Reduced Intensity Hematopoietic Cell Transplantation for Patients With Resistant Langerhans Cell Histiocytosis

NCT ID: NCT00618540

Last Updated: 2017-12-28

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE2
• Total Enrollment: 1 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-01-31
• Study Completion Date: 2013-05-31

Brief Summary

RATIONALE: Giving a monoclonal antibody, such as alemtuzumab, and chemotherapy drugs, such as fludarabine and melphalan, before a donor stem cell transplant helps stop the patient's immune system from rejecting the donor's stem cells and helps stop the growth of abnormal 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 cyclosporine and mycophenolate mofetil before and after transplant may stop this from happening.

PURPOSE: This phase II trial is studying how well giving alemtuzumab together with fludarabine and melphalan followed by a donor stem cell transplant works in treating young patients with resistant Langerhans cell histiocytosis.

Detailed Description

OBJECTIVES:

Primary

• To determine the overall and disease-free survival of poor-risk pediatric patients with Langerhans cell histiocytosis at 1 and 3 years after reduced-intensity hematopoietic cell transplantation (RI-HCT).

Secondary

• To determine day 100 transplantation-related mortality.
• To determine the incidence of hematopoietic recovery and chimerism at day 100 and at 1 year post RI-HCT.
• To determine the incidence of grades II-IV and III-IV acute graft-versus-host disease (GVHD).
• To determine the incidence of chronic GVHD.

OUTLINE: This is a multicenter study.

• Non-myeloablative conditioning: Patients receive alemtuzumab intravenously (IV) over 2 hours on days -8 to -4, fludarabine phosphate IV over 30-60 minutes on days -7 to -3, and melphalan IV over 15-30 minutes on day -2. Some patients may receive anti-thymocyte globulin IV on days -6 to -2 instead of alemtuzumab.
• Graft-versus-host disease prophylaxis and immunosuppression: Patients receive cyclosporine A (CSA) IV or orally 2-3 times daily beginning on day -3 and continuing until day 50 post transplantation, followed by a taper over 8 weeks in the absence of GVHD or donor lymphocyte infusion given for decreasing donor chimerism. Patients with mismatched donors (any source) and those receiving peripheral blood stem cells also receive mycophenolate mofetil (MMF) IV or orally 2-3 times daily beginning on day -3 and continuing to day 30 or 7 days after engraftment, whichever day is later, in the absence of GVHD. In patients with acute GVHD requiring systemic therapy, Mycophenolate mofetil (MMF) may be stopped 7 days after initiation of systemic therapy.
• Allogeneic hematopoietic stem cell infusion: Patients undergo infusion of bone marrow (preferred) or peripheral blood stem cells on day 0. Patients also receive filgrastim (G-CSF) subcutaneously or IV beginning on day 8 and continuing until blood counts recover for 2 consecutive days.
• Donor lymphocyte infusion (DLI): Patients with mixed chimerism (i.e., < 95% donor) and those with < 50% donor T-cell engraftment at any engraftment assessment time point are eligible for DLI, in the absence of GVHD. If mixed chimerism persists, escalating doses of CD3-positive lymphocytes are administered every 3-4 weeks, in the absence of GVHD.

After completion of study therapy, patients are followed from engraftment through day 100, and then at 6 months, 1 year, and annually thereafter for 2-5 years.

Conditions

Histiocytosis, Langerhans-cell

Keywords

childhood Langerhans cell histiocytosis

Study Design

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

Study Groups

Alemtuzumab

Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis.

Group Type: EXPERIMENTAL

alemtuzumab

Intervention Type: BIOLOGICAL

Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4.

fludarabine phosphate

Intervention Type: DRUG

Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age \<12 months)

melphalan

Intervention Type: DRUG

Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age \<12 months)

stem cell transplantation

Intervention Type: PROCEDURE

Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation

Interventions

alemtuzumab

Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4.

Intervention Type: BIOLOGICAL

fludarabine phosphate

Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age \<12 months)

Intervention Type: DRUG

melphalan

Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age \<12 months)

Intervention Type: DRUG

stem cell transplantation

Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation

Intervention Type: PROCEDURE

Other Intervention Names

Campath(R); Fludara(R); Alkeran; Stem cell transplant

Eligibility Criteria

Inclusion Criteria

• Histologically confirmed Langerhans cell histiocytosis (LCH) by demonstration of CD1a positivity or Birbeck granules in lesions
• Considered poor-risk, defined as multisystem disease with involvement of one or more risk organs (i.e., liver, spleen, lungs, and/or hematopoietic system)

• No isolated "lung only" LCH
• Progressive disease after one of the following treatments:

• LCH-III protocol or other standard LCH-directed therapies
• At least 1 course of the current salvage protocol (i.e., LCH-2 2005) or similar therapy (e.g., cytosine arabinoside or cladribine-based regimens)
• HLA-matched related or unrelated donor OR unrelated umbilical cord blood (UCB) available

• 1 locus mismatch for donor allowed
• Up to 2 loci mismatch for unrelated UCB allowed
• Any hematologic status (transfusion support allowed)
• Adequate hepatic, renal, cardiac, and pulmonary function to undergo reduced-intensity hematopoietic cell transplantation (RI-HCT) including the following:

• Transaminases < 5 times upper limit of normal (ULN)
• Bilirubin < 3 times ULN (unless secondary to hepatic LCH)
• Creatinine ≤ 2 mg/dL (adults) (if creatinine > 1.2 OR history of renal dysfunction, must have estimated creatinine clearance > 40 mL/min)
• Creatinine clearance > 40 mL/min (pediatrics)
• Glomerular filtration rate ≥ 50mL/min
• Negative pregnancy test

Exclusion Criteria

• Decompensated congestive heart failure, uncontrolled arrhythmia, or left ventricular ejection fraction ≥ 35%
• Pulmonary failure (i.e., requiring mechanical ventilation) unless secondary to active underlying LCH
• Isolated liver sclerosis or pulmonary fibrosis unless secondary to active underlying LCH
• Uncontrolled active life-threatening infection
• Pregnant or nursing
• Less than 4 weeks after last attempted salvage chemotherapy treatment
• Other concurrent chemotherapy agents (e.g., methotrexate) during entire transplantation period up to day 100 post-transplantation

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Masonic Cancer Center, University of Minnesota

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Angela Smith

Role: PRINCIPAL_INVESTIGATOR

Masonic Cancer Center, University of Minnesota

Locations

Masonic Cancer Center at University of Minnesota

Minneapolis, Minnesota, United States

Countries

United States

Other Identifiers

UMN-0612M98407

Identifier Type: OTHER

Identifier Source: secondary_id

LCH-HCT-2006

Identifier Type: OTHER

Identifier Source: secondary_id

UMN-MT2006-07

Identifier Type: OTHER

Identifier Source: secondary_id

2007UC002

Identifier Type: -

Identifier Source: org_study_id