Sirolimus, Cyclosporine, and Mycophenolate Mofetil in Preventing Graft-versus-Host Disease in Treating Patients With Blood Cancer Undergoing Donor Peripheral Blood Stem Cell Transplant

NCT01251575 | Completed Phase 2 Results DMC

• 5 other identifiers: 2206.00NCI-2010-02222P01CA018029P30CA015704RG9213055
• Study Type: interventional
• Target: 77
• Locations: 2 countries
• Sites: 5

Brief Summary

This phase II trial studies how well sirolimus, cyclosporine and mycophenolate mofetil works in preventing graft-vs-host disease (GVHD) in patients with blood cancer undergoing donor peripheral blood stem cell (PBSC) transplant. Giving chemotherapy and total-body irradiation before a donor peripheral blood stem cell transplant 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. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving total-body irradiation together with sirolimus, cyclosporine, and mycophenolate mofetil before and after transplant may stop this from happening.

Conditions

Adult Acute Lymphoblastic Leukemia; Adult Acute Myeloid Leukemia; Adult Diffuse Large B-Cell Lymphoma; Adult Myelodysplastic Syndrome; Adult Non-Hodgkin Lymphoma; Aggressive Non-Hodgkin Lymphoma; Childhood Acute Lymphoblastic Leukemia; Childhood Acute Myeloid Leukemia; Childhood Diffuse Large B-Cell Lymphoma; Childhood Myelodysplastic Syndrome; Childhood Non-Hodgkin Lymphoma; Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia in Remission; Chronic Phase Chronic Myelogenous Leukemia, BCR-ABL1 Positive; Hematopoietic and Lymphoid Cell Neoplasm; Mantle Cell Lymphoma; Plasma Cell Myeloma; Prolymphocytic Leukemia; Recurrent Chronic Lymphocytic Leukemia; Refractory Chronic Lymphocytic Leukemia; T-Cell Prolymphocytic Leukemia; Waldenstrom Macroglobulinemia; Recurrent Diffuse Large B-Cell Lymphoma; Recurrent Hodgkin Lymphoma

Outcome Measures

Primary Outcomes (1)

• Number of Patients With Grade II-IV Acute Graft Versus Host Disease (GVHD)

  Number of patients with grades II-IV acute GVHD aGVHD Stages Skin: 1. a maculopapular eruption involving \< 25% BSA 2. a maculopapular eruption involving 25 - 50% BSA 3. generalized erythroderma 4. generalized erythroderma w/ bullous formation and often w/ desquamation Liver: 1. bilirubin 2.0 - 3.0 mg/100 mL 2. bilirubin 3 - 5.9 mg/100 mL 3. bilirubin 6 - 14.9 mg/100 mL 4. bilirubin \> 15 mg/100 mL Gut: Diarrhea is graded 1 - 4 in severity. Nausea and vomiting and/or anorexia caused by GVHD is assigned as 1 in severity. The severity of gut involvement is assigned to the most severe involvement noted. Patients w/ visible bloody diarrhea are at least stage 2 gut and grade 3 overall. aGVHD Grades Grade II: Stage 1 - 2 skin w/ no gut/liver involvement Grade III: Stage 2 - 4 gut involvement and/or stage 2 - 4 liver involvement Grade IV: Pattern and severity of GVHD similar to grade 3 w/ extreme constitutional symptoms or death

  100 days post-transplant

Secondary Outcomes (2)

• Number of Non-Relapse Mortalities

  100 days post-transplant

• Number of Patients With Grade III-IV Acute GVHD

  100 days post-transplant

Study Arms (1)

Treatment (fludarabine, transplant, immunosuppression)

EXPERIMENTAL

CONDITIONING: Patients receive fludarabine phosphate IV over 30 minutes on days -4 to -2. Patients also undergo total-body irradiation on day 0. TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell transplantation. IMMUNOSUPPRESSION: Patients receive sirolimus PO QD on days -3 to 180 with taper to day 365; cyclosporine PO BID on days -3 to 150 with taper to day 180; and mycophenolate mofetil PO TID on days 0-30 and then BID to day 100 with taper to day 150.

Procedure: Allogeneic Hematopoietic Stem Cell Transplantation; Drug: Cyclosporine; Drug: Fludarabine Phosphate; Other: Laboratory Biomarker Analysis; Drug: Mycophenolate Mofetil; Procedure: Peripheral Blood Stem Cell Transplantation; Drug: Sirolimus; Radiation: Total-Body Irradiation

Interventions

Allogeneic Hematopoietic Stem Cell Transplantation PROCEDURE

Undergo allogeneic peripheral blood stem cell transplant

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

Treatment (fludarabine, transplant, immunosuppression)

Cyclosporine DRUG

Given PO or IV

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

Treatment (fludarabine, transplant, immunosuppression)

Fludarabine Phosphate DRUG

Given IV

Also known as: 2-F-ara-AMP, 9H-Purin-6-amine, 2-fluoro-9-(5-O-phosphono-.beta.-D-arabinofuranosyl)-, Beneflur, Fludara, SH T 586

Treatment (fludarabine, transplant, immunosuppression)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (fludarabine, transplant, immunosuppression)

Mycophenolate Mofetil DRUG

Given PO

Also known as: Cellcept, MMF

Treatment (fludarabine, transplant, immunosuppression)

Peripheral Blood Stem Cell Transplantation PROCEDURE

Undergo allogeneic peripheral blood stem cell transplant

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

Treatment (fludarabine, transplant, immunosuppression)

Sirolimus DRUG

Given PO

Also known as: AY 22989, RAPA, Rapamune, Rapamycin, SILA 9268A, WY-090217

Treatment (fludarabine, transplant, immunosuppression)

Total-Body Irradiation RADIATION

Undergo total-body irradiation

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

Treatment (fludarabine, transplant, immunosuppression)

Eligibility Criteria

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

You may qualify if:

• Ages \> 50 years with hematologic malignancies treatable by related or unrelated HCT
• Ages =\< 50 years of age with chronic lymphocytic leukemia (CLL)
• 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
• CLL: must have either 1) failed to meet National Cancer Institute (NCI) Working Group criteria for complete or partial response after therapy with a regimen containing fludarabine (FLU) (or another nucleoside analog, e.g. cladribine \[2-CDA\], pentostatin) or experience disease relapse within 12 months after completing therapy with a regimen containing FLU (or another nucleoside analog); 2) failed FLU-cyclophosphamide (CY)-Rituximab (FCR) combination chemotherapy at any time point; or 3) have "17p deletion" cytogenetic abnormality; patients should have received induction chemotherapy but could be transplanted in first (1st) CR; 4) patients with a diagnosis of CLL (or small lymphocytic lymphoma) that progresses to prolymphocytic leukemia (PLL); or 5) 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 in chronic phase 1 (CP1) must have failed or be intolerant of tyrosine kinase inhibitors (TKIs); patients beyond CP1 will be accepted if they 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 with related or unrelated donors for whom the best available donor is: a) mismatched at antigen level for any single class I locus (HLA-A, -B, -C) +/- an additional class I mismatch at the allele level OR mismatched at the allele level for any 2 class I loci (if typed at the molecular level) OR mismatched at the antigen or allele level for class II loci HLA-DRB1 and/or - DQB1; must be matched for at least one DRB1 allele and one DQB1 allele; b) there is a likelihood of rapid disease progression while HLA typing and results of a preliminary search and the donor pool suggests that a 10/10 HLA-A, B, C, DRB1 and DQB1 matched donor will not be found; c) there is no HLA-A, -B or -C one locus allelic mismatched donor available
• DONOR: Related or unrelated volunteer donors who are mismatched with the recipient within one of the following limitations:

You may not qualify if:

• Patients for whom the best available donor is mismatched at both HLA class I and class II
• A positive cross-match exists between the donor and recipient
• Patients with rapidly progressive intermediate or high grade NHL
• Patients with a diagnosis of chronic myelomonocytic leukemia (CMML)
• Patients with refractory anemia with excess blasts (RAEB)-2 who have not received myelosuppressive chemotherapy i.e. induction chemotherapy
• Presence of circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with AML, ALL or CML
• Presence of \>= 5% circulating leukemic blasts (in the peripheral blood) detected by standard pathology for patients with MDS/MPS
• Central nervous system (CNS) involvement with disease refractory to intrathecal chemotherapy
• Fertile men or women unwilling to use contraceptives during and for up to 12 months following treatment
• Female patients who are pregnant or breast-feeding
• Human immunodeficiency virus (HIV) positive patients
• Fungal infections with radiological progression after receipt of amphotericin B or active triazole for greater than 1 month
• Patients with active bacterial or fungal infections unresponsive to medical therapy
• Cardiac ejection fraction \< 35% (or, if unable to obtain ejection fraction, shortening fraction of \< 26%); ejection fraction is required if the patient is \> 50 years of age, or history of cardiac disease or anthracycline exposure; patients with a shortening fraction \< 26% may be enrolled if approved by a cardiologist
• Corrected diffusion capacity of carbon monoxide (DLCO) \< 40%, total lung capacity (TLC) \< 40%, forced expiratory volume in one second (FEV1) \< 40% and/or receiving supplementary continuous oxygen; if unable to perform complete pulmonary function tests (PFTs), patients will be excluded if their oxygen saturation is \< 95% with a formal six-minute walk test (ambulatory oximetry)

Sponsors & Collaborators

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

Study Sites (5)

Presbyterian - Saint Lukes Medical Center - Health One

Denver, Colorado, 80218, United States

Location

Huntsman Cancer Institute/University of Utah

Salt Lake City, Utah, 84112, 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

Rigshospitalet University Hospital

Copenhagen, 2100, Denmark

Location

Related Publications (1)

• Kornblit B, Storer BE, Andersen NS, Maris MB, Chauncey TR, Petersdorf EW, Woolfrey AE, Flowers MED, Storb R, Maloney DG, Sandmaier BM. Sirolimus with CSP and MMF as GVHD prophylaxis for allogeneic transplantation with HLA antigen-mismatched donors. Blood. 2020 Sep 24;136(13):1499-1506. doi: 10.1182/blood.2020005338.

  PMID: 32603426 DERIVED

MeSH Terms

Conditions

Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Myeloid, Acute; Lymphoma, Large B-Cell, Diffuse; Anemia, Refractory, with Excess of Blasts; Lymphoma, Non-Hodgkin; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Chronic-Phase; Hematologic Neoplasms; Lymphoma, Mantle-Cell; Multiple Myeloma; Leukemia, Prolymphocytic; Leukemia, Prolymphocytic, T-Cell; Waldenstrom Macroglobulinemia; Hodgkin Disease

Interventions

Cyclosporine; Cyclosporins; fludarabine phosphate; Mycophenolic Acid; Peripheral Blood Stem Cell Transplantation; Sirolimus; Whole-Body Irradiation

Condition Hierarchy (Ancestors)

Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, Myeloid; Lymphoma, B-Cell; Lymphoma; Anemia, Refractory; Anemia; Myelodysplastic Syndromes; Bone Marrow Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myeloproliferative Disorders; Neoplasms by Site; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Leukemia, T-Cell

Intervention Hierarchy (Ancestors)

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; Macrolides; Lactones; 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: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 29, 2010
• First Posted: December 2, 2010
• Study Start: December 1, 2010
• Primary Completion: November 23, 2018
• Study Completion: February 11, 2019
• Last Updated: December 9, 2019
• Results First Posted: December 9, 2019

Record last verified: 2019-11

Locations

US (4); DK (1)