 cycle to obtain CR; second or greater
CR. Must be in remission by morphology. Patients in morphologic relapse/ persistent
disease defined as > 5% blasts in normocellular bone marrow OR any % blasts if blasts have
unique morphologic markers or associated cytogenetic markers that allows morphologic
relapse to be distinguished are not eligible for arms 2 or 3. Note cytogenetic relapse or
persistent disease without morphologic relapse is acceptable. Also a small percentage of
blasts that is equivocal between marrow regeneration vs early relapse is acceptable
provided there are no associated cytogenetic markers consistent with relapse.
Chronic myelogenous leukemia all types except blast crisis (note treated blast crisis in
chronic phase is eligible)
NHL, Hodgkins, chronic lymphocytic leukemia, multiple myeloma demonstrating
chemosensitive disease
Acquired bone marrow failure syndromes


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Myelodysplastic syndrome of all subtypes including refractory anemia (RA) or all IPSS
categories if severe pancytopenia, transfusion requirements not responsive to therapy, or
high risk cytogenetics. Blasts must be less than 5%. If >5% requires therapy (induction or
Hypomethylating agents) pre-transplant to decrease disease burden.
Renal cell cancer
Chronic myeloproliferative disorder, i.e. myelofibrosis
3.3
Disease Criteria (High Risk Patients)
Patients with refractory leukemia or MDS may be taken to transplant in aplasia after induction
or re-induction chemotherapy or radiolabeled antibody.
3.4
Organ Function, Performance Status, Other Eligibility
3.4.1
Cardiac: No decompensated CHF, or uncontrolled arrhythmia; EF > 35%
3.4.2
Pulmonary: DLCO > 30% predicted, No O2 Requirements
3.4.3
Liver: Transaminases < 5.0 x ULN; total bilirubin < 3 x ULN
3.4.4
Renal: Creatinine < 2.0 mg/dl (adults) or creatinine clearance > 40 ml/min). All adults
with a creatinine > 1.2 mg/dl or a history of renal dysfunction must have creatinine
clearance (must be > 40 ml/min).
3.4.5
Albumin > 2.5 g/dL
3.4.6
Performance status - Karnofsky > 60% (16 years and older) or Lansky > 50 (less then
16 years of age).
3.4.7
If recent mold infection (e.g. aspergillus) must have minimum of 30 days of therapy
and responsive disease and be cleared by Infectious Disease.
3.4.8
Must be > 3 months after prior myeloablative transplant, if applicable
3.5
Exclusion Criteria
3.5.1
Pregnancy or breast feeding
3.5.2
Evidence of HIV infection or known HIV positive serology
3.5.3
Active serious infection
3.5.4
Congenital bone marrow failure syndrome
3.5.5
Previous irradiation that precludes the safe administration of an additional dose of 200
cGy of TBI
3.5.6
CML in refractory blast crisis
3.5.7
Intermediate or high grade NHL, mantle cell NHL, and Hodgkins disease that is
progressive on salvage therapy. Stable disease is acceptable to move forward provided
it is non-bulky.
3.5.8
Multiple Myeloma progressive on salvage chemotherapy.
4
DONOR ELIGIBILITY
4.1
Donors weighing less than 40 kg (children) will need evaluation by a pediatrician for
suitability of the apheresis procedure
4.2
In general good health as determined by the evaluating medical provider
4.3
Appropriate HLA-match to patient


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4.4
Able and willing to have up to 3 separate mobilized apheresis collections performed or if
unable to undergo apheresis agrees to a bone marrow harvest (requires additional consent)
4.5
Not pregnant
4.6
Agree to undergo donor viral screening panel
4.7
Voluntary written consent
5
TREATMENT PLAN/DONOR PROCEDURES
Refer to section 5.2 for Donor Procedures.
5.1
Patient
5.1.1
Preparative Regimen
All patients will receive allopurinol 300 mg/day starting at day -6 through day 0.
Day
Treatment
ATG* (see below for patients requiring ATG)
Day –6
Cyclophosphamide 50 mg/kg IV over 2 hours
Fludarabine 30 mg/m2 IV over 1 hour
ATG 15 mg/kg IV every 12 hours for 6 doses (start
day -6)
Methylprednisolone 1 mg/kg IV prior to each ATG
dose
Day –5
Fludarabine 30 mg/m2 IV over 1 hour
Day –4
Fludarabine 30 mg/m2 IV over 1 hour
Day –3
Fludarabine 30 mg/m2 IV over 1 hour
Day –2
Fludarabine 30 mg/m2 IV over 1 hour
Day - 1
TBI 200cGy
Day 0
Transplant
*The follow subset of patients should receive ATG as part of the preparative regimen:

Related donor recipients who have not had exposure to combination chemotherapy in the
six months preceding transplant

Unrelated donor recipients who have not had exposure to combination chemotherapy in
the three months preceding transplant

Unrelated donor recipients who have had only a single induction cycle for the treatment of
ALL/AML or MDS or CML blast crisis
Recipients with a prior autologous transplant in the year prior to second transplant do not
require ATG.
Fludarabine will be given IV over 1 hour day -6 through day -2. Preparation, administration
and monitoring will be according to institutional guidelines.
Cyclophosphamide will be administered as a 2 hour intravenous infusion with a high volume
fluid flush and mesna per institutional guidelines on day -6.
ATG, for patients meeting one of the above conditions, will be administered IV every 12
hours for 6 doses on days -6, -5, and -4 according to institutional guidelines.


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Methylprednisolone 1 mg/kg IV administered immediately prior to each dose of ATG (6
doses).
TBI 200 cGy given in a single fraction will be given on day -1 per institutional guidelines.
Patients will receive prophylaxis for GVHD beginning at day -3 as follows unless another
prophylaxis plan is indicated (e.g. co-enrollment with another study).
Cyclosporine A (CSA) will start day -3 and will be administered PO/IV until day +100
maintaining a trough level > 200 ng/mL. The initial dose will be 2.5 mg/kg IV given per
institutional practices. CSA dosing will be monitored and altered as clinically appropriate per
University of Minnesota Medical Center - Fairview Pharmacy guidelines. Dose adjustments
will be made on the basis of toxicity and/or low CSA levels. If no GVHD, the dose will be
tapered 10% per week beginning on day 101.
Mycophenolate mofetil (MMF) 1.5 gram BID or if < 50 kg will be given 15mg/kg PO/IV
bid beginning on day -3 (adjust to tablet size). MMF dosing will be monitored and altered as
clinically appropriate per University of Minnesota Medical Center - Fairview Pharmacy
guidelines. No dose adjustment for liver disease. MMF dosing to be monitored and altered as
clinically appropriate by pharm D or physician.
Discontinue MMF at day +30 or 7 days after engraftment (3 consecutive days of absolute
neutrophil count (ANC) > 0.5 x 109 /L), whichever day is later. If the patient has acute
GVHD requiring systemic therapy, MMF may be stopped 7 days after control of GVHD (e.g.
resolution of skin rash, vomiting, and diarrhea).
5.1.2
Hematopoietic Stem Cell Transplantation (day 0)
Peripheral Blood Stem Cells - On day 0, patients will receive an allogeneic transplant using
PBSC which are CD34+ selected as the donor graft. The graft will be infused over 15-60
minutes after premedication with acetaminophen 650 mg PO and diphenhydramine 25 mg
PO/IV with doses adjusted for pediatric patients.
Related or Unrelated Bone Marrow Cells - A target dose of 3 x 108 nucleated cells/kg
recipient weight will be collected and infused after arrival and processing. The graft will be
infused over 15-60 minutes after premedication with acetaminophen 650 mg PO and
diphenhydramine 25 mg PO/IV with doses adjusted for pediatric patients.
The day 0 cell infusion may be shifted to day +1 or day +2 to shift donor collections to
weekdays if needed for scheduling purposes. All associated procedures (i.e. G-CSF doses
etc.) will shift accordingly.
5.1.3
Supportive Care
All supportive care including antimicrobial prophylaxis directed towards bacteria, fungi and
viruses will be per University Of Minnesota Blood and Marrow Program guidelines.


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Acute and chronic GVHD will be staged and treated using current University of Minnesota
BMT program GVHD protocols
All patients will receive standard supportive transfusion care according to transfusion
committee guidelines or as modified based on clinical parameters.
Patients with WBC counts < 2500 any time after stem cell infusion will be started on G-CSF
support at Day +5 at a dose of 5 mcg/kg (IV/SQ) daily rounded to vial size until ANC > 2500
for 2 consecutive days.
5.2
Donor Procedures
5.2.1
Peripheral Blood - Mobilized Donor Leukapheresis
G-CSF Administration
Transplant Day
G-SCF
-4
G-CSF 10 mcg/kg SQ
-3
G-CSF 10 mcg/kg SQ
-2
G-CSF 10 mcg/kg SQ
-1
G-CSF 10 mcg/kg SQ
0
G-CSF 10 mcg/kg SQ
+1 (if needed)
G-CSF 10 mcg/kg SQ
Premedication consisting of acetaminophen 650 mg PO (for pediatric donors: 10-
15mg/kg/dose PO with a maximum of 650mg) every 8-12 hours should be given beginning
the day of G-CSF administration and ending on the last day of apheresis.
Donors may experience any of the following side effects from G-CSF:
Less common

bone and muscle pain relieved with acetaminophen

changes in liver function tests
Rare, but can be serious

injection site reaction (redness, pain, or swelling)

allergic reaction (fever, chills, skin itching, or feeling flushed) - More serious reactions
happen rarely, but can be dangerous. Symptoms can include feeling lightheaded or dizzy
(due to low blood pressure), chest tightness, shortness of breath, back pain, or swelling of
the face, eyes, tongue, or throat.

spleen enlargement or rupture – presenting as pain or swelling on the left side under the
rib cage or pain in your left shoulder area.

trouble breathing or coughing up blood
Donors experiencing intolerable symptoms attributed to G-CSF therapy may have a dose
reduction according to institutional guidelines.


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5.2.2
Apheresis
The collection will be performed by the University of Minnesota Medical Center - Fairview
Transfusion Service using standard collections techniques. Peripheral blood mononuclear
cells (PBMC) will be collected using a Fenwal CS-3000® Plus blood cell separator
(#4R4538) with granulocyte separation chamber and small volume collection chamber
(SVCC) (Fenwal Division, Baxter Healthcare, Deerfield, IL).
The cells will be selected for the CD34+ fraction and infused after collection and processing.
A target dose of 5 x 106 CD 34+ cells/kg, with a minimum of 3 x 106 CD34+ cell/kg recipient
weight, will be collected by apheresis for transplant. In most cases this dose will be recovered
in a single apheresis; however, additional apheresis may be required to achieve the minimum
dose.
The apheresis product will be administered to the recipient without cryopreservation on the
day(s) of apheresis.
5.2.3
Related or Unrelated Donor Bone Marrow Cells
A target dose of 3 x 108 nucleated cells/kg recipient weight will be collected.
6
REQUIRED OBSERVATIONS
Targeted day may be altered if clinically appropriate
6.1
History and Physical Exam of Recipient
A complete medical history with full details of the patient’s previous treatment and response
including: duration of disease, prior chemotherapy, hormonal therapy or immunotherapy
regimens; radiation (including dose and field size); previous complications of therapy
including end-organ toxicity and infections; previous CNS disease and therapy; previous
plasmapheresis or lymphapheresis.
6.2
History and Physical Exam of Donor
A complete medical history with special reference to infections past and present (especially
viral).
6.3
Pre-Transplant Studies
All patients receive routine BMT recipient malignancy work-up, including bone marrow
biopsy and evaluation of renal, liver, cardiac and pulmonary function. Patients with a history
of MDS or a history of 2 or more consecutive inductions/reinductions to treat acute leukemia
or CML blast crisis or prolonged neutropenia of at least 2 months immediately preceding
transplant should have a chest CT without contrast to exclude occult fungal infection prior to
transplant.

MDS/CML blast crisis

2 or more consecutive inductions

prolonged neutropenia 2 months prior to BMT


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6.4
Post-Transplant Studies
Study tests may be omitted at the physician’s discretion
6.4.1
Blood and Bone marrow aspiration and biopsy for chimerism (and malignant markers
as appropriate) at days 21, 60, 100, 6 months, 1 year and 2 years post transplantation.
6.4.2
Quantitative immunoglobulins at days 100, 6 months and 1 year post transplantation.
7
EXPECTED TOXICITIES AND COMPLICATIONS -- see Appendix I
8
MANAGEMENT OF SELECTED RISKS
8.1
Donor Lymphocyte Infusion For Deterioration Of Donor Chimerism
Recipients without active GVHD are eligible for DLI for progressive deterioration in donor
chimerism not responsive to taper of immune suppression. Refer to the appropriate
University Of Minnesota DLI protocol.
For all patients if the decision is made to give DLI, taper CSA over 14 days.
8.2
Donor PBSC Infusion for Graft Failure
Graft failure and pancytopenia requiring consideration of G-CSF stimulated donor PBSC
infusion will be defined as:

WBC < 100 at day 21 or

ANC < 300 at day 28

Or secondary neutropenia (ANC < 300 for > 7 days) anytime after day 28
9
ADVERSE EVENT REPORTING
Toxicity and adverse events will be classified according to NCI's Common Toxicity Criteria version
2.0 (CTC v2). A copy of the CTC can be downloaded from
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcv20_4-30-992.pdf
9.1
Definitions
An adverse event (AE) is any symptom, sign, illness or experience, regardless of causality, that
develops or worsens in severity during the course of the study.
A serious adverse event (SAE) is any adverse event, regardless of causality that:

Results in death.

Is life-threatening.

Requires inpatient hospitalization or prolongation of existing hospitalization.

Results in persistent or significant disability/incapacity.


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
Is a congenital anomaly/birth defect.

Is an important medical event.
Attribution:

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
Unanticipated (unexpected) problems/events are those that are not already described as
potential risks in the consent form, not listed in the Investigator’s Brochure or not part of an
underlying disease.
Anticipated (expected) problems are those that are already described as potential risks in the
consent form, listed in the Investigator’s Brochure or part of an underlying disease. These do
NOT meet the IRB’s definition of UPIRTSO and should be reported in summary form only at
the time of IRB continuing review. For example, if death is an expected outcome, this event
should be reported only at the time of continuing review.
Federal regulations [45CFR46.103(b)(5) and 21CFR56.108(b)(1)] require the IRB to ensure
that researchers promptly report “any unanticipated problems involving risk to subjects or
others” (UPIRTSOs). The University of Minnesota IRB defines a UPIRTSO as any event
which in the opinion of the local investigator was unanticipated, reflects new or increased risk
to the subjects and was possibly related to the research procedures.
9.2
Adverse Event Monitoring
All patients will be monitored for adverse events during the first 100 days after hematopoietic
stem cell transplantation with the reporting of any events meeting the definition of UPIRTSO
to the University Of Minnesota IRB per section 9.3. After day 100, monitoring will lessen
according to standard transplant follow-up guidelines; however, upon knowledge, the
investigator is obligated to report any event that meets the definition of UPRITSO per section
9.3.
In addition, the following events will be reported to the University of Minnesota University
Of Minnesota Blood and Bone Marrow Database: graft failure/ autologous recovery, severe
acute GVHD (Grades III and IV), relapse, and death.


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9.3
Required Adverse Event Reporting to University Of Minnesota IRB and MCC
The SAE Coordinator will provide the Cancer Center’s Data and Safety Monitoring Council (DSMC)
with the SAE in an appropriate format depending on the individual SAE (as reported or in a summary
format).
* Problems meeting the definition of UPIRTSO:

Any accidental or unintentional change to the IRB-approved protocol that increases risk or has the
potential to recur

Any deviation from the protocol taken without prior IRB review to eliminate apparent immediate
hazard to a research subject

Any publication in the literature, safety monitoring report (including Data and Safety Monitoring
Reports), interim result or other finding that indicates an unexpected change to the risk/benefit ratio of
the research

Any breach in confidentiality that may involve risk to the subject or others

Any complaint of a subject that cannot be resolved by the research staff

Any other possibly related event which in the opinion of the investigator constitutes an unanticipated
risk
10
STUDY DATA COLLECTION AND MONITORING PLAN
10.1
Data Management
This study will register patients using The Online Enterprise Research Management
Environment (OnCoreTM), a web based Oracle® database. Key study personnel are trained on
the use of OnCore and will comply with protocol specific instructions embedded within the
OnCore. Patient registration with demographics will be placed in OnCore and other research
databases maintained by MCC IT.
In addition, specific transplant related endpoints will be recorded in the University Of
Minnesota Blood and Bone Marrow Database as part of the historical database maintained by
the department.
Agency
Criteria for reporting
Timeframe
Form to Use
Submission
address/ fax
numbers
Copy AE to:
U of MN
IRB
Any event meeting the
definition of UPIRTSO
10 Working Days
UMCC SAE
MMC 820
SAE Coordinator
mcc-
saes@umn.edu
Any problem meeting the
definition of UPIRTSO*
10 Working
Days
UPIRTSO
All problems/events that do
not meet the IRB’s definition
of UPIRTSO* (see next page)
Annually
Summary format
MCC
SAE
Coordinator
Any event that counts toward
a study stopping rule (refer to
section 12.1)
Time of reporting
to BMT database
Stopping Rule
SAE
Coordinator
mcc-
saes@umn.edu
Not applicable


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10.2
Data and Safety Monitoring Plan (DSMP)
The study’s Data and Safety Monitoring Plan will be in compliance with the University of
Minnesota Masonic Cancer Center's Data & Safety Monitoring Plan (DSMP), which can be
accessed at http://www.cancer.umn.edu/exfiles/research/dandsmplan.pdf.
For the purposes of data and safety monitoring, this study is classified as moderate risk.
Therefore the following requirements will be fulfilled:

The PI will complete and submit twice yearly Trial Progress Report to the Masonic
Cancer Center Data and Safety Monitoring Council (DSMC)

The PI will comply with at least twice yearly monitoring of the project by the
Masonic Cancer Center monitoring services.

The PI will oversee the submission of all reportable adverse events per the
definition of reportable in section 9.3 to the Masonic Cancer Center’s SAE
Coordinator and the University of Minnesota IRB.
In addition, at the time of the continuing review with the University of Minnesota IRB, a copy
of the report with any attachments will be submitted to the Cancer Protocol Review
Committee (CPRC).
10.3
Monitoring
The investigator will permit study-related monitoring, audits, and inspections by the Masonic
Cancer Center, IRB, government regulatory bodies, and University of Minnesota compliance
groups. The investigator will make available all study related documents (e.g. source
documents, regulatory documents, data collection instruments, study data, etc.). The
investigator will ensure the capability for inspections of applicable study-related facilities
(e.g. pharmacy, diagnostic laboratory, etc.) will be available for trial related monitoring,
audits, or regulatory inspections.
10.4
Record Retention
The investigator will retain study records including source data, copies of case report form,
consent forms, HIPAA authorizations, and all study correspondence in a secured facility for at
6 years after the study file is closed with the IRB.
In addition, the Clinical Trials Office (CTO) will keep a master log of all patients
participating in the study with sufficient information to allow retrieval of the medical records
for that patient.
Please contact the CTO before destroying any study related records.


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11
ENDPOINTS
11.1
Primary Clinical Endpoint: Engraftment
Peripheral blood and bone marrow chimerism will be studied at day 21, day 60 and day 100.
Peripheral blood chimerism will also be evaluated as clinically indicated.
Successful sustained engraftment is defined as primary neutrophil engraftment by day 42 and
>90% donor cells at day 100, with or without DLI.
11.2
Safety Endpoints
Development of severe adverse events within 100 days of transplantation
> 30% transplant related mortality at 100 days
12
EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS
The primary objective of this study is to evaluate the efficacy and safety of fludarabine,
cyclophosphamide plus TBI as a nonmyeloablative preparative regimen for hematopoietic stem cell
transplantation.
As of 10/12/09, 147 patients of a planned 150 were enrolled on this protocol with the current
fludarabine dose of 40mg/m2 Day -6 through -2. We propose to enroll an additional 150 patients on
this trial with a new, lower fludarabine dose of 30mg/m2 Day -6 through -2. Assessment of
engraftment, rates of acute GVHD, chronic GVHD, overall survival (OS), treatment related mortality
(TRM), and incidence of relapse will be evaluated.
12.1
Stopping Boundaries
There will be monitoring for stopping rules for non-relapse mortality by day 100. Monitoring
will be performed separately for related and unrelated donor transplants and for arms 1-6
(standard risk) vs high risk (arm 7). If any of the stopping rules for arms 1-6 are reached,
enrollment in all 7 arms will be halted.
Arms 1-6 (Standard Risk Patients – refer to section 3.2):
For the unrelated donors, consideration will be made to close the study if there are 4 of 4, 5 of
6, 6 of 9, 7 of 11, 8 of 13, 9 of 15 or 11 of 20 non-relapse deaths prior to day 100. This
boundary has a type I error rate of 0.05 for a rate of 30% and a power of 51% to detect a rate
of 50%.
After 1/31/2004, we expect an additional 30 related donor patients to be enrolled. For these
patients, consideration will be made to close the study if there are 3 of 4, 4 of 6, 5 of 8, 6 of
11, 7 of 13, 8 of 16, 9 of 18, 10 of 21, 11 of 23, 12 of 26, 13 of 28 or 14 of 30 non-relapse
deaths prior to day 100. This boundary has a type I error rate of 0.05 for a rate of 30% and
power of 80% to detect a rate of 50%.


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As of this renewal (10/12/09), we expect an additional 150 patients to be enrolled. For these
patients, consideration will be made to close the study if there are 6 of 6, 7 of 9, 8 of 11, 9 of
14, 10 of 16, 11 of 19, 12 of 21, 13 of 24, 14 of 27, 15 of 29, 16 of 32, 17 of 34, 18 out of 37,
19 out of 39, 20 out of 42, 21 out of 44, 22 out of 47, 23 out of 49, 24 out of 52, 25 out of 54,
26 out of 57, 27 out of 59, 28 out of 62, 29 out of 64, 30 out of 67, 31 out of 69, 32 out of 72,
33 out of 74, 34 out of 77, 35 out of 79, 36 out of 84, 38 out of 87, 39 out of 89, 40 out of 92,
41 out of 95, 42 out of 97, 43 out of 100, 44 out of 102, 45 out of 105, 46 out of 107,
47 out of 110, 48 out of 112, 49 out of 115, 50 out of 117, 51 out of 120, 52 out of 122, 53 out
of 125, 54 out of 127, 55 out of 130, 56 out of 132, 57 out of 135, 58 out of 137, 59 out of
140, 60 out of 142, 61 out of 145, 62 out of 147 and 63 out of 150 non-relapse deaths prior to
day 100. This boundary has a type I error rate of 0.05 for a rate of 30% and power of 80% to
detect a rate of 50%.
For Arm 7 (High-Risk Patients – refer to section 3.3):
Continuous stopping boundaries have been designed to stop enrollment if the Day 100 non-
relapse mortality is significantly higher than 30%. The trial will be stopped if 4 of 4, 5 of 6, 6
of 9, 7 of 11, 8 of 13, 9 of 15, or 11 of 20 patients experience non-relapse mortality by Day
100. This boundary has a type I error of 0.051 for a D100 mortality rate of 30%, and a power
of 51% to detect a rate of 50%.
12.2
Statistical Analysis
The primary outcome variable is (P), the proportion of patients with engraftment. Patients
who do not have sustained engraftment will be considered to have graft failure.
Patients who die before day 21 will be considered non-evaluable for engraftment and the
cause of death noted.
Secondary outcomes include survival, non-relapse mortality, and grade III-IV acute GvHD.
Survival will be estimated by Kaplan-Meier methods. Non-relapse mortality and acute GvHD
will be estimated using cumulative incidence, treating non-event deaths as a competing risk.
12.4
Rationale for Sample Size
We estimate that we can enroll about 25 patients per year.
13
ETHICAL CONSIDERATIONS
13.1
Good Clinical Practice
The study will be conducted in accordance with the appropriate regulatory requirement(s).
Essential clinical documents will be maintained to demonstrate the validity of the study and
the integrity of the data collected. Master files should be established at the beginning of the
study, maintained for the duration of the study and retained according to the appropriate
regulations.


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13.2
Ethical Considerations
The study will be conducted in accordance with ethical principles founded in the Declaration
of Helsinki. The IRB will review all appropriate study documentation in order to safeguard
the rights, safety and well-being of the patients. The study will only be conducted at sites
where IRB approval has been obtained. The protocol, informed consent, written information
given to the patients, safety updates, annual progress reports, and any revisions to these
documents will be provided to the IRB by the investigator.
13.3
Informed Consent
All potential study participants will be given a copy of the IRB-approved consent to review.
The investigator or designee will explain all aspects of the study in lay language and answer
all questions regarding the study. If the participant decides to participate in the study, he/she
will be asked to sign and date the consent document. Patients who refuse to participate or who
withdraw from the study will be treated without prejudice.
14
REFERENCES
1.
Giralt S, Estey E, Albitar M, et al: Engraftment of allogeneic hematopoietic progenitor cells with
purine analog-containing chemotherapy: Harnessing graft-versus-leukemia without myeloablative
therapy. Blood 89: 4531-4536, 1997.
2.
Khouri IF, Keating M, Korbling M, et al: Transplant-lite: Induction of graft-versus-malignancy using
fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as
treatment for lymphoid malignancies. J Clin Oncol 16: 2817-2824, 1998.
3.
Grigg A, Bardy P, Byron K, et al: Fludarabine-based non-myeloablative chemotherapy followed by
infusion of HLA-identical stem cells for relapsed leukaemia and lymphoma. Bone Marrow Transplant
23: 107-110, 1999.
4.
Slavin S, Nagler A, Naparstek E, et al: Nonmyeloablative stem cell transplantation and cell therapy
as an alternative to conventional bone marrow transplantation with lethal cytoreduction for the
treatment of malignant and nonmalignant hematologic diseases. Blood 91: 756-763, 1998.
5.
Storb R, Yu C, Sandmaier BM, et al: Mixed hematopoietic chimerism after marrow allografts:
transplantation in the ambulatory care setting. Ann N Y Acad Sci 872: 372-375, 1999.
6.
Sykes M, Preffer F, McAfee S, et al: Mixed lymphohaemopoietic chimerism and graft-versus-
lymphoma effects after non-myeloablative therapy and HLA-mismatched bone-marrow
transplantation. The Lancet 353: 1755-1759, 1999.
7.
Champlin R, Khouri I, Kornblau S, et al: Reinventing bone marrow transplantation:
Nonmyeloablative preparative regimens and induction of graft-vs-malignancy effect. Oncology 13:
621-641, 1999.
8.
Champlin R, Khouri I, Kornblau S, et al: Reinventing bone marrow transplantation: reducing toxicity
using nonmyeloablative, preparative regimens and induction of graft-versus-malignancy. Current
Opinion in Oncology 11:87-95, 1999.
9.
Aksentijevich I, Sachs DH, Sykes M. Humoral tolerance in xenogeneic BMT recipients conditioned
by a nonmyeloablative regimen. Transplantation 53: 1108-1114, 1992.
10. Colson YL, Wren SM, Schuchert MJ, et al: A nonlethal conditioning approach to achieve durable
multilineage mixed chimerism and tolerance across major, minor, and hematopoietic
histocompatibility barriers. J Immunol 155: 4179-4188, 1995.
11. Manilay JO, Pearson DA, Sergio JJ, et al: Intrathymic deletion of alloreactive T cells in mixed bone
marrow chimeras prepared with a nonmyeloablative conditioning regimen. Transplantation 66: 96-
102, 1998.


MT2001-10 Allogeneic Transplant Using Less Intensive Therapy
November 12, 2013
Page 21 of 26
CPRC #2001LS058
12. Prigozhina TB, Gurevitch O, Zhu J, Slavin S: Permanent and specific transplantation tolerance
induced by a nonmyeloablative treatment to a wide variety of allogeneic tissues. Transplantation 63:
1394-1399, 1997.
13. Plunkett W, Saunders P P: Metabolism and action of purine nucleoside analogs. Pharmac Ther 49:
239-268, 1991.
14. Parsons DG, Bowman EPW, Blakley RL: Selective toxicity of deoxyadenosine analogues in human
melanoma cell lines. Biochemical Pharmacology 35: 4025-29, 1986.
15. Cheson B D: Infectious and immunosuppresive complications of purine analog therapy. J Clin Oncol
13: 2431-2448, 1995.
16. Allison A C, Eugui E M: The design and development of an immunosuppressive drug,
mycophenolate mofetil. Springer Sem Immunopathol 14: 353-380, 1993.
17. Morris R E, Hoyt E G, Murphy M P, et al: Mycophenolic acid morpholinoethylester (RS-61443) is a
new immunosuppressant that prevents and halts heart allograft rejection by selective inhibition of %-
and B-cell purine synthesis. Transplant Proc 22: 1659-1662, 1990.
18. Yu C, Seidel K, Nash RA, et al: Synergism between mycophenolate mofetil cyclosporine in
preventing graft-versus-host disease among lethally irradiated dogs given DLA- nonidentical unrelated
marrow grafts. Blood 91: 2581-7, 1998.
19. Goldman AI: Issues in designing sequential stopping rules for monitoring side effects in clinical trials,
Controlled Clinical Trials 8:327-337, 1987.
20. Goldman A I, Hannan P J: Toxicity monitoring in Phase II clinical trials. Statistics in Medicine.
Optimal continuous sequential boundaries for monitoring toxicity in clinical trials, a restricted search
algorithm. Statistics in Medicine 20:11, 2001.
21. Lachin J M: Introduction to sample size determination and power analysis for clinical trials.
Controlled Clinical Trials 2: 93-113, 1981.


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APPENDIX I: TOXICITIES AND COMPLICATIONS
Toxicities Associated with the Preparative Regimen:
Cyclophosphamide –
Common
Less Common
Rare
low white blood cell count
hair loss or thinning, including face and
body hair
nausea
vomiting
loss of appetite
sores in mouth or on lips
bleeding from bladder, with blood in
urine
diarrhea
long-term or short-term infertility in
women and men
low platelet count
darkening of nail beds
acne
tiredness
infection
fetal changes if
pregnancy occurs while
taking cyclophosphamide
heart problems with high doses, with
chest pain, shortness of breath, or
swollen feet
severe allergic reactions
skin rash
scarring of bladder
renal tubular necrosis which can lead to
kidney failure
scarring of lung tissue, with cough and
shortness of breath
second cancer
death from infection, bleeding, heart
failure, allergic reaction, or other causes
Fludarabine -
Common
Less Common
Rare
severe suppression of blood counts
fatigue
nausea
vomiting
fever and chills
infection
pneumonia
diarrhea
loss of appetite
weakness
pain
numbness and tingling in hands and/or
feet related to irritation of nerves
changes in vision
agitation
confusion
clumsiness
seizures
coma
cough
trouble breathing
intestinal bleeding
weakness
death due to effects on the brain,
infection, bleeding, severe anemia, skin
blistering, or other causes


MT2001-10 Allogeneic Transplant Using Less Intensive Therapy
November 12, 2013
Page 23 of 26
CPRC #2001LS058
Total Body Irradiation (TBI) -
Common
Less Frequent
Uncommon
diarrhea
nausea
stomach cramps
vomiting
painful swelling of the parotid gland
for a few days
short-term hair loss
anemia
infection
bleeding
cataracts
sterility
growth failure
endocrinopathies (such as thyroid
disease or diabetes)
mouth sores
pneumonia
redness of the skin
lowered liver function
risk of developing other cancers in the
future
difficulty swallowing
back problems (deformities in the
vertebrae)
lowered kidney function
Thymoglobulin (ATG)
Common
Less Frequent
Uncommon
fever
chills
leukopenia
pain
headache
abdominal pain
diarrhea
hypertension
nausea
thrombocytopenia
peripheral edema
dyspnea
asthenia
hyperkalemia
tachycardia
malaise
dizziness
severe allergic reaction (anaphylaxis)


MT2001-10 Allogeneic Transplant Using Less Intensive Therapy
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CPRC #2001LS058
Toxicities associated with GVHD Prophylaxis:
Cyclosporine (CSA)
Mycophenolate Mofetil (MMF)
nephrotoxcity
seizures
hypertension
hirsutism
increased risk of relapse
thrombotic thrombocytopenic purpura
electrolyte imbalances
paresthesias/neuropathy
gingival hyperplasia
increased risk of opportunistic infection
pancytopenia
headache
insomnia
electrolyte imbalances
leg cramps/bone pain
hypertension
dizziness
hyperglycemia
rash
nausea/diarrhea
Hematopoietic Stem Cell Transplantation

nausea and vomiting

possible allergic reaction (including itching, hives, flushing [red face], shortness of breath, wheezing, chest
tightness, skin rash, fever, chills, stiff muscles, or trouble breathing)

graft-versus-host-disease (GVHD)

veno-occlusive disease,

mucositis,

infections (sepsis)


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CPRC #2001LS058
APPENDIX II: CHEMOTHERAPY DRUG INFORMATION
Cyclophosphamide (Cytoxan)
Formulation: parenteral 100 mg and 500 mg vials. Commercially available
Availability: Commercially available
Storage: room temperature
Mixing: IV drug should be mixed with sterile water for IV use. Dissolves very slowly with cold
water.
Administration: Cytoxan is added to 250 ml of D5W and administered IV drip over a 1-2 hour
period usually at 10 am. Use an appropriate smaller volume for children.
Toxicity: Nausea and vomiting, alopecia, bone marrow depression, immunosuppression,
hemorrhagic cystitis, azospermia.
Fludarabine (Fludara- Berlex) (F-Ara-A, fludarabine phosphate)
Formulation: Vials (lyophilized solid cake): 50 mg (25 mg/ml after reconstitution)
Availability: Commercially available
Storage: Between 2 and 8° centigrade (36 and 46 F)
Mixing: Adding 2 mL of sterile water for injection to the 50 mg vial, producing a solution containing
25 mg/mL (the solid cake should fully dissolve within 15 seconds). Solutions may be further diluted
in 100 or 125ml of 5% dextrose injection or 0.9% sodium chloride injections for administration by
intravenous infusion.
Stability: Once diluted, solutions should be promptly administered or stored in the refrigerator for no
more than 8 hours prior to administration.
Administration: Fludarabine is administered over a 1-hour period.
Toxicity: Nausea and vomiting, bone marrow depression, fever, immunosuppression.


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CPRC #2001LS058
APPENDIX III: RESEARCH RELATED CONTROL COHORT FOR ITREG
STUDY (MT2012-06)
In November 2013, MT2012-06: “Dose Escalation Study with Extension of Inducible Regulatory T
Cells (iTregs) in Adult Patients Undergoing Non-Myeloablative HLA-Identical Sibling Donor
Peripheral Blood Stem Cell Transplantation” (M MacMillan, PI) opened to enrollment. As MT2012-
06 recruits a sub-set of the same patient population as does MT2001-10, this sub-study serves to
enroll 10 MT2001-10 patients who consent to act as controls for the “iTreg patients” by providing
additional blood for research related testing prior to the start of the preparative regimen, prior to the
transplant on day 0, and at 7 time points over the 1st 100 days post-transplant.
This is an optional sub-study for persons 18 years and older enrolling on MT2001-10 with one of the
following diagnoses for which a related donor will be used as the stem cell source:

Acute myelogenous leukemia

Acute lymphocytic leukemia

Chronic myelogenous leukemia

Non-Hodgkin lymphoma or Hodgkin lymphoma

Myelodysplastic syndrome
The samples will be used to assess for the number of T regs and T effector cells at each time point
compared with the patients enrolled on MT2012-06. The need for the control is to be able to
determine what contribution the iTregs have versus the PBSC. As the Tregs are from the same donor
as the peripheral blood stem cell (PBSC) graft the comparison is not possible without a control.
Research Related Sample Collection Schedule
Activity/ Laboratory
Pre
Chemo
Days Post-HCT (+/- day)
-6 or
earlier
+0
Pre
HCT
+1
(1)
+3
(1)
+7
(1)
+14
(1)
+28 (3),
+60 (7),
+100 (7)
Consent for additional
sample collection
Pre-
HCT
5 – 10 ml green top tubes
1 – 5 ml red top tube
To TTL
X
X
X
X
X
X
X