Nonneoplastic ConditionPhase 3NCT00334672
Combination Chemotherapy Followed By Donor Stem Cell Transplant in Treating Patients With Hemophagocytic Lymphohistiocytosis
A Phase 3 study testing anti-thymocyte globulin, busulfan and cyclophosphamide in people with Nonneoplastic Condition, run by Children's Cancer and Leukaemia Group at 13 sites in United Kingdom.
Trial summary
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of hemophagocytic lymphohistiocytosis cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more hemophagocytic lymphohistiocytosis cells. Read more about this study
- Who is it for?
- Ages Up to 17 years
- Conditions the study is for
- Nonneoplastic Condition
- What is being tested?
- anti-thymocyte globulin, busulfan and cyclophosphamide
- Type of treatment
- Surgery or procedure
- How many people
- 288 participants
- Where
- 13 sitesUnited Kingdom
- Study dates
- Mar 2006to Nov 2010
- Phase
- Phase 3
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Up to 17 years
- All sexes
- No healthy volunteers
- Child
DISEASE CHARACTERISTICS:
- Newly diagnosed hemophagocytic lymphohistiocytosis (HLH) meeting 1 of the following criteria*:
- Diagnosis by molecular/genetic methods
- Diagnosis by meeting 5 out of 8 of the following criteria:
- Clinical criteria:
- Fever
- Splenomegaly
- Laboratory criteria:
- Cytopenias affecting ≥ 2 of 3 lineages in the peripheral blood, including the following:
- Hemoglobin < 9.0 g/dL (< 10.0 g/dL in infants < 4 weeks of age)
- Platelet count < 100,000/mm^3
- Neutrophil count < 1,000/mm^3
- Hypertriglyceridemia and/or hypofibrinogenemia:
- Fasting triglycerides ≥ 3.0 mmol/L (i.e., ≥ 265 mg/dL)
- Fibrinogen ≤ 1.5 g/L
- Histopathologic criteria:
- Hemophagocytosis in bone marrow, spleen, or lymph nodes
- No evidence of malignancy
- New diagnostic criteria:
- Low or absent natural killer (NK) cell activity
- Ferritin ≥ 500 mcg/L
- Soluble CD25 (i.e., soluble interleukin-2 receptor) ≥ 2,400 U/mL NOTE: *Patients who do not meet the diagnostic criteria for HLH but who have a strong clinical suspicion of HLH may be eligible at the discretion of the investigator
- Primary HLH (i.e., familial hemophagocytic lymphohistiocytosis [FLH]) OR secondary HLH (i.e., severe acquired form of HLH)
- Acceptable donor meeting 1 of the following criteria:
- HLA-identical related donor
- Matched unrelated donor
- Mismatched unrelated donor
- Familial haploidentical donor
PATIENT CHARACTERISTICS:
- Not specified
PRIOR CONCURRENT THERAPY:
- No prior cytotoxic treatment for HLH
- No prior cyclosporine treatment for HLH
Trial locations and contacts
13 sites in 1 country.
13 sites in 1 country
United Kingdom13 sites
Royal Aberdeen Children's Hospital
Aberdeen, Scotland, AB25 2ZG
Birmingham Children's Hospital
Birmingham, England, B4 6NH
Institute of Child Health at University of Bristol
Bristol, England, BS2 8AE
Addenbrooke's Hospital
Cambridge, England, CB2 2QQ
Royal Hospital for Sick Children
Edinburgh, Scotland, EH9 1LF
Royal Hospital for Sick Children
Glasgow, Scotland, G3 8SJ
Watford General Hospital
Herts, England, WD18 0HB
Leeds Cancer Centre at St. James's University Hospital
Leeds, England, LS9 7TF
Royal Liverpool Children's Hospital, Alder Hey
Liverpool, England, L12 2AP
Great Ormond Street Hospital for Children
London, England, WC1N 3JH
Royal Manchester Children's Hospital
Manchester, England, M27 4HA
Children's Hospital - Sheffield
Sheffield, England, S10 2TH
Southampton General Hospital
Southampton, England, SO16 6YD
About this study
Official title: Hemophagocytic Lymphohistiocytosis
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of hemophagocytic lymphohistiocytosis cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more hemophagocytic lymphohistiocytosis cells. A donor stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Cyclosporine and methotrexate may stop this from happening.
PURPOSE: This phase III trial is studying how well combination chemotherapy followed by a donor stem cell transplant works in treating patients with hemophagocytic lymphohistiocytosis.
Read the detailed description
OBJECTIVES:
Primary
- Provide and evaluate revised induction and maintenance therapy comprising etoposide, dexamethasone, and cyclosporine, in terms of achieving and maintaining an acceptable clinical condition in order to perform a curative allogeneic hematopoietic stem cell transplantation (AHSCT), in patients with primary inherited or severe and persistent secondary hemophagocytic lymphohistiocytosis (HLH).
- Evaluate and improve the outcome of AHSCT with various types of donors.
- Determine the prognostic importance of the state of remission at the time of AHSCT.
- Evaluate the neurological complications, in terms of early neurological alterations and cerebrospinal fluid (CSF) findings, in patients treated with this regimen.
Secondary
- Improve the understanding of the pathophysiology of HLH by conducting biological studies of genetics and cytotoxicity in these patients, including genotype-phenotype studies and the prognostic value of natural killer (NK) cell activity subtyping.
OUTLINE: This is a multicenter study.
- Induction therapy (weeks 1-8): Patients receive etoposide IV over 1-3 hours twice weekly in weeks 1 and 2 and then once weekly in weeks 3-8. Patients also receive dexamethasone IV or orally once daily and cyclosporine IV or orally twice daily in weeks 1-8. Patients with clinically evident, progressive neurological symptoms or an abnormal cerebrospinal fluid (CSF) (cell count and protein) that has not improved after 2 weeks of induction therapy undergo intrathecal therapy comprising methotrexate and hydrocortisone once weekly in weeks 3-6.
Patients are evaluated after 8 weeks of induction therapy. Patients with primary (i.e., familial) hemophagocytic lymphohistiocytosis (HLH) or genetic evidence of HLH proceed to maintenance therapy. Patients with severe and persistent secondary (i.e., nonfamilial) HLH and no genetic evidence of HLH proceed to maintenance therapy only if their disease is still active after induction therapy. Patients with nonfamilial HLH and no genetic evidence of HLH who have achieved complete remission (CR) discontinue treatment. If their disease reactivates, they may then proceed to allogeneic hematopoietic stem cell transplantation (AHSCT).
- Maintenance therapy (weeks 9-40): Patients receive dexamethasone IV on days 1-3 in weeks 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40; etoposide IV over 1-3 hours once in weeks 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 39; and cyclosporine IV or orally twice daily in weeks 9-40.
After completion of maintenance therapy, patients with primary (i.e., familial) HLH, severe and persistent secondary (i.e., nonfamilial) HLH, or reactivating disease proceed to AHSCT. Patients with nonfamilial HLH who have completed maintenance therapy, but do not go on to receive AHSCT, may be recommended for additional maintenance therapy at the discretion of the treating physician.
- AHSCT:
- Preparative regimen: Patients receive a preparative regimen comprising busulfan orally or IV four times daily on days -8 to -5, etoposide IV over 6 hours on day -4, and cyclophosphamide IV over 1 hour on days -3 and -2. Patients who are undergoing unrelated AHSCT, also receive antithymocyte globulin (ATG) IV over 12 hours on days -3 to -1.
- Transplantation: Patients undergo AHSCT on day 0.
- Graft-versus-host disease prophylaxis: Beginning on day -1, patients receive cyclosporine IV continuously and then orally, when tolerated, once daily for 6-12 months. Patients also receive methotrexate* IV on days 1, 3, and 6.
NOTE: *As a substitute for methotrexate, patients may receive oral mycophenolate mofetil twice daily on days 0-40, followed by a taper and discontinuation.
Patients undergo periodic blood collection and bone marrow biopsies for biological studies.
After completion of study treatment, patients are followed periodically for up to 5 years.
PROJECTED ACCRUAL: A total of 288 patients will be accrued for this study.
- Conditions
- Nonneoplastic Condition
- Being tested
- anti-thymocyte globulin, busulfan, cyclophosphamide, cyclosporine, dexamethasone
- Keywords
- hemophagocytic lymphohistiocytosis
- Medical subject headings
- Lymphohistiocytosis, Hemophagocytic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
anti-thymocyte globulinBiological
busulfanDrug
cyclophosphamideDrug
cyclosporineDrug
dexamethasoneDrug
etoposideDrug
methotrexateDrug
therapeutic hydrocortisoneDrug
laboratory biomarker analysisOther
allogeneic hematopoietic stem cell transplantationProcedure or surgery
biopsyProcedure or surgery
What is being measured
The primary outcome is the main question the study is designed to answer.
Survival
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jun 2006 (estimated)
- Study startMar 2006
- Primary completionNov 2010 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Nonneoplastic ConditionStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Masking
- None (open label)
- Enrolment
- 288 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Children's Cancer and Leukaemia Group
- Sponsor type
- University, hospital or other
- Investigators
- Vasanta Nanduri, MD, Study chair, Watford General Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00334672
- Sponsor's protocol ID
- CDR0000481605
- Other IDs
- CCLG-LCH-2006-02, EU-20619, UKCCSG-HLH-2004, EUDRACT-2005-002187-28
- Status last verified
- Jun 2009
- First submitted
- 7 Jun 2006
- Last updated
- 17 Sep 2013
- Results posted
- No
Study at a glance
From the registry record, last updated by the sponsor on 17 Sep 2013. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Hemophagocytic Lymphohistiocytosis
- ClinicalTrials.gov ID
- NCT00334672
- Acronym / sponsor ID
- CDR0000481605
- Conditions
- Nonneoplastic Condition
- Keywords
- hemophagocytic lymphohistiocytosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 288 participants (estimated)
- Lead sponsor
- Children's Cancer and Leukaemia GroupUniversity, hospital or other
- Study start
- Mar 2006
- Primary completion
- Nov 2010 (estimated)
- First posted
- 8 Jun 2006 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of hemophagocytic lymphohistiocytosis cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more hemophagocytic lymphohistiocytosis cells. A donor stem cell transplant may be able to replace blood-forming cells that were destroyed by chemotherapy. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Cyclosporine and methotrexate may stop this from happening.
PURPOSE: This phase III trial is studying how well combination chemotherapy followed by a donor stem cell transplant works in treating patients with hemophagocytic lymphohistiocytosis.
Detailed description
OBJECTIVES:
Primary
- Provide and evaluate revised induction and maintenance therapy comprising etoposide, dexamethasone, and cyclosporine, in terms of achieving and maintaining an acceptable clinical condition in order to perform a curative allogeneic hematopoietic stem cell transplantation (AHSCT), in patients with primary inherited or severe and persistent secondary hemophagocytic lymphohistiocytosis (HLH).
- Evaluate and improve the outcome of AHSCT with various types of donors.
- Determine the prognostic importance of the state of remission at the time of AHSCT.
- Evaluate the neurological complications, in terms of early neurological alterations and cerebrospinal fluid (CSF) findings, in patients treated with this regimen.
Secondary
- Improve the understanding of the pathophysiology of HLH by conducting biological studies of genetics and cytotoxicity in these patients, including genotype-phenotype studies and the prognostic value of natural killer (NK) cell activity subtyping.
OUTLINE: This is a multicenter study.
- Induction therapy (weeks 1-8): Patients receive etoposide IV over 1-3 hours twice weekly in weeks 1 and 2 and then once weekly in weeks 3-8. Patients also receive dexamethasone IV or orally once daily and cyclosporine IV or orally twice daily in weeks 1-8. Patients with clinically evident, progressive neurological symptoms or an abnormal cerebrospinal fluid (CSF) (cell count and protein) that has not improved after 2 weeks of induction therapy undergo intrathecal therapy comprising methotrexate and hydrocortisone once weekly in weeks 3-6.
Patients are evaluated after 8 weeks of induction therapy. Patients with primary (i.e., familial) hemophagocytic lymphohistiocytosis (HLH) or genetic evidence of HLH proceed to maintenance therapy. Patients with severe and persistent secondary (i.e., nonfamilial) HLH and no genetic evidence of HLH proceed to maintenance therapy only if their disease is still active after induction therapy. Patients with nonfamilial HLH and no genetic evidence of HLH who have achieved complete remission (CR) discontinue treatment. If their disease reactivates, they may then proceed to allogeneic hematopoietic stem cell transplantation (AHSCT).
- Maintenance therapy (weeks 9-40): Patients receive dexamethasone IV on days 1-3 in weeks 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, and 40; etoposide IV over 1-3 hours once in weeks 9, 11, 13, 15, 17, 19, 21, 23, 25, 27, 29, 31, 33, 35, 37, and 39; and cyclosporine IV or orally twice daily in weeks 9-40.
After completion of maintenance therapy, patients with primary (i.e., familial) HLH, severe and persistent secondary (i.e., nonfamilial) HLH, or reactivating disease proceed to AHSCT. Patients with nonfamilial HLH who have completed maintenance therapy, but do not go on to receive AHSCT, may be recommended for additional maintenance therapy at the discretion of the treating physician.
- AHSCT:
- Preparative regimen: Patients receive a preparative regimen comprising busulfan orally or IV four times daily on days -8 to -5, etoposide IV over 6 hours on day -4, and cyclophosphamide IV over 1 hour on days -3 and -2. Patients who are undergoing unrelated AHSCT, also receive antithymocyte globulin (ATG) IV over 12 hours on days -3 to -1.
- Transplantation: Patients undergo AHSCT on day 0.
- Graft-versus-host disease prophylaxis: Beginning on day -1, patients receive cyclosporine IV continuously and then orally, when tolerated, once daily for 6-12 months. Patients also receive methotrexate* IV on days 1, 3, and 6.
NOTE: *As a substitute for methotrexate, patients may receive oral mycophenolate mofetil twice daily on days 0-40, followed by a taper and discontinuation.
Patients undergo periodic blood collection and bone marrow biopsies for biological studies.
After completion of study treatment, patients are followed periodically for up to 5 years.
PROJECTED ACCRUAL: A total of 288 patients will be accrued for this study.
Study design
- Primary purpose
- Treatment
- Masking
- None (open label)
Who may qualify
- Ages
- Up to 17 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| anti-thymocyte globulin | Biological | – |
| busulfan | Drug | – |
| cyclophosphamide | Drug | – |
| cyclosporine | Drug | – |
| dexamethasone | Drug | – |
| etoposide | Drug | – |
| methotrexate | Drug | – |
| mycophenolate mofetil | Drug | – |
| therapeutic hydrocortisone | Drug | – |
| laboratory biomarker analysis | Other | – |
| allogeneic hematopoietic stem cell transplantation | Procedure or surgery | – |
| biopsy | Procedure or surgery | – |
Primary outcome
Survival
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Sep 2013.
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Vasanta Nanduri, MD study chair
Watford General Hospital
13 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing anti-thymocyte globulin, busulfan and cyclophosphamide in people with Nonneoplastic Condition, run by Children's Cancer and Leukaemia Group at 13 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 17 Sep 2013. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 13 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Survival. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Sep 2013.