Clofarabine, Cytarabine, and Thymoglobulin for Allogeneic Transplantation

A Non-Myeloablative Conditioning Regimen for Allogeneic Transplantation With Clofarabine, Cytarabine, and Thymoglobulin for Myelodysplastic Syndrome and Acute Myeloid Leukemia

This study will test the combination of clofarabine, cytarabine, and thymoglobulin as a non-myeloablative conditioning regimen for patients with myelodysplastic syndromes or acute myeloid leukemia undergoing allogeneic stem cell transplant.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Clofarabine; Drug: Thymoglobulin; Drug: Cytarabine; Procedure: Stem cell infusion

Detailed Description

Current reduced intensity conditioning regimens have been able to decrease TRM (treatment related mortality) but suffer from increased rates of disease relapse. Disease burden at transplantation, as measured by percent myeloblasts, predicts relapse. Current regimens employ fludarabine and busulfan with various adjutants, but these agents are not part of the usual armamentarium used versus leukemia and have questionable anti-leukemic activity. By substituting clofarabine and cytarabine, a combination with proven anti-leukemic activity in the relapsed and refractory setting as well as activity versus MDS, as the back bone of the regimen we hope overcome residual disease and improve post-transplant relapse rates. Furthermore the principal toxicity of this regimen is myelosuppression, which should be abrogated by the infusion of stem cells. Thymoglobulin is included due to its minimal contribution to toxicity but significant benefits in engraftment, and controlling acute and chronic GVHD, which are major contributors to TRM and disease specific activity in MDS.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Missouri
    • St. Louis, Missouri, United States, 63110
      • Ravi Vij, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (Patient):

1. Myelodysplastic Syndrome (MDS), as defined by the World Health Organization criteria, OR Chronic Myelomonocytic Leukemia (CMML) as defined by the French American British classification OR Acute Myeloid Leukemia (AML) in complete remission [excluding FAB-M3] diagnosed by standard criteria and meet the criteria below:

   1. Patients may be in any CR
   2. No more than 2 cycles of consolidation. Any consolidation regimen may be used.
   3. No more than 6 months from documented CR to transplant.
2. Age 18 years or older.
3. ECOG performance status <=2
4. Identification of suitable donor
5. DLCO >=40% with no symptomatic pulmonary disease
6. LVEF by MUGA >= 30%
7. Serum creatinine <=1.0 mg/dL; if serum creatinine >1.0 mg/dL, then the estimated glomerular filtration rate (GFR) must be >60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female) x (1.212 if patient is black).
8. Bilirubin <=2 times the upper limit of normal
9. AST <=3 times the upper limit of normal

Donor criteria:

1. HLA-Matched Sibling: The donor must be an adequate HLA match as determined by serologic typing for class (A, B) and low resolution molecular typing for class II (DRB1) as defined by institutional standards.
2. Matched Unrelated Donor: An acceptable match per NMDP standards based on high resolution molecular typing.
3. The donor must be healthy and must be an acceptable donor as per institutional standards for stem cell collection.
4. The donor must have no significant cardiopulmonary, renal, endocrine, or hepatic disease.
5. There is no upper age restriction for donors, but they must be at least 18 years of age.
6. Syngeneic donors are not eligible.
7. No known HIV.

Exclusion Criteria:

1. Pregnant or nursing.
2. Active systemic infection considered opportunistic, life threatening or clinically significant at the time of treatment.
3. Severe concurrent disease, including severe insulin-dependent diabetes, uncontrolled hypertension, transient ischemic attacks, uncontrolled symptomatic coronary artery disease, or symptomatic CNS involvement or psychiatric illness/social situations that would limit compliance with study requirements.
4. Known HIV disease.
5. History of other malignancy except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast unless the subject has been off treatment and free from disease for > 3 years.
6. Active disease at the time of transplant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Arm 1: Non-myeloablative conditioning regimen; Clofarabine 40mg/m2/day IV over two hours daily x 5 days on Days -6 thru -2; Cytarabine 1gm/m2/day IV over two hours daily x 5 days on Days -6 thru -2 after the START of Clofarabine.; Thymoglobulin 1.0mg/kg IV over 6 hours X 1 day on Day -4, then 2.5mg/kg/day x 2 days on Days -3 and -2.; Stem Cell Transplant - On day 0 a minimum of total CD34+ cell dose of 2 x10E6/kg (actual weight of recipient) will be infused.

Drug: Clofarabine; Other Names: Clolar; Drug: Thymoglobulin; Other Names: Anti-thymocyte globulin; Drug: Cytarabine; Other Names: Ara-C; Cytosar; Procedure: Stem cell infusion; Other Names: Bone marrow transplant; Stem cell transplant; Hematopoietic stem cell transplant; Peripheral blood stem cell transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Six-month Treatment Related Mortality	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease Specific Response Rates	Disease-specific partial response and complete response.	One, three, six and twelve months.
Engraftment as Measured by Percent Donor Chimerism		Day +30
Engraftment as Measured by Percent Donor Chimerism		Day +40-+60
Engraftment as Measured by Percent Donor Chimerism		Day +80-+90
Overall Survival		5 years from time of restaging
Disease-free Survival	Disease-free survival is defined as the length of time after treatment ends that the participant survives without any signs or symptoms of that cancer.	5 years from time of restaging
Rate of Acute Graft-versus-host Disease (GVHD)	Acute GVHD occurs within 100 days of transplant.	Up to 100 days after transplant
Rate of Chronic Graft-versus-host Disease (GVHD)		100 days-1 year after transplant
Use Conventional STR-PCR Method for Monitoring Engraftment	Includes assessment of mixed chimerism in the whole blood, myeloid cells, T cells, and B cells.	Up to 1 year after transplant
Median Time to Progression	Time to progression is defined as the length of time from the start of treatment until the disease starts to get worse or spread to other parts of the body.	5 years from time of restaging

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Investigators: Principal Investigator: Ravi Vij, M.D., Washington Universtiy of St. Louis

Publications and helpful links

Helpful Links

• Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start: November 1, 2007
• Primary Completion (Actual): December 1, 2008
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: January 2, 2008
• First Submitted That Met QC Criteria: January 14, 2008
• First Posted (Estimate): January 15, 2008

Study Record Updates

• Last Update Posted (Estimate): September 12, 2014
• Last Update Submitted That Met QC Criteria: September 5, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Cytarabine; Stem Cell Transplantation; Allogeneic Stem Cell Transplantation; Hematopoietic Stem Cell Transplantation; Clofarabine; Anti-thymocyte globulin; Conditioning regimens; Nonmyeloablative conditioning
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Myelodysplastic Syndromes; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Preleukemia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Clofarabine; Cytarabine; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: 07-0702; No grant number (Other Grant/Funding Number: The Swedish Society of Spinal Surgeons)