Clinical trial NCT00612716
Conditions: Leukemia Lymphoma Multiple Myeloma and Plasma Cell Neoplasm
Keywords: stage I multiple myeloma stage II multiple myeloma stage III multiple myeloma refractory multiple myeloma recurrent adult Hodgkin lymphoma recurrent/refractory childhood Hodgkin lymphoma refractory chronic lymphocytic leukemia stage III chronic lymphocytic leukemia stage IV chronic lymphocytic leukemia recurrent adult grade III lymphomatoid granulomatosis adult nasal type extranodal NK/T-cell lymphoma Waldenstrom macroglobulinemia recurrent adult Burkitt lymphoma stage I adult Burkitt lymphoma stage II adult Burkitt lymphoma stage III adult Burkitt lymphoma stage IV adult Burkitt lymphoma recurrent adult diffuse large cell lymphoma recurrent adult diffuse mixed cell lymphoma recurrent adult diffuse small cleaved cell lymphoma recurrent adult immunoblastic large cell lymphoma stage I adult immunoblastic large cell lymphoma stage II adult immunoblastic large cell lymphoma stage III adult immunoblastic large cell lymphoma stage IV adult immunoblastic large cell lymphoma recurrent adult lymphoblastic lymphoma stage I adult lymphoblastic lymphoma stage II adult lymphoblastic lymphoma stage III adult lymphoblastic lymphoma stage IV adult lymphoblastic lymphoma recurrent grade 1 follicular lymphoma recurrent grade 2 follicular lymphoma recurrent grade 3 follicular lymphoma recurrent mantle cell lymphoma extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue nodal marginal zone B-cell lymphoma recurrent marginal zone lymphoma splenic marginal zone lymphoma recurrent small lymphocytic lymphoma recurrent childhood anaplastic large cell lymphoma recurrent childhood grade III lymphomatoid granulomatosis childhood diffuse large cell lymphoma childhood immunoblastic large cell lymphoma recurrent childhood large cell lymphoma recurrent childhood lymphoblastic lymphoma childhood nasal type extranodal NK/T-cell lymphoma Burkitt lymphoma recurrent childhood small noncleaved cell lymphoma stage I childhood small noncleaved cell lymphoma stage II childhood small noncleaved cell lymphoma stage III childhood small noncleaved cell lymphoma stage IV childhood small noncleaved cell lymphoma
Sponsor: Masonic Cancer Center, University of Minnesota
Start date: 1999-10-06; Completion date: 2019-12-15
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
RATIONALE: Giving chemotherapy, such as cyclophosphamide and busulfan, and total-body irradiation before a donor stem cell transplant helps stop the growth of cancer cells. It also stops the patient's immune system from rejecting the donor's stem cells. The donated stem cells from bone marrow or umbilical cord blood may replace the patient's immune cells and help destroy any remaining cancer cells (graft-versus-tumor effect). Sometimes the transplanted cells from a donor can also make an immune response against the body's normal cells. Giving methotrexate and cyclosporine after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well a donor stem cell transplant works in treating patients with previously treated lymphoma, multiple myeloma, or chronic lymphocytic leukemia.

Detailed description:
OBJECTIVES:

* Determine if allogeneic stem cell transplantation using unrelated matched or related haploidentical donor bone marrow or unrelated matched cord blood results in timely, complete, and durable engraftment in patients with previously treated lymphoma, multiple myeloma, or chronic lymphocytic leukemia.
* Determine the incidence and grade of acute and chronic graft-versus-host disease in patients treated with this regimen.
* Determine if the augmented graft-versus-tumor effect accompanying unrelated or partially matched donor allogeneic transplant reduces the incidence of relapse in these patients.

OUTLINE:

* Preparative regimen: Patients receive cyclophosphamide IV over 2 hours on days -7 and -6 and undergo total-body irradiation (TBI) twice daily on days -4 to -1. Patients who are unable to undergo TBI receive busulfan IV or orally 4 times daily on days -9 to -6 and cyclophosphamide IV over 2 hours on days -5 to -2.
* Stem cell transplantation: All patients undergo unrelated matched bone marrow or umbilical cord blood transplantation or partially matched related allogeneic bone marrow transplantation on day 0.
* Graft-versus-host disease (GVHD) prophylaxis: Patients receive GVHD prophylaxis comprising methotrexate and cyclosporine. Patients may be enrolled in other protocols directed towards GVHD prophylaxis.

Arms: arm 1: Patients receiving total body irradiation, stem cell infusion (allogeneic)transplantation using unrelated or partially matched allogeneic marrow or cord blood donors, busulfan, and cyclophosphamide.
Interventions: intervention 1: busulfan intervention 2: cyclophosphamide intervention 3: Stem cell infusion intervention 4: Total body irradiation
Intervention descriptions: intervention 1: For those not eligible for total body irradiation: busulfan 4 mg/kg/day orally (1 mg/kg orally every 6 hrs) on Days -9 through -6. intervention 2: Cyclophosphamide 60 mg/kg/day on days -7 and -6. For patients not eligible for total body irradiation: cytoxan 50 mg/kg intravenously (IV) on days -5 through -2. intervention 3: Infused on Day 0 intervention 4: 165 cGy morning and evening on days -4 through -1.

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
UNIVERSITY OF MINNESOTA BONE MARROW TRANSPLANTATION PROGRAM 
 
 
 
 
UNRELATED OR PARTIALLY MATCHED ALLOGENEIC DONOR STEM CELLS FOR 
LYMPHOMA, MYELOMA, AND CHRONIC LYMPHOCYTIC LEUKEMIA 
 
MT1999-14 
 
 
August 30, 1999 
Revised October 11, 1999 
Revised November 18, 1999 
Revised January 8, 2004 
Revised May 9, 2008 
 
 
 
 
Study Committee 
 
Daniel Weisdorf, M.D., Chair 
 
Linda Burns, M.D. 
Jeffrey Miller, M.D. 
Bruce Blazar, M.D. 
Kathryn Dusenbery, M.D. 
John Wagner, Jr. M.D. 


 
2
Protocol Changes and Amendments 
May 9, 2008 
Cord blood grafts may be single or double 
Updated protocol for IRB reapplication process (changed 
enrollment goals, added DSM plan) 
8/6/08 
January 8, 2004 
Busulfan pharmacokinetics added (section 4.1.2) 
 
September, 
2002 
Protocol Amendment page added 
 
November 18, 
1999 
Radiation guidelines changed at the request of Dr. Katie 
Dusenbery, Therapeutic Radiation Department (section 
4.1.2). 
December 10, 1999 
(final IRB approval 
for project) 
October 11, 
1999 
At the request of the CPRC, a schema, drug information, 
data items, and adverse event procedures were added to this 
study (items needed before final approval could be granted). 
December 10, 1999 
(final IRB approval 
for project) 
 


 
3
 
TABLE OF CONTENTS 
 
 
Section 
Title 
 
 
 
 
 
 
 
 
Page 
 
 
1.0 
 
Objectives 
 
 
 
 
 
 
 
3 
2.0 
 
Background and Rationale 
 
 
 
 
 
3 
3.0 
 
Eligibility and Exclusion Criteria 
 
 
 
 
5 
4.0 
 
Treatment Schema 
 
 
 
 
 
 
6 
5.0 
 
Required Observations 
 
 
 
 
 
9 
6.0 
 
Toxicities and Complications  
 
 
 
 
10 
7.0 
 
Experimental Design and Statistical Consideration  
 
12 
8.0 
 
Data and Safety Monitoring Plan  
 
 
 
 
12 
 
 
References 


 
4
1.0 
OBJECTIVES 
 
In order to reduce the risk of relapse and to improve long-term survival for chronic lymphoid 
malignancies this allogeneic donor stem cell study is designed to answer the following questions:  
 
1.1 
Can allogeneic transplantation using unrelated or partially matched allogeneic marrow 
or cord blood donors result in timely, complete and durable engraftment in recipients 
with advanced lymphoproliferative malignancies? 
 
1.2 
What is the incidence and grade of acute and of chronic GVHD observed following 
such allogeneic transplant? 
 
1.3 
Can the augmented graft versus tumor effect accompanying unrelated or partially 
matched donor allogeneic transplant reduce the incidence of relapse for these high risk 
malignancies? 
 
2.0 
BACKGROUND AND RATIONALE 
 
For many years, histocompatible related donor marrow was used as source of stem cells for almost all 
allogeneic transplantations.  However over the last 15 years, over 8000 patients have undergone 
unrelated donor allogeneic marrow transplants, and over the last several years, over 1000 have 
undergone unrelated donor umbilical cord stem cell transplants.  Both these sources of stem cells 
have been able to effect complete myeloid and lymphoid reconstitution, restoring hematopoiesis and 
defense against infection.  The immune systems developing from the unrelated donor marrow or cord 
blood cells have had variable problems associated with their transplantation including a somewhat 
higher risk of graft failure or slow engraftment and possibly more frequent Graft versus Host Disease, 
at least as compared with sibling donor bone marrow.  Matched unrelated donor marrow transplants 
yield results for various diseases that are either similar to or slightly inferior (10 to 15 percent more 
frequent complications and mortality) compared to sibling donor BMT.  However even with the 
extended resources of the National Marrow Donor Program (NMDP) not all patients have an 
available sibling or unrelated adult donor marrow available.  Umbilical cord blood, perhaps because 
of its immunologic immaturity and greater ease of establishing immunologic tolerance with tissues of 
the recipient, might provide allogeneic cells available for transplantation for those patients lacking an 
unrelated or related adult donor for transplantation.  Additionally, UCB might be associated with less 
risks of Graft versus Host Disease and thus lower peri-transplant related mortality. 
 
As an additional option, partially matched (haploidentical) stem cells from a related donor would 
provide a source for allo-transplantation for nearly all other patients.  Though clinical experience is 
less, haploidentical BMT yields similarly increased risks of graft failure, GVHD, and post-transplant 
immunodeficiency yet can be performed promptly, with a large cell dose for nearly all patients using 
either parents, most siblings or the patient's children as obligate at least halploidentical or better 
donor. 
 
For treatment of advanced lymphoproliferative disease including non-Hodgkin's Lymphoma, 
Hodgkin's disease, Multiple Myeloma, and Chronic Lymphocytic Leukemia, both allogeneic and 
autologous transplantation have been used widely.  For early stage patients such as those in PR1 or 


 
5
CR2 PR2, some categories of Hodgkin's Disease and non-Hodgkin's Lymphoma can be effectively 
cured in sizable fractions of patients using auto transplantation.   For patients with more advanced 
disease, for low grade lymphoma, for mantle cell lymphoma, myeloma, and CLL, autografting is not 
widely accepted as potentially curative therapy, though published experience suggests its potential 
value in achieving extended remission duration. 
 
In contrast, allogeneic transplantation for these advanced lymphoproliferative diseases has resulted in 
extended relapse free or progression free survival for a substantial number of patients suggesting the 
curative potential of these allogeneic approaches.  In this trial, we propose to evaluate unrelated or 
partially matched related donor stem cells either from adult unrelated donor marrow available 
through the NMDP or unrelated donor umbilical cord blood cells to facilitate allogeneic 
transplantation for patients who are poor candidates for autografting and have no available matched 
related donor.  Evaluation of the success of prompt engraftment, acute and chronic graft versus host 
disease, overall peri-transplant mortality and extended disease free survival will be evaluated in 
contrast with other experience using matched related donor hematopoietic stem cells for 
transplantation. 
 
2.1 
Clinical Trial 
 
We propose to perform closely matched unrelated donor transplants using either adult 
donor marrow or cryopreserved umbilical cord blood stem cells or in some patients, 
partially matched related donor transplants. Eligible patients will include individuals 
who have advanced Hodgkin's disease, non-Hodgkin's lymphoma, myeloma, or 
chronic lymphocytic leukemia. Patients will receive standard acute GVHD 
prophylaxis with a combination of methotrexate and cyclosporine, or, if eligible, 
alternative GVHD prophalaxis. 
 
We will assess engraftment, time to engraftment, incidence and severity of acute 
GVHD, incidence and severity of chronic GVHD, development of unusual GVHD 
syndromes; post-transplant infections, lymphoproliferative disease and immune 
reconstitution; survival and persistence or relapse of malignant disease.   
 
3.0 
ELIGIBILITY AND EXCLUSION CRITERIA 
 
3.1 
Donors will be <55 years of age and in good health as approved by the NMDP donor and 
collection centers. Related donors will be < 70 years of age. 
 
3.2 
Recipients will be <55 years, will have satisfactory organ function (excluding bone marrow) 
and will have a Karnofsky activity assessment >90% and will have: 
 
3.2.1 Creatinine <2.0 mg/dl. 
3.2.2 Bilirubin, AST, ALK <2 x normal. 
3.2.3 Pulmonary function test and DLCO > 50% of normal. 
3.2.4 MUGA >45% injection fraction. 
 


 
6
3.3 
Recipients with unrelated donor matched at the HLA A, B, DRBI loci, or if < 35 years 
mismatched at a single HLA A or B, or DRBI locus. 
 
3.4 
Umbilical cord blood (5) used as an unrelated stem cell source will provide > 2.0 x 107 
cells/kg and will be matched at 4 - 6 of 6 HLA A, B, and DRBI loci.  Cord blood grafts may include a 
single or pair of cord units depending on the cell dose. 
 
3.5 
Partially matched related donors will be at least haploidentical (matched at >3 of 6 HLA A, B, 
DRB1 loci). 
 
3.6 
Recipients will fall under one of the following disease categories 
 
3.6.1 Chronic lymphocytic leukemia -- must have all three: 
 
1. 
Rai Stage III/IV 
2. 
Progression after previous CR or PR including purine antagonist (i.e. 
fludarabine). 
3. 
Recent chemotherapy responsiveness 
 
3.6.2 Advanced non-Hodgkin's (NHL). 
 
3.6.2.1 Low-grade NHL (Working Formulation A, B, C) following progression after 
initial therapy if asymptomatic at diagnosis (>CR2, > PR2; response duration < 
1 year from last therapy) or if no CR was achieved (>PR1).  At least one prior 
therapy of intermediate intensity (e.g. CHOP). 
 
3.6.2.2 Mantle zone lymphoma after any progression following initial therapy (>CR1, 
> PR1). At least one prior therapy of intermediate intensity (e.g. CHOP). 
 
3.6.2.3 Intermediate grade lymphoma (> PR2).  Response duration < 1 year from prior 
therapy. 
 
3.6.2.4 High-grade NHL (IWF H, I, J) after initial therapy if >stage III at diagnosis; 
after any progression even if localized (stage I, II) at diagnosis with prior 
response duration < 1 year. 
 
3.6.2.5 Recent chemotherapy responsiveness after treatment with > 3 intermediate 
intensity regimens. 
 
3.6.3 Advanced Hodgkin's disease beyond PR2 (>CR3, >PR3). 
 
3.6.3.1 Recent chemotherapy responsiveness 
 
3.6.4 Multiple Myeloma  (> CR2, > PR2) or after initial therapy if no prior PR. 
 
3.6.4.1 Recent chemotherapy responsiveness 


 
7
 
3.7 
Recipients will sign informed consent approved by the Committee on the Use of Human 
Subjects at the University of Minnesota. 
 
3.8 
Exclusions:  No available histocompatible related donor; 2nd BMT, HIV-1 positive; active 
uncontrolled infection; or resistant malignancy. 
 
4.0 
TREATMENT SCHEMA 
 
4.1 
Transplant procedure 
4.1.1 Preparative therapy. 
 
Day  
Therapy 
-7 
cyclophosphamide 60 mg/kg/day 
 
-6 
cyclophosphamide 60 mg/kg/day 
 
-5 
Rest 
 
-4 
TBI, 165 cGy a.m. and p.m. 
 
-3 
TBI, 165 cGy a.m. and p.m. 
 
-2 
TBI, 165 cGy a.m. and p.m. 
 
-1 
TBI, 165 cGy a.m. and p.m. 
 
0 
Infusion of stem cells. 
 
 
Total cyclophosphamide 120/kg 
Total TBI 1320 cGy. 
4.1.2 Alternative therapy for patients not eligible to receive TBI. 
 
Day  
Therapy 
-9 
busulfan 4 mg/kg/day po (1 mg/kg po every 6 hrs.) 
(may be administered intravenously see below)* 
 
-8 
busulfan 4 mg/kg/day po (1 mg/kg po every 6 hrs.) 
 
-7 
busulfan 4 mg/kg/day po (1 mg/kg po every 6 hrs.) 
 
-6 
busulfan 4 mg/kg/day po (1 mg/kg po every 6 hrs.) 
 
-5 
cytoxan 50 mg/kg IV 
 


 
8
-4 
cytoxan 50 mg/kg IV 
 
-3 
cytoxan 50 mg/kg IV 
 
-2 
cytoxan 50 mg/kg IV 
 
-1 
Rest 
 
0 
Infusion of stem cells. 
 
 
Total cyclophosphamide 200 mg/kg. 
Total busulfan 16 mg/kg if oral or IV equivalent 
* Busulfan (intravenous BUSULFEX) dose, administration and phamacokinetic 
monitoring to be administered as described in MT2003-19S.   
 
4.1.3 Cyclophosphamide will be given in a two-hour infusion with attention to vigorous 
hydration, fluid balance and maintenance of urine output. 
 
4.1.4 Mesna will be administered according to support protocol MT(S) 9006 during 
cyclophosphamide infusion. 
 
4.1.5 TBI will be administered in the mid-plane dose of 1,320 cGy in eight fractions of 165 
cGy over four days at 10 to 19 cGy/minute prescribed to the midplane at the 
umbilicus.  The two daily fractions are given at least 6 hours apart.  Radiation will be 
administered through bilateral ports.  A "beam spoiler" will be used to increase the 
skin dose.  Individually designed compensations are used to keep the dose 
homogeneity along the axis of the patient to within  10% of the prescribed dose. 
 
4.2 
Supportive Care 
 
4.2.1 All patients will receive allopurinol (300 mg/d or 150 mg/M2/d p.o.) beginning one 
day prior to conditioning and on day zero unless hyperuricemia (>10 mg/dl) persists. 
 
4.2.2 Vigorous intravenous hydration (20003000 ml/m2/day) should be given from 12 
hours prior to the first cyclophosphamide dose until 24 hours past the termination of 
cyclophosphamide therapy.  Adequate diuretics should be given and patients urged to 
urinate every 1-2 hours to ensure urinary output of at least 200 ml/two hours to 
maintain appropriate fluid balance.  Patients should be weighed b.i.d. during 
cyclophosphamide administration to aid in managing fluid balance. 
 
4.2.3 Mesna should be given in total milligram dose equivalent to the cyclophosphamide 
dose q.d. (divided in 5 doses: pre, 1 hour, 3, 6 and 12 hours after) beginning at the 
time of cyclophosphamide administration and continuing until cyclophosphamide 
therapy is terminated. 
 


 
9
4.2.4 Vigorous hydration should also be administered (approximately 1500 ml/m2/d) during 
busulfan or irradiation therapy. 
 
4.2.5 Patients receiving busulfan should also receive phenytoin (po or if needed IV) as anti-
convulsant therapy for 11 days, beginning day -10. 
 
4.2.6 Patients will be eligible for additional transplant studies related to unrelated marrow, 
cord blood, or other allogeneic transplantation. 
 
4.2.7 Patients will be eligible for additional supportive care study protocols including, but 
not limited to, those related to prophylaxis and treatment of infection, mucositis and/or 
nutritional support. 
 
4.2.8 All blood product support administered within one week preceding, and following 
initiation of chemotherapy will be irradiated to prevent inadvertent blood donor 
lymphoid engraftment. 
 
4.2.9 Standard blood product support techniques will be used, including packed red cell 
transfusions to maintain hemoglobin > 8.0 g/dl, platelet transfusion support to 
maintain platelet counts > 10,000/l.  Leukocyte transfusions will be indicated only 
under extraordinary circumstances after discussion with the attending physician. 
 
5.0 
REQUIRED OBSERVATIONS 
 
5.1 
Pre-transplant: Anti-HIV, hepatitis B surface antigen, anti-HCV, CMV HSV serologies. 
 
5.2 
Suitable markers of donor recipient chimerism pretransplant to include cytogenetics, HLA 
typing, RFLP, in situ Y chromosome hybridization as needed. 
 
5.3 
Engraftment: 
 
5.3.1 Time to first of 3 consecutive days with ANC > 500/l. 
 
5.3.2 Time to platelet transfusion independence (platelets > 20,000 with no transfusions for 
the following 7 days). 
 
5.3.3 Time to RBC transfusion independence (Hb > 9.0 with no transfusions for the 
following 15 days). 
 
5.4 
Incidence of initial and late graft failure. 
 
5.5 
Incidence and severity of acute GVHD (grade II/IV; grade III/IV). 
 
5.6 
Incidence and severity of chronic GVHD. 
 
5.7 
Donor chimerism at +3 mos., +6 mos., +12 mos. 


 
10 
 
6.0 
TOXICITIES AND COMPLICATIONS 
 
6.1 
Cyclophosphamide: is manufactured and commercially available in the United States. 
 
Hemorrhagic cystitis may occur following the use of cyclophosphamide despite aggressive 
fluid replacement, frequent voiding and Mesna. 
 
Cyclophosphamide can cause fatal cardiac necrosis with clinical irreversible heart failure.  
EKG changes are not infrequent and reduction in EKG voltage may be observed.  Patients 
previously treated with anthracyclines or with mediastinal irradiation may be at higher risk.  
Cyclophosphamide (with or without irradiation) may also induce pericarditis. 
 
Nausea, vomiting and diarrhea are frequent following high doses of cyclophosphamide.  
Aggressive anti-emetic therapy, including Ondansetron, may be helpful in minimizing this 
problem. 
  
Alopecia is common.  It is usually reversible, but changes in hair color or texture after 
regrowth may occur. 
 
Skin rash may occur, but is infrequent. 
 
Sterility:  Permanent sterility is likely at this dose of cyclophosphamide, particularly when 
given with other drugs and/or irradiation. 
 
6.2 
Total body irradiation 
 
1320 cGy is administered in 8 fractions over 4 days.  Nausea, vomiting and diarrhea are 
common. 
 
Generalized mild cutaneous erythema is frequently seen. 
 
Parotitis may occur. 
 
Lung:  Inflammatory pneumonitis or even respiratory failure may develop in the first three 
months following TBI.  Late respiratory failure has been seen in a small fraction of patients. 
 
Sterility:  Sterility is common after this dose of total body irradiation. 
 
Brain damage can develop in a small fraction of treated patients. 
 
6.3 
Busulfan Oral and IV Busulfan are manufactured and commercially available. 
 
6.3.1 Action:  a bifunctional alkylating agent  
 
6.3.2 Supplied as:  2 mg tablets for oral use only or as IV formulation (busulfex) 


 
11 
 
6.3.3 Toxicity:  myelosuppression, mucositis, diarrhea, alopecia, pulmonary fibrosis, 
amenorrhea, azoospermia, hepatitis, veno-occlusive disease, seizures  
 
6.4 
Myelosuppression 
 
Both the chemotherapy + TBI, or the chemotherapy only conditioning induce significant 
myelosuppression requiring reinfusion of viable hematopoietic stem cells for prompt marrow 
recovery.  During the period of myelosuppression and pancytopenia, the patient is highly 
vulnerable to infection and/or bleeding.  Irradiated red cell transfusions will be given to 
maintain adequate oxygen delivery and platelet transfusions will be given in an attempt to 
prevent bleeding.  Various isolation and prophylactic measures to reduce risks of infection 
and to vigorously treat any infections will also be required. 
 
6.5 
Graft Failure  
 
Infusion of allogeneic stem cells may be associated with failure to engraft, partial engraftment 
of one, two, or three cell lineages or late graft failure. Graft failure may be treated with 
growth factors, infusion of additional marrow or available stem cells obtained from the 
original donor after recognition of graft failure. 
 
6.6 
Graft vs. Host Disease (GVHD) 
 
Infusion of allogeneic cells may be associated with development of acute and/or chronic 
GVHD.  An attempt to reduce incidence and severity of GVHD  will be made by using 
GVHD prophylaxis consisting of methotrexate (MTX) and cyclosporine  (CSA), which are 
both commercially available or other GVHD prophylaxis.  Cord blood recipients will 
receive MMF (mycophenylate mofetil) from day -3 to +30 instead of methotrexate, or other 
GVHD prophylaxis depending on current institutional standards.  Patients may be enrolled 
on other study protocols directed toward the prevention of GVHD.  Acute and chronic 
GVHD will be treated according to established protocols. 
 
6.7 
Second Malignancy 
 
The potential carcinogenic effects of the pre-transplant chemotherapy and/or radiation may 
compound any inherent risks of second malignancy already induced by treatment the patient 
may have already received.  Both late second epithelial malignancies and early treatment-
associated neoplasms (particularly myelodysplastic syndrome and/or leukemia) may develop 
after transplantation. 
 
6.8 
Reporting of Adverse Reactions:  It is the responsibility of the investigator to report all 
adverse reactions, or suspected adverse reactions.  The principal investigator with the 
assistance all co-investigators, are responsible for assessing all adverse events, then 
classifying the toxicity according to the protocol designed toxicity scale.  
 
7.0 
EXPERIMENTAL DESIGN AND STATISTICAL CONSIDERATIONS 


 
12 
 
7.1 
Patient Accrual 
 
Based on the BMT patient referral pattern of the University of Minnesota, we expect to accrue 
3 cases to this study each year.  The overall case accrual will be 15. Other transplant 
approaches and higher priority clinical trials limit accrual for this transplant study but selected 
patient populations may have no more promising treatment option. 
 
7.2 
Statistical Analysis 
 
The major end points of this study are engraftment failure, time to engraftment, incidence and 
severity of acute and chronic GVHD, persistence or relapse of malignancy and survival of the 
recipient.  These end points will be evaluated using standard survival analysis methods, 
including the product limit method and Cox proportional hazard model.  Results will be 
compared to historical data of bone marrow transplantation from histocompatible related 
donor allogeneic bone marrow or blood stem cells. 
 
 
8.0 
DATA AND SAFETY MONITORING PLAN 
This study will be in compliance with the University of Minnesota Cancer Center's Data & 
Safety Monitoring Plan, which can be accessed at 
http://www.cancer.umn.edu/page/resource/dataplan.html  
 
Regular meetings of the study's principal investigator and staff will be held to discuss matters 
related to the safety of protocol participants (SAE reporting), validity and integrity of the data, 
enrollment rate, retention of participants, adherence to protocol, and data completeness 
 
The Principal Investigator will provide at least monthly monitoring of patient safety with 
quarterly reporting to the Clinical Trials Office (CTO) for distribution to the Cancer Protocol 
Review Committee's (CPRC) Data & Safety Monitoring Council (DSMC). 
 
At the time of the IRB continuing review, the Principal Investigator will report to the CPRC 
the number of patients entered on the trial, the number of patients, treated, a summary of all 
adverse events reported to date using CTC grading, a specific list of serious adverse events 
requiring immediate reporting, and significant literature reporting developments that may 
affect the safety of participants or the ethics of the study.