Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Trial Description

Summary

The purpose of the current study is to continue to optimize conditioning regimens in high-risk patients with severe aplastic anemia transplanted with marrow from HLA-compatible unrelated donors. Specifically, the study will determine whether the addition of fludarabine to the conditioning regimen previously described by Deeg et al. will permit a reduction in the CY dose, to a point where sustained hematopoietic engraftment and survival are maintained (or improved), while the frequency of major regimen-related toxicity (RRT) and early deaths is reduced.

Further Study Information

BACKGROUND:

Aplastic anemia (AA) remains a life-threatening illness. Treatment options include supportive care (transfusions, growth factors, etc.), immunosuppression therapy and stem cell transplantation. Only the latter two have favorably impacted the natural history of the disease. The prognosis of AA patients, particularly SAA, as defined by Camitta et al., who fail to respond to immunosuppressive therapy (IS) or who relapse after an initial response to IS is poor. Although many of these patients can be supported in the short term with growth factors, transfusions and possibly rechallenged successfully with IS, the cumulative morbidity and mortality from infection, hemorrhage or transfusion-related complications is substantial.

While allogeneic bone marrow transplantation is potentially curative in AA, no more than 25% of patients have an HLA-identical sibling donor. Cyclophosphamide (CY)-ATG has been recommended as the preparative regimen of choice in sibling donor transplants. Results of bone marrow transplantation from alternative donors, such as matched unrelated donors and mismatched related donors in AA patients who have failed IS, have largely been unsatisfactory. The cyclophosphamide-ATG conditioning regimen has proved inadequate in ensuring engraftment in allogeneic transplants from matched, unrelated donors for AA. This was the major reason why total body radiation (TBI) has been added to the conditioning regimen.

Graft failure is a very serious and frequently life-threatening or fatal event following MUD allografts in aplastic anemia. It is an immunologically mediated event. Risk factors for graft failure include the use of HLA nonidentical or unrelated donors, a poor marrow nucleated cell dose as well as prolonged transfusional support prior to BMT (which increases the probability of patient sensitization to multiple antigens). While some patients may achieve autologous hematopoietic recovery, prolonged pancytopenia is common and infection-related morbidity and mortality are very substantial. Reconditioning for a second allograft from the same or a different donor is frequently not successful. While the addition of TBI and intensive pre-transplant conditioning has led to a sizable improvement in engraftment rates, this has come with a price, particularly in adult patients. Transplant-related toxicity has been a major and frequent problem. Radiation-induced pulmonary toxicity in particular has been common, usually in the form of diffuse alveolar damage or diffuse interstitial pneumonitis. In addition, GVHD-related morbidity and mortality in these patients have also been substantial.

DESIGN NARRATIVE:

The study is a prospective Phase I/II dose optimization study. All patients are given a fixed dose of ATG (either thymoglobulin: 3 mg/kg IV daily x 3 or ATGAM 30 mg/kg IV daily x 3, on Days -4 to -2), Fludarabine (30 mg/m^2 IV daily x 4, on Days - 5 to -2), and TBI (200 cGy from a linear accelerator at less than 20 cGy/min on Day -1). The starting CY dose will be 150 mg/kg (50 mg/kg intravenously daily, Days -4 to -2), and will be de-escalated depending on engraftment and toxicity. The Phase I portion of the trial (maximum of 24-27 patients) tests each of four dose levels of CY for adequate safety and graft retention. The Phase II portion of the trial refines the dose selection and allocates an additional 54 patients to the optimal dose, at which two-year post-transplant survival will be assessed. The combined enrollment in Phase I and II will total 78-81 patients.

The study is a prospective single-arm Phase I/II dose-selection and evaluation study. The study will seek the optimal dose level of CY based on assessments of graft failure, toxicity and early death during 100 days of follow-up post-transplant. A brief synopsis is given below.

Phase I - Test Each Dose for Adequate Safety and Graft Retention

1. Proceed from the highest dose (150 mg/kg CY) to the lowest dose (0 mg/kg CY), treating a minimum of six patients at each dose.

2. Evaluate the 100-Day outcomes for toxicity, death and graft failure on each patient enrolled at the current dose, or until stopping criteria are met.

3. If there are three or more graft failures at the current dose, the current dose and all lower doses are closed to further enrollment.

4. If there are five or more severe regimen-related toxicities and/or early deaths at the current dose, the current dose is closed to further enrollment, and the next lower dose is tested.

5. Dose de-escalation ceases once all four doses are tested or closed to further enrollment.

Phase II - Refine Dose Selection and Allocate Patients to the Optimal Dose

1. Treat each newly enrolled patient at the most desirable of the dose levels remaining open to enrollment. This can involve de-escalation, escalation, or no change in dose.

2. As each patient completes the observation period, evaluate the 100-Day outcomes for graft failure, toxicity and/or early death for this patient, or until stopping criteria are met.

3. If there are excess (according to the criteria in Table 5.8) graft failures, that patient's dose and all lower doses are closed to further enrollment.

4. If there are excess (according to the criteria in Table 5.8) toxicities and/or early deaths, that patient's dose is closed to further enrollment.

5. Re-evaluate the desirability of the current dose level based on the 100-Day outcomes for toxicity and/or early death and graft failure.

6. Repeat steps 1-5 until 54 patients are enrolled in Phase II, or all dose levels are closed to further enrollment.

Dosage Levels for CY:

3 Days (Day -4, -3, -2): Dose of 50 mg/kg/day; total dose of 150 mg/kg; dose level 3

2 Days (Day -3, -2): Dose of 50 mg/kg/day; total dose of 100 mg/kg; dose level 2

1 Day (Day -2): Dose of 50 mg/kg/day; total dose of 50 mg/kg; dose level 1

0 Days (None): No dose; no total dose; dose level 0

There may be wait periods between enrollment of successive patients and/or cohorts for endpoint assessment. Under these circumstances, the final decision about waiting versus treating the patient off study will be made at the local transplant center.

Primary Outcomes:

1. Graft Failure: Neutrophil engraftment is defined as the achievement of an ANC ≥ 0.5 x 10^9/L for three consecutive measurements on different days. Primary graft failure is defined by the lack of neutrophil engraftment; i.e., ANC < 0.5 x 10^9/L measured for three consecutive measurements on different days by 100 days post-transplant. Secondary graft failure prior to Day 100 post-transplant will count towards the graft failure endpoint.

2. Regimen-related Toxicity (RRT): RRT will be scored according to the Bearman scale. Major RRT is defined as severity of grade 4 in any organ system or grade 3 for pulmonary, cardiac, renal, oral mucosal or hepatic, in keeping with the approach adopted in FHCRC Protocol #800. The assessment for RRT will be carried out weekly until Day 100 post-transplant. The NCI's CTCAE version 3.0 will be used to supplement the Bearman toxicity criteria.

3. Early Death:This endpoint is defined as death prior to Day 100 post-transplant.

Secondary Outcomes:

1. Post-transplant survival- as defined as time from transplant to death from any cause.

2. Secondary Graft Failure - This endpoint is defined (in patients surviving at least 100 days) by initial neutrophil engraftment followed by subsequent decline in the ANC to < 0.5 x 10^9/L for 3 consecutive measurements on different days, unresponsive to growth factor therapy.

3. Acute GVHD of Grades 2-4 and 3-4 - Acute GVHD is graded according to the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Manual of Procedures (MOP). The first day of acute GVHD onset at a certain grade will be used to calculate cumulative incidence curves for that GVHD grade (e.g., if the onset of grade 1 acute GVHD is on Day 19 post-transplant and onset of grade 3 is on Day 70 post-transplant, time to grade 3 is Day 70). This endpoint will be evaluated through 100 days.

4. Chronic GVHD - Chronic GVHD is scored according to the BMt CTN MOP. The first day of chronic GVHD onset will be used to calculate cumulative incidence curves.

Eligibility Criteria

Inclusion Criteria:

• Patients up to 65 years of age at time of registration with a diagnosis of SAA; SAA is defined as follows:

1. Bone marrow cellularity less than 25% or marrow cellularity less than 50% but with less than 30% residual hematopoietic cells

2. Two out of three of the following (in peripheral blood): neutrophils less than 0.5 x 10^9/L; platelets less than 20 x 10^9/L; reticulocytes less than 20 x 10^9/L

• Patient must have an available unrelated donor with a 7/8 or 8/8 match for HLA-A, B, C, and DRB1 antigen; typing is by DNA techniques: intermediate resolution for A, B, and C, and high resolution for DRB1; HLA-DQ typing is recommended but will not count in the match

• Patient and/or legal guardian able to provide signed informed consent

• Matched unrelated donor must consent to provide a marrow allograft

• Patients with adequate organ function as measured by:

1. Cardiac: left ventricular ejection fraction at rest must be greater than 40% or shortening fraction greater than 20%

2. Hepatic: serum bilirubin less than 2x upper limit of normal for age as per local laboratory) (with the exception of isolated hyperbilirubinemia due to Gilbert's syndrome), ALT and AST less than 4x upper limit of normal for age (as per local laboratory)

3. Renal: serum creatinine less than 2x upper limit of normal for age (as per local laboratory)

4. Pulmonary: FEVl, FVC, and DLCO (corrected for Hb) greater than 50% predicted; for patients in which pulse oxymetry is performed, O2 saturation greater than 92%

• Diagnosis of Fanconi anemia must be excluded in patients younger than 18 years of age by diepoxybutane testing on peripheral blood or comparable testing on marrow.

Exclusion Criteria:

• Clonal cytogenetic abnormalities associated with MDS or AML on marrow examination

• Diagnosis of other "congenital" aplastic anemias such as: Diamond-Blackfan; Shwachmann-Diamond; congenital amegakaryocytosis

• Symptomatic or uncontrolled cardiac failure or coronary artery disease

• Karnofsky performance status less than 60% or Lansky less than 40% for patients younger than 16 years old

• Uncontrolled bacterial, viral or fungal infections (currently taking medication and progression of clinical symptoms)

• Seropositive for the human immunodeficiency virus (HIV)

• Pregnant (positive total HCG) or breastfeeding

• Presence of large accumulation of ascites or pleural effusions, which would be a contraindication to the administration of methotrexate for GVHD prophylaxis

• Known severe or life-threatening allergy or intolerance to ATG or cyclosporine/ tacrolimus

• Planned administration of alemtuzumab (Campath-1H) or other investigational agents as alternative agent for GVHD prophylaxis

• Concomitant enrollment in a Phase I study

• Positive patient anti-donor lymphocyte crossmatch in HLA-A or B mismatched transplants; the definition of match is in Section 2.2.1; the crossmatch would only apply to mismatches at HLA-A or B, not DRB1 or HLA-C

• Prior allogeneic marrow or stem cell transplantation

• Patients with prior malignancies except resected basal cell carcinoma or treated carcinoma in-situ; cancer treated with curative intent less than 5 years previously will not be allowed unless approved by the Medical Monitor or Protocol Chair; cancer treated with curative intent more than 5 years previously will be allowed

Trial Contact Information

Trial Lead Organizations/Sponsors

Medical College of Wisconsin Cancer Center

Roberta Adams, MD

Principal Investigator

Neena Kapoor, MD

Principal Investigator

Meg O'Donnell, MD

Principal Investigator

Theodore Moore, MD

Principal Investigator

Sally Arai

Principal Investigator

John Reid Wingard

Principal Investigator

John T. Horan

Principal Investigator

Leslie E. Lehmann

Principal Investigator

Joseph Harry Antin

Principal Investigator

Carrie Kitko, MD

Principal Investigator

Jakub Tolar

Principal Investigator

Joel A. Brochstein

Principal Investigator

Hugo R. Castro-Malaspina

Principal Investigator

Nelson J. A. Chao

Principal Investigator

Richard Harris, MD

Principal Investigator

Amanda Termuhlen, MD

Principal Investigator

Victor Aquino

Principal Investigator

Paul Shaughnessy

Principal Investigator

Paolo Anderlini, MD

Study Chair

John M. McCarty

Principal Investigator

H. Joachim Deeg

Principal Investigator

Naynesh R. Kamani

Principal Investigator

Gretchen Eames, MD

Principal Investigator

Philip L. McCarthy

Principal Investigator

Gabrielle Meyers, MD

Principal Investigator

Stephen Medlin, DO

Principal Investigator

Mary Horowitz, MD, MS
		Email: marymh@mcw.edu

U.S.A.
Arizona
	Phoenix
		Roberta Adams	Principal Investigator
	Phoenix Children's Hospital
		Roberta Adams, MD	Ph: 602-546-0920
			Email: radams@phoenixchildrens.com
California
	Los Angeles
		Neena Kapoor	Principal Investigator
	Childrens Hospital Los Angeles
		Neena Kapoor, MD	Ph: 323-669-2546
			Email: nkapoor@chla.usc.edu
		Theodore Moore, MD	Principal Investigator
	Jonsson Comprehensive Cancer Center at UCLA
		Theodore Moore, MD	Ph: 310-825-6708
			Email: tbmoore@mednet.ucla.edu
	Stanford
		Sally Arai	Principal Investigator
	Stanford Cancer Center
		Sally Arai, MD	Ph: 650-728-4425
			Email: sarai1@stanford.edu
District of Columbia
	Washington
		Brett Loechelt, MD	Principal Investigator
	Children's National Medical Center
		Brett Loechelt, MD	Ph: 202-476-2805
			Email: bloechel@cnmc.org
Florida
	Gainesville
		Vijay Reddy, MD	Sub-Investigator
		John Reid Wingard	Principal Investigator
	University of Florida Shands Cancer Center
		John Wingard, MD	Ph: 352-273-8021
			Email: wingarjr@medicine.ufl.edu
	Tampa
	H. Lee Moffitt Cancer Center and Research Institute at University of South Florida
		Lia Perez, MD
			Email: Lia.Perez@moffitt.org
Georgia
	Atlanta
		John T. Horan	Principal Investigator
	AFLAC Cancer Center and Blood Disorders Service of Children's Healthcare of Atlanta - Egleston Campus
		John Horan, MD, MPH	Ph: 404-785-0857
			Email: john.horan@choa.org
		Asad Bashey, MD, PhD	Principal Investigator
	Blood and Marrow Transplant Program at Northside Hospital
		Asad Bashey, MD, PhD	Ph: 404-851-8238
			Email: abashey@bmtga.com
Massachusetts
	Boston
		Joseph Harry Antin	Principal Investigator
	Dana-Farber/Brigham and Women's Cancer Center
		Joseph Antin, MD	Ph: 617-632-2525
			Email: jantin@partners.org
		Leslie E. Lehmann	Principal Investigator
	Dana-Farber/Harvard Cancer Center at Dana-Farber Cancer Institute
		Leslie Lehmann, MD	Ph: 617-632-2095
			Email: leslie_lehmann@dfci.harvard.edu
Michigan
	Ann Arbor
		Carrie Kitko, MD	Principal Investigator
	University of Michigan Comprehensive Cancer Center
		Carrie Kitko, MD	Ph: 734-936-5406
			Email: ckitko@umich.edu
Minnesota
	Minneapolis
		Jakub Tolar	Principal Investigator
	Masonic Cancer Center at University of Minnesota
		Jakub Tolar, MD, PhD	Ph: 612-626-5501
			Email: tolar003@umn.edu
New Jersey
	Hackensack
		Scott D. Rowley	Principal Investigator
	Hackensack University Medical Center Cancer Center
		Alfred Gillio, MD	Ph: 201-996-5600
			Email: agillio@humed.com
New York
	Buffalo
		Philip L. McCarthy	Principal Investigator
	Roswell Park Cancer Institute
		Philip McCarthy, MD	Ph: 716-845-1051
			Email: philip.mccarthy@roswellpark.org
	New York City
		Hugo R. Castro-Malaspina	Principal Investigator
	Memorial Sloan-Kettering Cancer Center
		Hugo Castro-Malaspina, MD	Ph: 212-639-8197
			Email: castro-h@mskcc.org
North Carolina
	Durham
		Joanne Kurtzberg	Principal Investigator
	Duke Cancer Institute
		Mitchell E Horwitz, MD	Ph: 919-668-1045
			Email: Mitchell.horwitz@duke.edu
Ohio
	Cincinnati
		Stella Davies, MD	Sub-Investigator
		Richard Harris, MD	Principal Investigator
	Cincinnati Children's Hospital Medical Center
		Richard Harris, MD	Ph: 513-636-8610
			Email: richard.harris@cchmc.org
Oregon
	Portland
		Gabrille Meyers, MD	Principal Investigator
	Knight Cancer Institute at Oregon Health and Science University
		Gabrielle Meyers, MD	Ph: 503-494-1026
			Email: meyersg@ohsu.edu
South Dakota
	Sioux Falls
		Stephen Medlin, DO	Principal Investigator
	Avera Cancer Institute
		Ramakrishnan (Vinod) Parameswaran Ramakrishnan, MD	Ph: 605-322-3035
			Email: Vinod.Parameswaran@avera.org
Texas
	Dallas
		Victor Aquino	Principal Investigator
	Center for Cancer and Blood Disorders at Children's Medical Center Dallas
		Victor Aquino, MD	Ph: 214-456-2382
			Email: victor.aquino@utsouthwestern.edu
	Fort Worth
		Gretchen Eames, MD	Principal Investigator
	Cook Children's Medical Center - Fort Worth
		Gretchen Eames, MD	Ph: 682-885-2580
			Email: geames@cookchildrens.org
	Houston
		Paolo Anderlini, MD	Principal Investigator
	M. D. Anderson Cancer Center at University of Texas
		Paolo Anderlini, MD	Ph: 713-794-5743
			Email: panderli@mdanderson.org
	San Antonio
		Paul Shaughnessy	Principal Investigator
	Texas Transplant Institute
		Paul Shaughnessy, MD	Ph: 210-575-8631
			Email: paul.shaughnessy@mhshealth.com
Virginia
	Richmond
		John M. McCarty	Principal Investigator
	Virginia Commonwealth University Massey Cancer Center
		John McCarty, MD	Ph: 804-828-4360
			Email: jmccarty@hsc.vcu.edu
Washington
	Seattle
		H. Joachim Deeg	Principal Investigator
	Fred Hutchinson Cancer Research Center
		Joachim Deeg, MD	Ph: 206-667-5985
			Email: jdeeg@fhcrc.org

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00326417
Information obtained from ClinicalTrials.gov on March 19, 2013

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