Clinical trial NCT01116232: Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
Official title: A Pilot Phase II Study of Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Myeloproliferative Disorders
Graft Versus Host Disease
Leukemia
Lymphoma
Lymphoproliferative Disorder
Multiple Myeloma and Plasma Cell Neoplasm
Myelodysplastic Syndromes
Myelodysplastic/Myeloproliferative Neoplasms
Keywords: graft versus host disease
accelerated phase chronic myelogenous leukemia
adult acute lymphoblastic leukemia in remission
adult acute myeloid leukemia in remission
adult acute myeloid leukemia with 11q23 (MLL) abnormalities
adult acute myeloid leukemia with inv(16)(p13;q22)
adult acute myeloid leukemia with t(15;17)(q22;q12)
adult acute myeloid leukemia with t(16;16)(p13;q22)
adult acute myeloid leukemia with t(8;21)(q22;q22)
atypical chronic myeloid leukemia, BCR-ABL negative
blastic phase chronic myelogenous leukemia
chronic myelomonocytic leukemia
chronic phase chronic myelogenous leukemia
meningeal chronic myelogenous leukemia
progressive hairy cell leukemia, initial treatment
prolymphocytic leukemia
recurrent adult acute lymphoblastic leukemia
recurrent adult acute myeloid leukemia
recurrent adult T-cell leukemia/lymphoma
refractory chronic lymphocytic leukemia
refractory hairy cell leukemia
relapsing chronic myelogenous leukemia
stage I adult T-cell leukemia/lymphoma
stage I chronic lymphocytic leukemia
stage II adult T-cell leukemia/lymphoma
stage II chronic lymphocytic leukemia
stage III adult T-cell leukemia/lymphoma
stage III chronic lymphocytic leukemia
stage IV adult T-cell leukemia/lymphoma
stage IV chronic lymphocytic leukemia
T-cell large granular lymphocyte leukemia
untreated adult acute lymphoblastic leukemia
untreated adult acute myeloid leukemia
untreated hairy cell leukemia
recurrent adult Hodgkin lymphoma
stage I adult Hodgkin lymphoma
stage II adult Hodgkin lymphoma
stage III adult Hodgkin lymphoma
stage IV adult Hodgkin lymphoma
anaplastic large cell lymphoma
angioimmunoblastic T-cell lymphoma
cutaneous B-cell non-Hodgkin lymphoma
recurrent cutaneous T-cell non-Hodgkin lymphoma
stage I cutaneous T-cell non-Hodgkin lymphoma
stage II cutaneous T-cell non-Hodgkin lymphoma
stage III cutaneous T-cell non-Hodgkin lymphoma
stage IV cutaneous T-cell non-Hodgkin lymphoma
recurrent mycosis fungoides/Sezary syndrome
stage I mycosis fungoides/Sezary syndrome
stage II mycosis fungoides/Sezary syndrome
stage III mycosis fungoides/Sezary syndrome
stage IV mycosis fungoides/Sezary syndrome
adult grade III lymphomatoid granulomatosis
adult nasal type extranodal NK/T-cell lymphoma
Waldenstrom macroglobulinemia
extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
nodal marginal zone B-cell lymphoma
splenic marginal zone lymphoma
contiguous stage II adult Burkitt lymphoma
contiguous stage II adult diffuse large cell lymphoma
contiguous stage II adult diffuse mixed cell lymphoma
contiguous stage II adult diffuse small cleaved cell lymphoma
contiguous stage II adult immunoblastic large cell lymphoma
contiguous stage II adult lymphoblastic lymphoma
contiguous stage II grade 1 follicular lymphoma
contiguous stage II grade 2 follicular lymphoma
contiguous stage II grade 3 follicular lymphoma
contiguous stage II mantle cell lymphoma
contiguous stage II marginal zone lymphoma
contiguous stage II small lymphocytic lymphoma
stage I adult Burkitt lymphoma
stage I adult diffuse large cell lymphoma
stage I adult diffuse mixed cell lymphoma
stage I adult diffuse small cleaved cell lymphoma
stage I adult immunoblastic large cell lymphoma
stage I adult lymphoblastic lymphoma
stage I grade 1 follicular lymphoma
stage I grade 2 follicular lymphoma
stage I grade 3 follicular lymphoma
stage I mantle cell lymphoma
stage I marginal zone lymphoma
stage I small lymphocytic lymphoma
noncontiguous stage II adult Burkitt lymphoma
noncontiguous stage II adult diffuse large cell lymphoma
noncontiguous stage II adult diffuse mixed cell lymphoma
noncontiguous stage II adult diffuse small cleaved cell lymphoma
noncontiguous stage II adult immunoblastic large cell lymphoma
noncontiguous stage II adult lymphoblastic lymphoma
noncontiguous stage II grade 1 follicular lymphoma
noncontiguous stage II grade 2 follicular lymphoma
noncontiguous stage II grade 3 follicular lymphoma
noncontiguous stage II mantle cell lymphoma
noncontiguous stage II marginal zone lymphoma
noncontiguous stage II small lymphocytic lymphoma
stage III adult Burkitt lymphoma
stage III adult diffuse large cell lymphoma
stage III adult diffuse mixed cell lymphoma
stage III adult diffuse small cleaved cell lymphoma
stage III adult immunoblastic large cell lymphoma
stage III adult lymphoblastic lymphoma
stage III grade 1 follicular lymphoma
stage III grade 2 follicular lymphoma
stage III grade 3 follicular lymphoma
stage III mantle cell lymphoma
stage III marginal zone lymphoma
stage III small lymphocytic lymphoma
stage IV adult Burkitt lymphoma
stage IV adult diffuse large cell lymphoma
stage IV adult diffuse mixed cell lymphoma
stage IV adult diffuse small cleaved cell lymphoma
stage IV adult immunoblastic large cell lymphoma
stage IV adult lymphoblastic lymphoma
stage IV grade 1 follicular lymphoma
stage IV grade 2 follicular lymphoma
stage IV grade 3 follicular lymphoma
stage IV mantle cell lymphoma
stage IV marginal zone lymphoma
stage IV small lymphocytic lymphoma
recurrent adult Burkitt lymphoma
recurrent adult diffuse large cell lymphoma
recurrent adult diffuse mixed cell lymphoma
recurrent adult diffuse small cleaved cell lymphoma
recurrent adult grade III lymphomatoid granulomatosis
recurrent adult immunoblastic large cell lymphoma
recurrent adult lymphoblastic lymphoma
recurrent grade 1 follicular lymphoma
recurrent grade 2 follicular lymphoma
recurrent grade 3 follicular lymphoma
recurrent mantle cell lymphoma
recurrent marginal zone lymphoma
recurrent small lymphocytic lymphoma
intraocular lymphoma
post-transplant lymphoproliferative disorder
chronic eosinophilic leukemia
chronic neutrophilic leukemia
primary myelofibrosis
stage I multiple myeloma
stage II multiple myeloma
stage III multiple myeloma
refractory multiple myeloma
de novo myelodysplastic syndromes
previously treated myelodysplastic syndromes
myelodysplastic/myeloproliferative neoplasm, unclassifiable
Lead sponsor: Barbara Ann Karmanos Cancer Institute
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-05-04
Enrollment: 4
Sex: ALL
Minimum age (years): 18
Maximum age (years): 120
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: SUPPORTIVE_CARE

Brief summary: This Phase II clinical trial was designed for patients with hematologic malignancies in need of donor peripheral blood stem cell transplant, and have no HLA matched donor. Therefore It will test the efficacy of combining sirolimus, tacrolimus, antithymocyte globulin, and rituximab in preventing graft versus host disease in transplants from HLA Haploidentical and partially mismatched donors.

Detailed description: OBJECTIVES:

Primary

* Determine the incidence and severity of acute graft-vs-host disease (GVHD) in patients with hematologic malignancies undergoing donor peripheral blood stem cell transplantation who are receiving sirolimus, tacrolimus, anti-thymocyte globulin, and rituximab as GVHD prophylaxis.
* Assess time to engraftment absolute neutrophil count (\> 0.5 x 10\^9/L for 3 consecutive days) and platelet count (\> 20 x 10\^9/L for 3 consecutive days) in these patients.
* Determine the safety, as defined by serious adverse events and adverse events related to this immunosuppressive regimen, in the first 6 months after treatment.

Secondary

* Assess the incidence of chronic GVHD measured within 2 years after transplantation.
* Assess overall and disease-free survival at 2 years after transplantation.
* Examine the incidence of opportunistic infections including fungal infections, pneumocystis carinii pneumonia, and viral infections (cytomegalovirus, varicella zoster virus, herpes simplex virus, BK virus, Epstein-Barr virus, and post-transplant lymphoproliferative disorder).
* Assess the incidence of thrombotic microangiopathy within 100 days of transplantation.
* Perform immunocorrelative studies, including T-cell, B-cell, NK-cell, regulatory cell, and allo-reactive T-cell measurement studies via flow cytometry, at 30, 60, 90, and 180 days after transplantation.

OUTLINE: Patients receive rituximab IV on days -7 and 3, tacrolimus IV continuously (may switch to orally when the patient is able to eat) and oral sirolimus beginning on day -3, and anti-thymocyte globulin IV over 6 hours on days -3 to -1. Tacrolimus and sirolimus are tapered at the discretion of the treating physician.

All patients also receive a standard transplant-preparative regimen and undergo transplantation on day 0.

Blood samples are collected before the preparative regimen and at 30, 60, 90, and 180 days after transplantation for correlative immunologic studies.

After completion of study treatment, patients are followed up for 2 years.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of a hematological malignancy, including:

  * Non-Hodgkin lymphoma
  * Hodgkin lymphoma
  * Acute myeloid leukemia or acute lymphoblastic leukemia
  * Myelodysplastic syndrome (treated or untreated)
  * Chronic myelogenous leukemia
  * Multiple myeloma
  * Chronic lymphocytic leukemia
  * Myelofibrosis and other myeloproliferative disorders
* No suitable related HLA-matched or unrelated HLA-matched (8/8 or 7/8 matched) donor
* Available suitable haploidentical or partial-matched unrelated donor (high-resolution molecular HLA typing is mandatory for HLA Class I and II)

  * No more than 4/8 HLA allele or antigen mismatch for a haploidentical-related first-degree family member donor
  * Only 6/8 or 5/8 allele or antigen match for an unrelated donor
* Scheduled to undergo peripheral blood stem cell transplantation

  * Not receiving bone marrow or ex vivo engineered or processed graft (e.g., CD34+ enrichment, T-cell depletion)
* No documented uncontrolled CNS disease

PATIENT CHARACTERISTICS:

* Karnofsky performance status (PS) 70-100%
* ECOG PS 0-2
* Serum bilirubin \< 3 times upper limit of normal (ULN)
* ALT and AST \< 3 times ULN
* Creatinine clearance \> 60 mL/min
* Ejection fraction \> 50%
* Forced vital capacity, FEV_1, or DLCO \> 50% predicted
* Negative pregnancy test
* Able to cooperate with oral medication intake
* Patients with coronary heart disease (recent myocardial infarctions, angina, cardiac stent, or bypass surgery in the past 6 months) are eligible provided they are cleared with a stress echo or nuclear myocardial perfusions stress test and a cardiology consult
* No ascites
* No HIV positivity
* No active hepatitis B or C virus infection
* No known contraindication to the administration of sirolimus, tacrolimus, anti-thymocyte globulin, or rituximab

PRIOR CONCURRENT THERAPY:

* See Disease Characteristics
* Not on home oxygen

Primary outcomes:
measure: Incidence and Severity of Acute Graft-vs-host Disease (GVHD)
timeFrame: During the first six months post transplant
measure: Time to Engraftment
timeFrame: During the first six months post transplant
measure: Safety Assessment
timeFrame: During the first six months post transplant
Secondary outcomes:
measure: Incidence of Chronic GVHD
timeFrame: Within two years after transplant
measure: Incidence of Infections Including Cytomegalovirus, Epstein-Barr Virus Reactivation, and Post-transplant Lymphoproliferative Disorder
timeFrame: At one year
measure: Incidence of Thrombotic Microangiopathy
timeFrame: Within 100 days of HCT
measure: Overall and Disease-free Survival
timeFrame: At 1 year
measure: Immunocorrelative Studies Pre- and Periodically Post-transplantation
timeFrame: Using flow cytometry at 30, 60, 90, and 180 days post transplant.
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
Study officials:
affiliation: Barbara Ann Karmanos Cancer Institute
name: Zaid Al-Kadhimi, M.D.
role: PRINCIPAL_INVESTIGATOR
References: