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Treatment of Familiar Lymphohistiocytosis (C-HLH)

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ClinicalTrials.gov Identifier: NCT02472054
Recruitment Status : Recruiting
First Posted : June 15, 2015
Last Update Posted : February 15, 2019
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE June 8, 2015
First Posted Date  ICMJE June 15, 2015
Last Update Posted Date February 15, 2019
Actual Study Start Date  ICMJE June 29, 2015
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 10, 2015)
Number of surviving patients until HSCT [ Time Frame: Day 1 until transplantation, up to 4 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02472054 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 10, 2015)
  • Number of complete remissions following treatment [ Time Frame: Day 14, Day 21, Day 28 ]
    To assess the efficacy of the Alemtuzumab
  • Time of delay between the first administration of Alemtuzumab and complete remission [ Time Frame: Day 14, Day 21, Day 28 ]
    To assess the efficacy of the Alemtuzumab
  • Dosage of Alemtuzumab [ Time Frame: Day1-3, Day7, Day15-16, Day22-23, Day28 ]
    Pharmacokinetic
  • Number of side effects [ Time Frame: Day 1 until transplantation, up to 4 months ]
    To assess the tolerance of the Alemtuzumab
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Familiar Lymphohistiocytosis
Official Title  ICMJE First Line Treatment of Familiar Lymphohistiocytosis by Alemtuzumab (CAMPATH®)
Brief Summary The purpose of this project is to study the number of surviving patients until hematopoietic stem cell transplantation (HSCT) after first line treatment of hemophagocytic lymphohistiocytosis (HLH) by Alemtuzumab
Detailed Description

The hemophagocytic lymphohistiocytosis (HLH) or lymphohistiocytic activation syndrome is an inflammatory condition caused by a uncontrolled proliferation of activated lymphocytes and macrophages secreting an excess of inflammatory cytokines. Familial hemophagocytic lymphohistiocytosis (FHL) is a rare disorder of the immune system, which is invariably fatal when untreated. Treatment requires the achievement of remission of HLH prior to allogeneic hematopoietic stem cell transplantation, the only curative therapy to date.

Despite significant progress in the treatment, mortality remains high and an important number of patients will die before being eligible for HSCT.

A better understanding of the pathophysiology of FHL has opened new avenues for immunotherapy. Based on previous observations concerning the utilization of Anti-thymoglobulins (ATG) for the treatment of patients with FHL, the protocol propose a new therapeutic strategy using Alemtuzumab in association with steroids as first line treatment in FHL. This proposition is based on the hypothesis that Alemtuzumab, capable of killing T lymphocytes efficiently in vivo, should be better tolerated than ATG. In fact, in contrast to the mechanism of action of ATG, Alemtuzumab does not activate T lymphocytes.

A better tolerance and efficacy of Alemtuzumab is expected in the treatment of the hemophagocytic lymphohistiocytic syndrome. This may have a positive impact not only on survival until HSCT, but also on overall survival and quality of life with regard to long-term neurological sequelae.

This is a multicenter, open, phase I/II, non-comparative, non randomized study. Patients are recruited by the investigators during hospitalization for a first episode of lymphohistiocytic activation syndrome requiring specific treatment.

Several visits (including the final visit) are scheduled within the trial over a period of approximately 10 months for all patients, from the signature of the consent up to 6 months after hematopoietic stem cell transplantation.

The recruitment period will be 48 months; the total period of the study is 58 months. The treatment consists in an intravenous administration of CAMPATH®.

For the research purpose, investigators will collect specific samples for:

  • biobank (Cytokine dosage) at the inclusion visit and the day prior to the conditioning;
  • pharmacokinetics of CAMPATH® : at every cure of CAMPATH® and every week. Also diagnostic lumbar puncture at the inclusion visit, day 14 is required to document the response to treatment and to determine the result of the therapeutic care.

The efficacy of the treatment will be measured to Day14, Day21 and Day28. All adverse events must be reported in the e-Case Report Form (e-CRF)

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Hemophagocytic Lymphohistiocytosis (HLH)
Intervention  ICMJE
  • Drug: Alemtuzumab
    Other Name: CAMPATH®
  • Drug: Methyl Prednisolone (MP)
  • Drug: Cyclosporin A (CSA)
Study Arms  ICMJE Experimental: hemophagocytic lymphohistiocytosis (HLH)

Alemtuzumab (CAMPATH®)

  1. Initial Treatment (D1 to D3) D1: 0.5 mg / kg / day Alemtuzumab combined with 2 mg /kg/d of IV Methylprednisolone (MP) or PO Prednisolone, and IVC or PO cyclosporine (CSA) (target rate from 150 to 200 ng / ml in the absence of renal failure) D2 and D3: 1 mg / kg / day Alemtuzumab combined with 2 mg / kg / d of IV MP or PO Prednisolone and IVC or PO CSA (target rate 150-200 ng / ml)

    The maximum dose of Alemtuzumab is limited to 30 mg per day (1 vial).

  2. Maintenance treatment (D4 to D14)

    • MP/Prednisolone progressive tapering starting at D4 (2 mg / kg / day) to reach the dose 0.5 mg / kg / day at D14
    • CSA IVC or PO at a target rate of 150-200 ng / ml
Interventions:
  • Drug: Alemtuzumab
  • Drug: Methyl Prednisolone (MP)
  • Drug: Cyclosporin A (CSA)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: June 10, 2015)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE April 2020
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria :

  • Patient < 18 years
  • Patient with diagnosis of hemophagocytic lymphohistiocytic syndrome confirmed by at least one of the following two criteria :

    • Genetic diagnosis FHL or other genetic disease predisposing to HLH like Chediak-Higashi syndrome, Griscelli syndrome type II and X-linked lymphoproliferative syndrome type I and II (XLP-1 and XLP-2) or positive family history of HLH
    • Presence of at least 5 of the following 8 criteria (diagnostic criteria as defined by the "Histiocyte Society" ) :
    • Fever
    • Splenomegaly
    • Cytopenia (affecting at least two cell lineages : Hemoglobin <9.0 g / dl, Platelets <100.000/μl, Absolute neutrophil count (ANC) <1.000/µl)
    • Hypertriglyceridemia and / or hypofibrinogenemia (Fasting triglycerides ≥ 3 mmol / l, Fibrinogen ≤ 1.5 g / l)
    • Haemophagocytosis found in a histological specimen (without evidence of a malignant process and rheumatic disease)
    • Decreased or absent NK function (<10% of the laboratory standard)
    • Ferritin ≥ 500μg / l
    • Soluble CD25 ≥ 2.400U/ml or presence of activated T cells in the immune phenotyping
  • Patient without prior specific treatment of lymphohistiocytic activation syndrome or under treatment with corticosteroids and / or ciclosporin.
  • Patient beneficiary of a health insurance scheme
  • Holder (s) of parental authority who signed the informed consent
  • Man or woman in reproductive age willing to take reliable contraceptive measures during the treatment and 6 months after the end of the treatment

Specific situation of patients with neurological involvement :

Most patients with neurological involvement caused by a HLH will meet the inclusion criteria. However some patients may present an isolated neurological involvement as the first manifestation of familiar lymphohistiocytosis as described in the literature. These patients do not always present all the inclusion criteria. However their clinical condition may justify their inclusion prior to the confirmation of a genetic diagnosis and/or the detection of all required diagnostic inclusion criteria.

In the absence of the required 5 out of 8 diagnostic criteria, the eventual inclusion of patients with predominant neurological involvement will be evaluated by a scientific committee to judge their inclusion or not in the study. The remaining inclusion and exclusion criteria must be fulfilled. A written report will be established.

Exclusion Criteria :

  • Age ≥ 18 years
  • Patients previously treated with Anti-Thymoglobulin (SAL), etoposide (VP16) or Alemtuzumab.
  • Confirmed or suspected diagnosis of a malignant or rheumatic disease
  • Contraindication (s) to the administration of Alemtuzumab :

    • Hypersensitivity to murine proteins or to any of the excipients (sodium chloride, dibasic sodium phosphate, potassium chloride, potassium dihydrogen phosphate, polysorbate 80, disodium edetate dihydrate, and water for injection)
    • General evolving infection except infections that are the triggering factor of the HLH .
    • HIV
    • Progressing malignant tumors
    • Pregnancy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Despina MOSHOUS, MD, PhD +33 (0) 1 44 49 48 23 despina.moshous@inserm.fr
Contact: Valérie JOLAINE, Master +33 (0) 1 42 19 28 79 valerie.jolaine@nck.aphp.fr
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02472054
Other Study ID Numbers  ICMJE P120109
2014-005585-30 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Alain FISCHER, MD, PhD Assistance Publique - Hôpitaux de Paris
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP