Tocilizumab in Improving Graft-Versus-Host Disease and Early Side Effects in Patients with Blood Cancers Undergoing Umbilical Cord Blood Transplant

Status: Active

Description

This phase II trial studies how well tocilizumab works in improving graft-versus-host disease (GVHD) and early side effects in patients with blood cancers undergoing umbilical cord blood transplant. Giving chemotherapy and total-body irradiation before an umbilical cord blood transplant helps stop the growth of cells in the bone marrow, including normal blood-forming cells (stem cells) and cancer 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 (called GVHD). Giving tocilizumab in addition to the standard approach for GVHD prevention after the transplant may stop this from happening.

Eligibility Criteria

Inclusion Criteria

  • Patients with no available and suitably matched related or unrelated donor in the required time period.
  • DIAGNOSIS:
  • Acute myelogenous leukemia (AML): * Complete first remission (CR1) at high risk for relapse such as any of the following: ** Known prior diagnosis of myelodysplasia (MDS) or myeloproliferative disorder. ** Therapy-related AML. ** White cell count at presentation > 100,000. ** Presence of extramedullary leukemia at diagnosis. ** Any unfavorable subtype by French-American-British (FAB) or World Health Organization (WHO) classification. ** High-risk cytogenetics (e.g. those associated with MDS, abnormalities of 5, 7, 8, complex karyotype) or high risk molecular abnormalities. ** Requirement for 2 or more inductions to achieve CR1. ** Any patient with newly diagnosed AML with intermediate risk cytogenetics who elects allograft with curative intent over consolidation chemotherapy. ** Any patient unable to tolerate consolidation chemotherapy as would have been deemed appropriate by the treating physician. ** Other high risk features not defined above. * Complete second remission (CR2). * Primary refractory or relapsed AML with less than 10% blasts before transplant. Persistent/relapsed AML with cytogenetic, flow cytometric, or molecular aberrations in >= 10% of cells are eligible.
  • Acute lymphoblastic leukemia (ALL): * Complete first remission (CR1) at high risk for relapse such as any of the following: ** White cell count at presentation > 30,000 for B-cell lineage and > 100,000 for T-cell lineage. ** Presence of any high-risk cytogenetic abnormalities such as t(9;22), t(1;19), t(4;11) or other MLL rearrangements (11q23) or other high-risk molecular abnormality. ** Failure to achieve complete remission after four weeks of induction therapy. ** Persistence or recurrence of minimal residual disease on therapy. ** Any patient with newly diagnosed ALL >= 50 years-old. ** Any patient unable to tolerate consolidation and/or maintenance chemotherapy as would have been deemed appropriate by the treating physician. ** Other high risk features not defined above. * Complete second remission (CR2). * Primary refractory or relapsed ALL with less than 5% blasts before transplant. Persistent/relapsed ALL with cytogenetic, flow cytometric or molecular aberrations in >= 5% of cells are eligible.
  • Other acute leukemias: leukemias of ambiguous lineage or of other types e.g. blastic plasmacytoid dendritic cell neoplasm with less than 5% blasts. Persistent/relapsed disease with cytogenetic, flow cytometric or molecular aberrations in >= 5% of cells are eligible.
  • Myelodysplastic syndrome (MDS)/myeloproliferative disorders (MPD) other than myelofibrosis: * International prognostic scoring system (IPSS) risk score of INT-2 or high risk at the time of diagnosis. * Any IPSS risk category if life-threatening cytopenia(s) exists. * Any IPSS risk category with karyotype or genomic changes that indicate high risk for progression to acute myelogenous leukemia. * MDS/ myeloproliferative disorder overlap syndromes without myelofibrosis. * MDS/MPD patients must have less than 10% bone marrow myeloblasts and ANC >= 0.2 (growth factor supported if necessary) at transplant work-up.
  • Non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL) at high-risk of relapse or progression if not in remission: * Eligible patients with aggressive histologies (such as, but not limited to, diffuse large B-cell NHL, mantle cell NHL, and T-cell histologies) in CR. * Eligible patients with indolent B cell NHL (such as, but not limited to, follicular, small cell or marginal zone NHL) will have 2nd or subsequent progression with stable disease/CR/partial remission (PR) with no single lesion equal to or more than 5 cm. * Eligible patients with HL will be without progression of disease (POD) after salvage chemotherapy with no single lesion equal to or more than 5 cm.
  • ORGAN FUNCTION AND PERFORMANCE STATUS CRITERIA:
  • Karnofsky score >= 70% (inpatient leukemia service transfers without discharge are acceptable provided patient has equivalent Karnofsky performance status [KPS] as if were outpatient).
  • Calculated creatinine clearance >= 60 ml/min.
  • Bilirubin < 1.5 mg/dL (unless benign congenital hyperbilirubinemia).
  • Alanine aminotransferase (ALT) =< 3 x upper limit of normal.
  • Pulmonary function (spirometry and corrected diffusion capacity of the lung for carbon monoxide [DLCO]) >= 50% predicted.
  • Left ventricular ejection fraction greater than 50%.
  • Albumin >= 3.0.
  • Age-adjusted hematopoietic cell transplantation-comorbidity index (aaHCT-CI) less than or equal to 7.
  • GRAFT CRITERIA:
  • 2 CB units will be selected according to current Memorial Sloan Kettering Cancer Center (MSKCC) unit selection algorithm. High resolution 8 allele HLA typing and recipient HLA antibody profile will be performed. Unit selection will occur based on HLA-match, total nucleated cell (TNC) and CD34+ cell dose adjusted per patient body weight. The bank of origin will also be taken into account. Donor specific HLA antibodies, if present, will also be taken into consideration and may influence the selection of the graft. * Each CB unit must be at least 3/8 HLA-matched to the patient considering high-resolution 8-allele HLA typing. * Each CB unit will be required to have a cryopreserved TNC dose of at least 1.5 x 10^7 TNC/ recipient body weight (TNC/ kg). * Each CB unit will be required to have a cryopreserved CD34+ cell dose of at least 1.0 x 10^5 CD34+ cells/ recipient body weight (CD34+/kg). * A minimum of one domestic will be reserved as a backup unit.

Exclusion Criteria

  • Indolent NHL or Hodgkin lymphoma with POD after most recent salvage chemotherapy.
  • Diagnosis of myelofibrosis or other malignancy with moderate-severe bone marrow fibrosis.
  • Any diagnosis without prior immunosuppressive chemotherapy within 3 months of intended admission for transplant.
  • Prior checkpoint inhibitors/blockade in the last 12 months.
  • Two prior stem cell transplants of any kind.
  • One prior autologous stem cell transplant within the preceding 12 months.
  • One prior allogeneic stem cell transplant within the preceding 24 months.
  • Prior radiation therapy with 400cGy or more of TBI.
  • Active and uncontrolled infection at time of transplantation.
  • Human immunodeficiency virus (HIV) infection.
  • Seropositivity for human T-lymphotropic virus type 1 (HTLV-1).
  • Inadequate performance status/organ function.
  • Pregnancy or breast feeding.
  • Patient or guardian unable to give informed consent or unable to comply with the treatment protocol including appropriate supportive care, long-term follow-up, and research tests.

Locations & Contacts

New York

New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Ioannis Politikos
Phone: 212-639-3468

Trial Objectives and Outline

PRIMARY OBJECTIVE:

I. Incidence of grade II-IV acute (a)GVHD by day 100 after double-unit umbilical cord blood transplantation (dCBT) with cyclophosphamide/fludarabine phosphate/thiotepa/total body irradiation (Cy/Flu/Thio/TBI)400 conditioning, standard GVHD prophylaxis with cyclosporine (CSA) and mycophenolate mofetil (MMF), and the addition of one dose of tocilizumab.

SECONDARY OBJECTIVES:

I. Incidence of grade III-IV aGVHD at 100 days.

II. Incidence of grades II-IV and III-IV aGVHD at 180 days and organ distribution.

III. Incidence and severity of chronic (c)GVHD at 1 and 2 years.

IV. Time to immunosuppression cessation.

V. Incidence and time to myeloid engraftment (neutrophil recovery to >= 0.5 x 10^9/L) and platelet engraftment (unsupported platelet recovery to >= 20,000 x 10^9/L).

VI. Contribution of each cord blood (CB) unit to donor chimerism in the first 100 days after CBT.

VII. Incidence of pre-engraftment syndrome (PES).

VIII. Incidence of transplant-related mortality (TRM) at 100 days, 6 months, 1 and 2 years.

IX. Incidence of relapse at 1 and 2 years after CBT.

X. The probability of progression free survival (PFS) at 1 and 2 years after CBT.

XI. The probability of overall survival (OS) at 1 and 2 years after CBT.

XII. T-cell and B-cell immune recovery in the first two years after CBT.

OUTLINE:

CONDITIONING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30-60 minutes on days -6 to -2, cyclophosphamide IV on day -6, thiotepa IV over 4 hours on days -5 and -4, and TBI on days -2 and -1.

TRANSPLANT: Patients undergo dCBT on day 0.

GVHD PROPHYLAXIS: Patients receive cyclosporine IV or orally (PO) beginning on day -3 and continuing for 6 months in the absence of GVHD, and mycophenolate mofetil IV or PO every 8 hours beginning on day -3 with a taper at approximately 60-100 days and completing by approximately 4-6 months in the absence of GVHD. Patients also receive tocilizumab IV over 60 minutes on day -1.

After completion of dCBT, patients are followed up at days 21, 28, 42, 60, and 100, and then at months 4, 6, 9, 12, 18, and 24.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Ioannis Politikos

Trial IDs

Primary ID 17-616
Secondary IDs NCI-2018-01427
Clinicaltrials.gov ID NCT03434730