Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2015 by Fred Hutchinson Cancer Research Center
Sponsor:
Collaborators:
Information provided by (Responsible Party):
Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier:
NCT01527045
First received: January 31, 2012
Last updated: March 3, 2015
Last verified: March 2015
  Purpose

This phase II trial studies how well donor atorvastatin treatment works in preventing severe graft-versus-host disease (GVHD) after nonmyeloablative peripheral blood stem cell (PBSC) transplant in patients with hematological malignancies. Giving low doses of chemotherapy, such as fludarabine phosphate, before a donor PBSC transplantation slows the growth of cancer cells and may also prevent the patient's immune system from rejecting the donor's stem cells. The donated stem cells 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 cause an immune response against the body's normal cells (GVHD). Giving atorvastatin to the donor before transplant may prevent severe GVHD.


Condition Intervention Phase
Adult Acute Lymphoblastic Leukemia
Adult Acute Myeloid Leukemia
Adult Diffuse Large B-Cell Lymphoma
Aggressive Non-Hodgkin Lymphoma
Childhood Acute Lymphoblastic Leukemia
Childhood Acute Myeloid Leukemia
Childhood Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Childhood Diffuse Large B -Cell Lymphoma
DS Stage I Plasma Cell Myeloma
DS Stage II Plasma Cell Myeloma
DS Stage III Plasma Cell Myeloma
Myelodysplastic/Myeloproliferative Neoplasm
Prolymphocytic Leukemia
Refractory Childhood Hodgkin Lymphoma
Refractory Chronic Lymphocytic Leukemia
Refractory Chronic Myelogenous Leukemia, BCR-ABL1 Positive
Stage I Adult Hodgkin Lymphoma
Stage I Aggressive Adult Non-Hodgkin Lymphoma
Stage I Childhood Hodgkin Lymphoma
Stage I Chronic Lymphocytic Leukemia
Stage I Diffuse Large B-Cell Lymphoma
Stage I Mantle Cell Lymphoma
Stage I Small Lymphocytic Lymphoma
Stage II Adult Hodgkin Lymphoma
Stage II Childhood Hodgkin Lymphoma
Stage II Chronic Lymphocytic Leukemia
Stage II Contiguous Adult Aggressive Non-Hodgkin Lymphoma
Stage II Contiguous Mantle Cell Lymphoma
Stage II Diffuse Large B-Cell Lymphoma
Stage II Non-Contiguous Aggressive Adult Non-Hodgkin Lymphoma
Stage II Non-Contiguous Mantle Cell Lymphoma
Stage II Small Lymphocytic Lymphoma
Stage III Adult Hodgkin Lymphoma
Stage III Aggressive Adult Non-Hodgkin Lymphoma
Stage III Childhood Hodgkin Lymphoma
Stage III Chronic Lymphocytic Leukemia
Stage III Diffuse Large B-Cell Lymphoma
Stage III Mantle Cell Lymphoma
Stage III Small Lymphocytic Lymphoma
Stage IV Adult Hodgkin Lymphoma
Stage IV Aggressive Adult Non-Hodgkin Lymphoma
Stage IV Childhood Hodgkin Lymphoma
Stage IV Chronic Lymphocytic Leukemia
Stage IV Diffuse Large B-Cell Lymphoma
Stage IV Mantle Cell Lymphoma
Stage IV Small Lymphocytic Lymphoma
T-Cell Prolymphocytic Leukemia
Waldenstrom Macroglobulinemia
Drug: Atorvastatin Calcium
Drug: Fludarabine Phosphate
Radiation: Total-Body Irradiation
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Drug: Cyclosporine
Drug: Mycophenolate Mofetil
Procedure: Peripheral Blood Stem Cell Transplantation
Other: Laboratory Biomarker Analysis
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Donor Statin Treatment for Prevention of Severe Acute GVHD After Nonmyeloablative Hematopoietic Cell Transplantation

Resource links provided by NLM:


Further study details as provided by Fred Hutchinson Cancer Research Center:

Primary Outcome Measures:
  • Proportion of patients who develop grade 3-4 acute GVHD after transplant [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
    The cumulative incidence of this endpoint in patients prepared with nonmyeloablative conditioning regimens after HCT from HLA-matched related donors, and with CSP-based immunosuppression is approximately 9%. A reduction in the cumulative incidence of acute GVHD from 9% to < 2% would represent a reasonable goal after nonmyeloablative HCT and constitute study success.


Secondary Outcome Measures:
  • Grades II-IV acute GVHD [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
    Assessed with the use of cumulative incidence plots.

  • Proportion of patients requiring secondary systemic immunosuppressive therapy [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Assessed with the use of cumulative incidence plots. The need for primary and secondary systemic immunosuppressive treatment with agents other than those used for prophylaxis and initial therapy, the reason for their administration (acute GVHD, chronic GVHD, or other reasons) will be determined.

  • Chronic extensive GVHD [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
    Assessed with the use of cumulative incidence plots. Patients will be evaluated for chronic GVHD as described in the NIH consensus project guidelines. Graft failure, recurrent malignancy and death without GVHD are considered to be competing risks for GVHD.

  • Recurrent or progressive malignancy [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
    Assessed with the use of cumulative incidence plots. Recurrent malignancy will be defined by hematologic criteria. Recurrent malignancy will also be defined as any unplanned medical intervention designed to prevent progression of malignant disease in patients who have molecular, cytogenetic or flow-cytometric evidence of malignant cells after transplantation.

  • Non-relapse mortality [ Time Frame: Up to 1 year ] [ Designated as safety issue: No ]
    Defined as death in the absence of recurrent or progressive malignancy after HCT. Assessed with the use of cumulative incidence plots.

  • Disease-free survival [ Time Frame: At 1 year after transplant ] [ Designated as safety issue: No ]
    Evaluated as Kaplan-Meier estimates.

  • Overall survival [ Time Frame: At 1 year after transplant ] [ Designated as safety issue: No ]
    Evaluated as Kaplan-Meier estimates.

  • Proportion of donors who have to discontinue atorvastatin because of toxicity [ Time Frame: Prior to stem cell collection ] [ Designated as safety issue: Yes ]
    The number of donors who prematurely discontinue atorvastatin therapy and the reasons for discontinuation will be described.


Estimated Enrollment: 100
Study Start Date: September 2012
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Prevention (donor statin treatment)
See Detailed Description
Drug: Atorvastatin Calcium
Given PO
Other Names:
  • CI-981
  • Lipitor
Drug: Fludarabine Phosphate
Given IV
Other Names:
  • 2-F-ara-AMP
  • Beneflur
  • SH T 586
Radiation: Total-Body Irradiation
Undergo TBI
Other Names:
  • TBI
  • Total Body Irradiation
  • Whole-Body Irradiation
Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
Undergo nonmyeloablative allogeneic PBSC transplant
Other Names:
  • Non-myeloablative allogeneic transplant
  • Nonmyeloablative Stem Cell Transplantation
  • NST
Drug: Cyclosporine
Given PO
Other Names:
  • 27-400
  • CsA
  • Neoral
  • OL 27-400
  • Sandimmun
Drug: Mycophenolate Mofetil
Given PO or IV
Other Names:
  • Cellcept
  • MMF
Procedure: Peripheral Blood Stem Cell Transplantation
Undergo nonmyeloablative allogeneic PBSC transplant
Other Names:
  • PBPC transplantation
  • Peripheral Blood Progenitor Cell Transplantation
  • Peripheral Stem Cell Support
  • Peripheral Stem Cell Transplantation
Other: Laboratory Biomarker Analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To assess whether 2 weeks of donor statin treatment reduces the risk of severe acute GVHD.

SECONDARY OBJECTIVES:

I. To assess whether 2 weeks of statin treatment of normal PBSC donors is feasible, tolerable and safe.

OUTLINE:

DONOR: Donors receive atorvastatin orally (PO) once daily (QD) beginning on day -14 and continuing until the last day of stem cell collection.

NONMYELOABLATIVE PREPARATIVE REGIMEN: If the patient is enrolled on an investigational nonmyeloablative hematopoietic cell transplant (HCT) protocol or a treatment plan that uses a nonmyeloablative preparative regimen with postgrafting cyclosporine (CSP) that does not use acute GVHD as its primary endpoint, the preparative regimen and immunosuppression after transplant will be according to respective protocol or treatment plan (Protocol 2546 serves as adjunct protocol).

If the patient is not enrolled on an investigational nonmyeloablative HCT protocol or a treatment plan that uses a nonmyeloablative preparative regimen, Protocol 2546 serves as an independent primary treatment protocol. The preparative regimen and immunosuppression after transplant is as follows:

Patients receive fludarabine phosphate intravenously (IV) on days -4 to -2 (except for patients who had prior autologous HCT or equivalent high-dose therapy without HCT) and undergo low-dose total body irradiation (TBI) on day 0.

TRANSPLANT: Patients undergo donor PBSC transplant on day 0.

POST-GRAFTING IMMUNOSUPPRESSION: Patients receive CSP PO twice daily (BID) on days -3 to +56 with taper to day +180. Patients also receive mycophenolate mofetil (MMF) PO BID or IV every 12 hours on days 0-27.

After completion of study treatment, patients are followed up at 1 year and then annually thereafter.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • If Protocol 2546 serves as an adjunct protocol, the patient only needs to meet inclusion criteria 1 through 5A
  • Availability of human leukocyte antigen (HLA)-identical sibling donor
  • Transplantation with PBSC
  • CSP-based postgrafting immunosuppression
  • Willingness to give informed consent
  • Patient is enrolled on an investigational nonmyeloablative hematopoietic cell transplant (HCT) protocol or a nonmyeloablative treatment plan with postgrafting CSP that does not use acute GVHD as its primary endpoint (protocol 2546 serves as adjunct protocol)
  • OR patient is not enrolled on an investigational nonmyeloablative HCT protocol, in which case protocol 2546 serves as an independent primary treatment protocol and the patient must meet the following inclusion and exclusion criteria:
  • Patients must have a hematologic malignancy treatable by nonmyeloablative HCT; the following diseases will be permitted although other diagnoses can be considered if approved by PCC and the principal investigator:
  • Aggressive non-Hodgkin lymphomas (NHL) and other histologies such as diffuse large B-cell NHL - not eligible for autologous HCT, not eligible for high-dose allogeneic HCT, or after failed autologous HCT
  • Mantle-cell NHL - may be treated in first complete remission (CR); (diagnostic lumbar puncture [LP] required pre-transplant)
  • Low grade NHL - with < 6 month duration of CR between courses of conventional therapy
  • Chronic lymphocytic leukemia (CLL) - must have either:

    • Failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine phosphate (FLU) (or another nucleoside analog) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog)
    • Failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or
    • Have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in 1st CR
    • Patients with a diagnosis of CLL (or small lymphocytic lymphoma) that progresses to prolymphocytic leukemia (PLL); or
    • Patients with T-cell CLL or PLL
  • Hodgkin lymphoma - must have received and failed frontline therapy
  • Multiple myeloma - must have received prior chemotherapy; consolidation of chemotherapy by autografting prior to nonmyeloablative HCT is permitted
  • Acute myeloid leukemia (AML) - must have < 5% marrow blasts at the time of transplant
  • Acute lymphocytic leukemia (ALL) - must have < 5% marrow blasts at the time of transplant
  • Chronic myeloid leukemia (CML) - Patients will be accepted if they have shown intolerance to tyrosine kinase inhibitors or are beyond CP1 and if they have received previous myelosuppressive chemotherapy or HCT, and have < 5% marrow blasts at time of transplant
  • Myelodysplasia (MDS)/ myeloproliferative syndrome (MPS) - Patients must have < 5% marrow blasts at time of transplant
  • Waldenstrom's macroglobulinemia - must have failed 2 courses of therapy
  • Patients < 12 years of age must be approved by the principal investigator and by a relevant patient review committee, such as the Fred Hutchinson Cancer Research Center (FHCRC) Patient Care Conference (PCC)
  • Patients must have either relapsed after previous high-dose chemotherapy and autologous or allogeneic HCT, or else be ineligible for such an approach due to age, failure to mobilize sufficient hematopoietic stem cells, medical comorbidities, or patient refusal
  • Patients who refuse to be treated on a conventional autologous or allogeneic HCT protocol
  • DONOR: Age >= 18 years
  • DONOR: HLA genotypically identical sibling
  • DONOR: Willingness to give informed consent

Exclusion Criteria:

  • IF PROTOCOL 2546 SERVES AS AN ADJUNCT PROTOCOL, THE PATIENT ONLY NEEDS TO MEET EXCLUSION CRITERIA 1 THROUGH 3
  • Myeloablative preparative regimen
  • Participation in an investigational study that has acute GVHD as the primary endpoint
  • The allogeneic PBSC donor has a contraindication to statin treatment
  • Patients eligible for and willing to receive potentially curative high-dose chemotherapy and autologous HCT
  • Cardiac ejection fraction < 30% on multi gated acquisition scan (MUGA) scan or cardiac echo or active symptomatic coronary artery disease; patients with cardiac disease should be evaluated with appropriate cardiac studies and/or cardiology consultation as clinically indicated
  • Corrected diffusion capacity of the lung for carbon monoxide (DLCO) < 40% of predicted, total lung capacity (TLC) < 30% of predicted, forced expiratory volume in one second (FEV1) < 30% of predicted, or receiving continuous supplementary oxygen
  • Patients with clinical or laboratory evidence of liver disease should be evaluated in conjunction with the gastrointestinal (GI) consult service for the cause of the liver disease, its clinical severity, 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, bridging fibrosis, alcoholic hepatitis, esophageal varices, a history of bleeding esophageal varices, hepatic encephalopathy, refractory ascites related to portal hypertension, bacterial or fungal liver abscess, chronic viral hepatitis with total serum bilirubin > 3mg/dl, or actively symptomatic biliary disease
  • Patients with renal failure are eligible; however, patients with pre-existing renal insufficiency will likely have further compromise in renal function and may require dialysis
  • Patients who are seropositive for human immunodeficiency virus (HIV)
  • Women who are pregnant or breast-feeding
  • Fertile men or women unwilling to use contraception during HCT and for 12 months afterward
  • Patients with active non-hematological malignancies (except for localized non-melanoma skin malignancies); patients with clinically indolent non-hematologic malignancies not requiring active treatment may be eligible, but must be approved by the relevant patient care committee (e.g. FHCRC PCC) and the principal investigator
  • Karnofsky score < 60 for adult patients
  • Lansky-play performance score < 50 for pediatric patients
  • Patients with fungal pneumonia with radiological progression after receipt of amphotericin formulation or mold-active azoles for greater than 1 month
  • DONOR: Age < 18 years
  • DONOR: History of liver disease; a donor with a history of liver disease would be eligible if the serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) are < 2 x upper limit of normal (ULN)
  • DONOR: History of myopathy
  • DONOR: Hypersensitivity to atorvastatin
  • DONOR: Pregnancy
  • DONOR: Nursing mother
  • DONOR: Current serious systemic illness
  • DONOR: Concurrent treatment with strong inhibitors of hepatic cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP 3A4) (i.e. clarithromycin, erythromycin, protease inhibitors, azole antifungals)
  • DONOR: Current use of statin drug
  • DONOR: Failure to meet local criteria for stem cell donation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01527045

Locations
United States, Colorado
Presbyterian - Saint Lukes Medical Center - Health One Recruiting
Denver, Colorado, United States, 80218
Contact: Richard A. Nash    720-754-4800      
Principal Investigator: Richard A. Nash         
United States, Washington
Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium Recruiting
Seattle, Washington, United States, 98109
Contact: Marco B. Mielcarek    206-667-2827      
Principal Investigator: Marco B. Mielcarek         
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
Investigators
Principal Investigator: Marco Mielcarek Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
  More Information

No publications provided

Responsible Party: Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01527045     History of Changes
Other Study ID Numbers: 2546.00, NCI-2011-03828, 2546.00, P30CA015704, P01CA018029
Study First Received: January 31, 2012
Last Updated: March 3, 2015
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Lymphoma, Non-Hodgkin
Aggression
Hodgkin Disease
Leukemia
Leukemia, Lymphocytic, Chronic, B-Cell
Leukemia, Lymphoid
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Leukemia, Myeloid
Leukemia, Myeloid, Acute
Leukemia, Prolymphocytic
Leukemia, Prolymphocytic, T-Cell
Lymphoma
Lymphoma, B-Cell
Lymphoma, Large B-Cell, Diffuse
Lymphoma, Mantle-Cell
Multiple Myeloma
Myelodysplastic-Myeloproliferative Diseases
Myeloproliferative Disorders
Neoplasms, Plasma Cell
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Waldenstrom Macroglobulinemia
Behavioral Symptoms
Blood Protein Disorders
Bone Marrow Diseases
Cardiovascular Diseases
Hematologic Diseases
Hemorrhagic Disorders
Hemostatic Disorders
Immune System Diseases
Immunoproliferative Disorders

ClinicalTrials.gov processed this record on May 21, 2015