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

NCT ID: NCT01527045

Last Updated: 2020-01-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 47 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-09-25
• Study Completion Date: 2019-04-30

Brief Summary

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.

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.

Conditions

Aggressive Non-Hodgkin Lymphoma; Blasts Under 5 Percent of Bone Marrow Nucleated Cells; Chronic Lymphocytic Leukemia; Loss of Chromosome 17p; Myelodysplastic/Myeloproliferative Neoplasm; Non-Hodgkin Lymphoma; Prolymphocytic Leukemia; Recurrent Adult Acute Lymphoblastic Leukemia; Recurrent Adult Acute Myeloid Leukemia; Recurrent Aggressive Adult Non-Hodgkin Lymphoma; Recurrent Childhood Acute Lymphoblastic Leukemia; Recurrent Childhood Acute Myeloid Leukemia; Recurrent Chronic Lymphocytic Leukemia; Recurrent Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma; Recurrent Mantle Cell Lymphoma; Recurrent Non-Hodgkin Lymphoma; Recurrent Plasma Cell Myeloma; Recurrent Small Lymphocytic Lymphoma; Waldenstrom Macroglobulinemia

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Prevention (donor statin treatment)

See Detailed Description

Group Type: EXPERIMENTAL

Atorvastatin Calcium

Intervention Type: DRUG

Given PO

Cyclosporine

Intervention Type: DRUG

Given PO

Fludarabine Phosphate

Intervention Type: DRUG

Given IV

Laboratory Biomarker Analysis

Intervention Type: OTHER

Correlative studies

Mycophenolate Mofetil

Intervention Type: DRUG

Given PO or IV

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo nonmyeloablative allogeneic PBSC transplant

Peripheral Blood Stem Cell Transplantation

Intervention Type: PROCEDURE

Undergo nonmyeloablative allogeneic PBSC transplant

Total-Body Irradiation

Intervention Type: RADIATION

Undergo TBI

Interventions

Atorvastatin Calcium

Given PO

Intervention Type: DRUG

Cyclosporine

Given PO

Intervention Type: DRUG

Fludarabine Phosphate

Given IV

Intervention Type: DRUG

Laboratory Biomarker Analysis

Correlative studies

Intervention Type: OTHER

Mycophenolate Mofetil

Given PO or IV

Intervention Type: DRUG

Nonmyeloablative Allogeneic Hematopoietic Stem Cell Transplantation

Undergo nonmyeloablative allogeneic PBSC transplant

Intervention Type: PROCEDURE

Peripheral Blood Stem Cell Transplantation

Undergo nonmyeloablative allogeneic PBSC transplant

Intervention Type: PROCEDURE

Total-Body Irradiation

Undergo TBI

Intervention Type: RADIATION

Other Intervention Names

ATORVASTATIN CALCIUM TRIHYDRATE; CI-981; Lipitor; 27-400; Ciclosporin; CsA; Cyclosporin; Cyclosporin A; Gengraf; Neoral; OL 27-400; Sandimmun; Sandimmune; SangCya; 2-F-ara-AMP; 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-; Beneflur; Fludara; SH T 586; Cellcept; MMF; Non-myeloablative allogeneic transplant; Nonmyeloablative Stem Cell Transplantation; NST; PBPC transplantation; PBSCT; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplant; Peripheral Stem Cell Transplantation; Total Body Irradiation; Whole-Body Irradiation

Eligibility Criteria

Inclusion Criteria

• 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

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

• 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 CYP 3A4 (i.e. clarithromycin, erythromycin, protease inhibitors, azole antifungals)
• DONOR: Failure to meet local criteria for stem cell donation
• DONOR: Total creatinine kinase > 2 times the ULN

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Cancer Institute (NCI)

NIH

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Fred Hutchinson Cancer Center

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Marco Mielcarek

Role: PRINCIPAL_INVESTIGATOR

Fred Hutch/University of Washington Cancer Consortium

Locations

Presbyterian - Saint Lukes Medical Center - Health One

Denver, Colorado, United States

Fred Hutch/University of Washington Cancer Consortium

Seattle, Washington, United States

Countries

United States

References

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.

Reference Type: DERIVED

PMID: 32499241 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

NCI-2011-03828

Identifier Type: REGISTRY

Identifier Source: secondary_id

2546.00

Identifier Type: OTHER

Identifier Source: secondary_id

P01CA018029

Identifier Type: NIH

Identifier Source: secondary_id

View Link

P30CA015704

Identifier Type: NIH

Identifier Source: secondary_id

View Link

2546.00

Identifier Type: -

Identifier Source: org_study_id