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 July 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: July 14, 2015
Last verified: July 2015

January 31, 2012
July 14, 2015
September 2012
December 2016   (final data collection date for primary outcome measure)
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.
Proportion of patients who develop grade 3-4 acute GVHD after transplant [ Time Frame: Baseline 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.
Complete list of historical versions of study NCT01527045 on ClinicalTrials.gov Archive Site
  • 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.
  • Disease-free survival [ Time Frame: At 1 year after transplant ] [ Designated as safety issue: No ]
    Evaluated as Kaplan-Meier estimates.
  • Grades II-IV acute GVHD [ Time Frame: Up to day 100 ] [ Designated as safety issue: No ]
    Assessed with the use of cumulative incidence plots.
  • 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.
  • 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.
  • Proportion of patients requiring secondary systemic immunosuppressive therapy [ Time Frame: Up to 4 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.
  • Recurrent or progressive malignancy [ Time Frame: Up to 4 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.
  • Grades II-IV acute GVHD [ Time Frame: Baseline to day 100 ] [ Designated as safety issue: No ]
  • Proportion of patients requiring secondary systemic immunosuppressive therapy [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Chronic extensive GVHD [ Time Frame: Baseline to day 100 ] [ Designated as safety issue: No ]
  • Recurrent or progressive malignancy [ Time Frame: Up to 3 years ] [ Designated as safety issue: No ]
  • Non-relapse mortality [ Time Frame: At day 100 and 1 year ] [ Designated as safety issue: No ]
  • Disease-free survival [ Time Frame: At 1 year after transplant ] [ Designated as safety issue: No ]
  • Proportion of donors who have to discontinue atorvastatin because of toxicity [ Time Frame: Prior to stem cell collection ] [ Designated as safety issue: Yes ]
  • Overall survival [ Time Frame: At 1 year after transplant ] [ Designated as safety issue: No ]
Not Provided
Not Provided
 
Donor Atorvastatin Treatment in Preventing Severe Acute GVHD After Nonmyeloablative Peripheral Blood Stem Cell Transplant in Patients With Hematological Malignancies
Donor Statin Treatment for Prevention of Severe Acute GVHD After Nonmyeloablative Hematopoietic Cell Transplantation

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.

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.

Interventional
Phase 2
Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Prevention
  • 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
    Given PO
    Other Names:
    • ATORVASTATIN CALCIUM
    • CI-981
    • Lipitor
  • Drug: Cyclosporine
    Given PO
    Other Names:
    • 27-400
    • Ciclosporin
    • CsA
    • Cyclosporin
    • Cyclosporin A
    • CYCLOSPORINE
    • Neoral
    • OL 27-400
    • Sandimmun
    • Sandimmune
    • SangCya
  • Drug: Fludarabine Phosphate
    Given IV
    Other Names:
    • 2-F-ara-AMP
    • 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-
    • Beneflur
    • Fludara
    • FLUDARABINE PHOSPHATE
    • Oforta
    • SH T 586
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Mycophenolate Mofetil
    Given PO or IV
    Other Names:
    • Cellcept
    • MMF
    • MYCOPHENOLATE MOFETIL
  • Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
    Undergo nonmyeloablative allogeneic PBSC transplant
    Other Names:
    • Non-myeloablative allogeneic transplant
    • Nonmyeloablative Stem Cell Transplantation
    • NST
  • 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
  • Radiation: Total-Body Irradiation
    Undergo TBI
    Other Names:
    • TOTAL BODY IRRADIATION
    • total-body irradiation
    • Whole-Body Irradiation
Experimental: Prevention (donor statin treatment)
See Detailed Description
Interventions:
  • Drug: Atorvastatin Calcium
  • Drug: Cyclosporine
  • Drug: Fludarabine Phosphate
  • Other: Laboratory Biomarker Analysis
  • Drug: Mycophenolate Mofetil
  • Procedure: Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation
  • Procedure: Peripheral Blood Stem Cell Transplantation
  • Radiation: Total-Body Irradiation
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
Not Provided
December 2016   (final data collection date for primary outcome measure)

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 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 Patient Care Conference (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 first chronic phase (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 echocardiogram (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 non-melanoma skin cancers) or those with non-hematological malignancies (except non-melanoma skin cancers) who have been rendered with no evidence of disease, but have a greater than 20% chance of having disease recurrence within 5 years; this exclusion does not apply to patients with non-hematologic malignancies that do not require therapy
  • 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 times 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
  • DONOR: Total creatinine kinase > 2 times the ULN
Both
Not Provided
No
United States
 
NCT01527045
2546.00, NCI-2011-03828, 2546.00, P01CA018029, P30CA015704
Yes
Fred Hutchinson Cancer Research Center
Fred Hutchinson Cancer Research Center
  • National Cancer Institute (NCI)
  • National Heart, Lung, and Blood Institute (NHLBI)
Principal Investigator: Marco Mielcarek Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
Fred Hutchinson Cancer Research Center
July 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP