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

This study has been terminated.
(Slow accrual)
Sponsor:
Information provided by (Responsible Party):
Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier:
NCT00618540
First received: February 19, 2008
Last updated: June 11, 2013
Last verified: June 2013
  Purpose

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.


Condition Intervention Phase
Histiocytosis, Langerhans-cell
Biological: alemtuzumab
Drug: fludarabine phosphate
Drug: melphalan
Procedure: stem cell transplantation
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Reduced Intensity Hematopoietic Cell Transplantation for Patients With Resistant Langerhans Cell Histiocytosis

Resource links provided by NLM:


Further study details as provided by Masonic Cancer Center, University of Minnesota:

Primary Outcome Measures:
  • Overall survival [ Time Frame: Year 1, Year 3 ] [ Designated as safety issue: No ]
    Count of patients alive at 1 and 3 years. Deaths from any cause are events. Surviving patients are censored at the date of last contact.

  • Disease-free survival at 12 months post transplantation [ Time Frame: Year 1 ] [ Designated as safety issue: No ]

    This outcome is defined as survival with resolution of LCH at 12 months post transplant.

    Unresolved disease for over 12 months post-transplant, progressive disease after this time period, recurrence of disease and death from any cause are considered events.

    Those who survive with resolution of disease are censored at the date of last contact.



Secondary Outcome Measures:
  • Transplantation-related Death [ Time Frame: Day 100 ] [ Designated as safety issue: Yes ]
    Count of patients who died at day 100 related to the transplantation.

  • Neutrophil and platelet engraftment [ Time Frame: Day 100, Year 1 ] [ Designated as safety issue: No ]
    Incidence of hematopoietic recovery ( and donor chimerism at Day 100 and Year 1 post transplant.

  • Incidence of grades II-IV and III-IV acute graft-versus-host-disease (GVHD) [ Time Frame: Day 100, Month 6, Year 1 ] [ Designated as safety issue: No ]
    The occurrence of skin, gastrointestinal or liver abnormalities fulfilling the criteria of Grades II, III and/or IV acute GVHD are considered events (Appendix II). Patients without acute GvHD will be censored at the time of death or last follow-up. Patients that survive <21 days and listed as not evaluable will be excluded. Patients receiving a second transplant will be censored at the time of second transplant.

  • Incidence of chronic GVHD [ Time Frame: Day 100, Month 6, Year 1 ] [ Designated as safety issue: No ]
    Occurrence of symptoms in any organ system fulfilling the criteria of limited or extensive chronic GvHD (Appendix III), among patients surviving > 90 days with evidence of engraftment. Patients without chronic GvHD will be censored at time of death or last follow-up.

  • Response to Treatment [ Time Frame: Day 100 ] [ Designated as safety issue: No ]
    Defined as Better (resolution of all signs or symptoms or improvement), Intermediate (unchanged) or Worse (progressive disease - Progression of signs or symptoms and/or appearance of new lesions)


Enrollment: 1
Study Start Date: January 2007
Estimated Study Completion Date: August 2013
Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Alemtuzumab
Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis.
Biological: alemtuzumab
Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4.
Other Name: Campath(R)
Drug: fludarabine phosphate
Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months)
Other Name: Fludara(R)
Drug: melphalan
Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months)
Other Name: Alkeran
Procedure: stem cell transplantation
Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Other Name: Stem cell transplant

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.

  Eligibility

Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00618540

Locations
United States, Minnesota
Masonic Cancer Center at University of Minnesota
Minneapolis, Minnesota, United States, 55455
Sponsors and Collaborators
Masonic Cancer Center, University of Minnesota
Investigators
Principal Investigator: Angela Smith Masonic Cancer Center, University of Minnesota
  More Information

No publications provided

Responsible Party: Masonic Cancer Center, University of Minnesota
ClinicalTrials.gov Identifier: NCT00618540     History of Changes
Other Study ID Numbers: 2007UC002, UMN-0612M98407, LCH-HCT-2006, UMN-MT2006-07
Study First Received: February 19, 2008
Last Updated: June 11, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Masonic Cancer Center, University of Minnesota:
childhood Langerhans cell histiocytosis

Additional relevant MeSH terms:
Histiocytosis
Histiocytosis, Langerhans-Cell
Lymphatic Diseases
Lung Diseases, Interstitial
Lung Diseases
Respiratory Tract Diseases
Fludarabine
Fludarabine phosphate
Alemtuzumab
Melphalan
Vidarabine
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Alkylating
Alkylating Agents
Myeloablative Agonists
Antiviral Agents
Anti-Infective Agents

ClinicalTrials.gov processed this record on September 18, 2014