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

• Sponsor: Masonic Cancer Center, University of Minnesota (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00618540
• Collaborator: (none)
• Enrollment: 1
• Location: 1
• Arm: 1
• Duration (Months): 76
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Histiocytosis, Langerhans-cell	Biological: alemtuzumab; Drug: fludarabine phosphate; Drug: melphalan; Procedure: stem cell transplantation	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Reduced Intensity Hematopoietic Cell Transplantation for Patients With Resistant Langerhans Cell Histiocytosis
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

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 Names: 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 Names: Fludara(R) ; Drug: melphalan; Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months); Other Names: Alkeran ; Procedure: stem cell transplantation; Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation; Other Names: Stem cell transplant

Outcome Measures

Primary Outcome Measures

1. Overall Survival [Year 1, Year 3]

   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.

2. Disease-free Survival at 12 Months Post Transplantation [Year 1]

   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

1. Transplantation-related Death [Day 100]

   Count of patients who died by day 100 related to the transplantation.

2. Neutrophil Engraftment [Day 100]

   Incidence of neutrophil recovery and donor chimerism at Day 100.

3. Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD) [Day 100 and Month 6]

   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.

4. Incidence of Chronic GVHD [Day 100 and Month 6]

   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.

5. Platelet Engraftment [Day 100]

   Incidence of platelet recovery and donor chimerism at Day 100.

6. Incidence of Grade III-IV Acute Graft-versus-host-disease (GVHD) [Day 100 and Month 6]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Masonic Cancer Center, University of Minnesota
• ClinicalTrials.gov Identifier: NCT00618540
• Other Study ID Numbers: 2007UC002; UMN-0612M98407; LCH-HCT-2006; UMN-MT2006-07
• First Posted: Feb 20, 2008
• Last Update Posted: Dec 28, 2017
• Last Verified: Dec 1, 2017

• Keywords provided by Masonic Cancer Center, University of Minnesota: childhood Langerhans cell histiocytosis
• Additional relevant MeSH terms: Histiocytosis, Langerhans-Cell; Histiocytosis; Fludarabine; Fludarabine phosphate; Melphalan; Alemtuzumab

Study Results

Participant Flow

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Period Title: Overall Study
STARTED	1
COMPLETED	1
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Overall Participants	1
Age (Count of Participants)
<=18 years	1 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	1 100%
Region of Enrollment (participants) [Number]
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	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.
Time Frame	Year 1, Year 3

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	0 0%

2. Primary Outcome

Title	Disease-free Survival at 12 Months Post Transplantation
Description	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.
Time Frame	Year 1

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	0 0%

3. Secondary Outcome

Title	Transplantation-related Death
Description	Count of patients who died by day 100 related to the transplantation.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	0 0%

4. Secondary Outcome

Title	Neutrophil Engraftment
Description	Incidence of neutrophil recovery and donor chimerism at Day 100.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	1 100%

5. Secondary Outcome

Title	Incidence of Grade II-IV Acute Graft-versus-host-disease (GVHD)
Description	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.
Time Frame	Day 100 and Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	1 100%

6. Secondary Outcome

Title	Incidence of Chronic GVHD
Description	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.
Time Frame	Day 100 and Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	0 0%

7. Secondary Outcome

Title	Platelet Engraftment
Description	Incidence of platelet recovery and donor chimerism at Day 100.
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	0 0%

8. Secondary Outcome

Title	Incidence of Grade III-IV Acute Graft-versus-host-disease (GVHD)
Description	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.
Time Frame	Day 100 and Month 6

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
Measure Participants	1
Number [participants]	0 0%

Adverse Events

Time Frame	The adverse event data were collected at 100 days post-transplantation.
Arm/Group Title	Alemtuzumab Conditioning
Arm/Group Description	Patients administered with alemtuzumab, fludarabine phosphate, melphalan and donor stem cell transplantation in children with resistant Langerhans cell histiocytosis. alemtuzumab: Administered intravenously (IV) 0.2 mg/kg on Days -8 through -4. fludarabine phosphate: Administered 30 mg/m2 intravenously (IV) over 30-60 min on Days -7 through -3. (dose adjust if age <12 months) melphalan: Administered 140 mg/m2 intravenously (IV) over 30 min on Day -2 (dose adjust if age <12 months) stem cell transplantation: Administered as allogeneic hematopoietic, peripheral blood or umbilical cord blood transplantation
All Cause Mortality
	Alemtuzumab Conditioning
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alemtuzumab Conditioning
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Respiratory, thoracic and mediastinal disorders
Respiratory syncytial virus (RSV) infection	1/1 (100%)	1
Other (Not Including Serious) Adverse Events
	Alemtuzumab Conditioning
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Infections and infestations
Multiple systemic infections	1/1 (100%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.