Clofarabine and Low-Dose Total-Body Irradiation in Treating Patients With Acute Myeloid Leukemia Undergoing Donor Peripheral Blood Stem Cell Transplant

NCT01252667 | Completed Phase 2 Results DMC

• 4 other identifiers: 2430.00NCI-2010-02247P01CA078902P30CA015704
• Study Type: interventional
• Target: 44
• Locations: 1 country
• Sites: 4

Brief Summary

This phase II trial studies the side effects and how well clofarabine works when given together with low-dose total-body irradiation (TBI) in treating patients with acute myeloid leukemia (AML) undergoing donor peripheral blood stem cell transplant (PBSCT). Giving chemotherapy and TBI before a donor PBSCT helps stop the growth of cancer cells. It may also stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets.

Conditions

Acute Myeloid Leukemia

Outcome Measures

Primary Outcomes (2)

• Part 1: Number of Participants With Dose Limiting Toxicities (DLT)

  The primary objective of part 1 is to determined the highest dose of clofarabine that can be tolerated safely in conjunction with nonmyeloablative transplant. If three patients successfully transplant without DLT, dose escalation occurs. If one of those three patients experiences DLT an additional three patients will be treated using the same dose. If a second DLT is observed in the first 3-6 patients, or if three patients are successfully transplanted without DLT at the highest dose the study will proceed to Part 2 using the maximum tolerated dose. A Clofarabine related dose-limiting toxicity is defined as a grade 4 toxicity involving the lungs, heart, liver (not resolving in 48 hours), kidneys (not resolving in 48 hours), gastrointestinal tract, and/or central nervous system.

  14 days post-transplant

• Part 2: Number of Participants With Relapsed Disease

  Number of high risk patients with relapsed disease after receiving the maximum dose of clofarabine. Relapse is defined as the presence of \>5% aberrant blasts by morphology on a marrow aspirate or the presence of circulating blasts in the peripheral blood.

  6 months post-transplant

Secondary Outcomes (7)

• Number of Participants Surviving Progression-free.

  1 Year post-transplant

• Number of Participants Surviving Overall

  1 Year post-transplant

• Number of Non-Relapse Mortalities (NRM)

  100 days post-transplant

• Number of Participants Who Graft Rejected.

  1 Year post-transplant.

• Prognostic Significance of Cytogenetic and Genetic Markers

  1 Year post-transplant

Study Arms (6)

Part 1 - Dose 1 (30 mg/m^2 Clofarabine)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive 30 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Clofarabine: Given IV Cyclosporine: Given PO Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Pharmacological Study: Optional correlative studies Total-Body Irradiation: Undergo TBI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Clofarabine; Drug: Cyclosporine; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Total-Body Irradiation

Part 1 - Dose 2 (40 mg/m^2 Clofarabine)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive 40 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Clofarabine: Given IV Cyclosporine: Given PO Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Pharmacological Study: Optional correlative studies Total-Body Irradiation: Undergo TBI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Clofarabine; Drug: Cyclosporine; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Total-Body Irradiation

Part 1 - Dose 3 (50 mg/m^2 Clofarabine)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive 50 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Clofarabine: Given IV Cyclosporine: Given PO Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Pharmacological Study: Optional correlative studies Total-Body Irradiation: Undergo TBI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Clofarabine; Drug: Cyclosporine; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Total-Body Irradiation

Part 2 - Dose 1 (30 mg/m^2 Clofarabine)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive 30 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Clofarabine: Given IV Cyclosporine: Given PO Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Pharmacological Study: Optional correlative studies Total-Body Irradiation: Undergo TBI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Clofarabine; Drug: Cyclosporine; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Total-Body Irradiation

Part 2 - Dose 2 (40 mg/m^2 Clofarabine)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive 40 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Clofarabine: Given IV Cyclosporine: Given PO Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Pharmacological Study: Optional correlative studies Total-Body Irradiation: Undergo TBI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Clofarabine; Drug: Cyclosporine; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Total-Body Irradiation

Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

EXPERIMENTAL

CONDITIONING REGIMEN: Patients receive 50 mg/m\^2 clofarabine IV over 2 hours on days -6 to -2. Patients also undergo TBI on day 0. IMMUNOSUPPRESSION: Patients with related donors receive cyclosporine PO every 12 hours on days -3 to 56 with taper to day 180 and mycophenolate mofetil PO every 12 hours on days 0 to 28. Patients with unrelated donors receive cyclosporine PO every 12 hours on days -3 to 100 with taper to day 180 and mycophenolate mofetil PO every 8 hours on days 0 to 40 with taper to day 96. TRANSPLANTATION: Patients undergo allogeneic PBSCT on day 0. Allogeneic Hematopoietic Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Clofarabine: Given IV Cyclosporine: Given PO Laboratory Biomarker Analysis: Correlative studies Mycophenolate Mofetil: Given PO Peripheral Blood Stem Cell Transplantation: Undergo allogeneic hematopoietic PBSCT Pharmacological Study: Optional correlative studies Total-Body Irradiation: Undergo TBI

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Clofarabine; Drug: Cyclosporine; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Other: Pharmacological Study; Radiation: Total-Body Irradiation

Interventions

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic hematopoietic PBSCT

Also known as: Allogeneic Hematopoietic Cell Transplantation, allogeneic stem cell transplantation, HSC, HSCT

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Clofarabine DRUG

Given IV

Also known as: Clofarex, Clolar

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Cyclosporine DRUG

Given PO

Also known as: 27-400, Ciclosporin, CsA, Cyclosporin, Cyclosporin A, Gengraf, Neoral, OL 27-400, Sandimmun, Sandimmune, SangCya

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Laboratory Biomarker Analysis OTHER

Correlative studies

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo allogeneic hematopoietic PBSCT

Also known as: PBPC transplantation, PBSCT, Peripheral Blood Progenitor Cell Transplantation, peripheral stem cell support, Peripheral Stem Cell Transplant, peripheral stem cell transplantation

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Pharmacological Study OTHER

Optional correlative studies

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Total-Body Irradiation RADIATION

Undergo TBI

Also known as: TOTAL BODY IRRADIATION, Whole-Body Irradiation

Part 1 - Dose 1 (30 mg/m^2 Clofarabine); Part 1 - Dose 2 (40 mg/m^2 Clofarabine); Part 1 - Dose 3 (50 mg/m^2 Clofarabine); Part 2 - Dose 1 (30 mg/m^2 Clofarabine); Part 2 - Dose 2 (40 mg/m^2 Clofarabine); Part 2 - Dose 3 (50 mg/m^2 Clofarabine)

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients age \>= 55 years with AML OR patients age \< 55 years with AML, who also through pre-existing medical conditions or prior therapy are considered to be at high risk for serious toxicities associated with a conventional, high-dose preparative regimen
• Patients must be in morphologic leukemia-free state (marrow blasts \< 5%) without evidence of extramedullary disease within 21 days of HCT
• Only patients with Relapse Risk Score \> 0 ("high risk") will be enrolled during Part 1; patients with all Relapse Risk Scores will be enrolled during Part 2 (low risk group terminated August 2014)
• HLA-identical related or HLA-matched unrelated donor available
• A signed informed consent form or minor assent form
• DONOR: FHCRC matching allowed will be grade 1.0 to 2.1: unrelated donors who are prospectively: matched for HLA-A, B, C, DRB1 and DQB1 by high resolution typing; only a single allele disparity will be allowed for HLA-A, B, or C as defined by high resolution typing
• DONOR: Patient and donor pairs homozygous at a mismatched allele are considered a two-allele mismatch, i.e., the patient is A\*0101 and the donor is A\*0102, and this type of mismatch is not allowed
• DONOR: Peripheral blood stem cells (PBSC) only will be permitted as a HSC source on this protocol

You may not qualify if:

• AML French-American-British (FAB) M3 in first complete remission (CR1)
• Active AML involvement of the central nervous system (CNS) with disease refractory to intrathecal chemotherapy
• Presence of circulating leukemic blasts in the peripheral blood detected by standard morphology
• Patients who are human immunodeficiency virus (HIV)+ (HIV+ patients registered at Fred Hutchinson Cancer Research Center \[FHCRC\] should be offered treatment on Protocol 1410)
• Fertile men and women unwilling to use contraceptive techniques during and for 12 months following treatment
• Left ventricular ejection fraction \< 35% (or, if unable to obtain ejection fraction, shortening fraction of \< 26%); ejection fraction is required if age \> 50 years or there is a history of anthracycline exposure or history of cardiac disease; patients with a shortening fraction \< 26% may be enrolled if approved by a cardiologist
• Diffusion capacity of the lung for carbon monoxide (DLCO) \< 40% (corrected), total lung capacity (TLC) \< 40%, forced expiratory volume in one second (FEV1) \< 40% and/or receiving supplementary continuous oxygen
• The FHCRC principal investigator (PI) of the study must approve enrollment of all patients with pulmonary nodules
• Patients with clinical or laboratory evidence of liver disease will be evaluated for the cause of liver disease, its clinical severity in terms of liver function, and the degree of portal hypertension; patients will be excluded if they are found to have fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction evinced by prolongation of the prothrombin time, ascites related to portal hypertension, bridging fibrosis, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis with total serum bilirubin \> 3 mg/dL, or symptomatic biliary disease
• Serum creatinine should be within normal limits as specified by institutional guidelines; for patients with serum creatinine \> upper limit of normal, a 24-hour creatinine clearance will be performed and should be equal to or more than the lower limit of normal
• Karnofsky score \< 60 or Lansky score \< 50
• Patients with poorly controlled hypertension and on multiple antihypertensives
• Females who are pregnant or breastfeeding
• The addition of cytotoxic agents for "cytoreduction" with the exception of tyrosine kinase inhibitors (such as imatinib mesylate), cytokine therapy, hydroxyurea, low dose cytarabine, chlorambucil, or Rituxan will not be allowed within three weeks of the initiation of conditioning
• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Cancer Institute (NCI): collaborator

Study Sites (4)

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Ochsner Medical Center Jefferson

New Orleans, Louisiana, 70121, United States

Location

VA Puget Sound Health Care System

Seattle, Washington, 98101, United States

Location

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, 98109, United States

Location

Related Publications (2)

• Krakow EF, Gyurkocza B, Storer BE, Chauncey TR, McCune JS, Radich JP, Bouvier ME, Estey EH, Storb R, Maloney DG, Sandmaier BM. Phase I/II multisite trial of optimally dosed clofarabine and low-dose TBI for hematopoietic cell transplantation in acute myeloid leukemia. Am J Hematol. 2020 Jan;95(1):48-56. doi: 10.1002/ajh.25665. Epub 2019 Nov 8.

  PMID: 31637757 RESULT

• Cooper JP, Storer BE, Granot N, Gyurkocza B, Sorror ML, Chauncey TR, Shizuru J, Franke GN, Maris MB, Boyer M, Bruno B, Sahebi F, Langston AA, Hari P, Agura ED, Lykke Petersen S, Maziarz RT, Bethge W, Asch J, Gutman JA, Olesen G, Yeager AM, Hubel K, Hogan WJ, Maloney DG, Mielcarek M, Martin PJ, Flowers MED, Georges GE, Woolfrey AE, Deeg JH, Scott BL, McDonald GB, Storb R, Sandmaier BM. Allogeneic hematopoietic cell transplantation with non-myeloablative conditioning for patients with hematologic malignancies: Improved outcomes over two decades. Haematologica. 2021 Jun 1;106(6):1599-1607. doi: 10.3324/haematol.2020.248187.

  PMID: 32499241 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute

Interventions

Clofarabine; Cyclosporine; Cyclosporins; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Adenine Nucleotides; Purine Nucleotides; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Arabinonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Nucleotides; Ribonucleotides; Peptides, Cyclic; Macrocyclic Compounds; Polycyclic Compounds; Peptides; Amino Acids, Peptides, and Proteins; Caproates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids; Lipids; Hematopoietic Stem Cell Transplantation; Stem Cell Transplantation; Cell Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Transplantation; Surgical Procedures, Operative; Radiotherapy; Investigative Techniques

Results Point of Contact

• Title: Dr. Brenda M. Sandmaier
• Organization: Fred Hutchinson Cancer Research Center

bsandmai@fredhutch.org

(206) 667-4961

Study Officials

• Brenda Sandmaier

  Fred Hutch/University of Washington Cancer Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: In part 1, patients are treated at each dose in cohorts of three and observed for any dose limiting toxicities. In Part 2, patients are treated at the maximum tolerated dose established in Part 1.

Study Record Dates

• First Submitted: November 29, 2010
• First Posted: December 3, 2010
• Study Start: January 25, 2011
• Primary Completion: January 25, 2019
• Study Completion: March 1, 2019
• Last Updated: April 16, 2020
• Results First Posted: April 16, 2020

Record last verified: 2020-04

Locations

US (4)