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Safety and Efficacy of ATIR101 as Adjunctive Treatment to Blood Stem Cell Transplantation From a Haploidentical Family Donor Compared to Post-transplant Cyclophosphamide in Patients With Blood Cancer (HATCY)

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ClinicalTrials.gov Identifier: NCT02999854
Recruitment Status : Recruiting
First Posted : December 21, 2016
Last Update Posted : September 11, 2018
Sponsor:
Information provided by (Responsible Party):
Kiadis Pharma

Brief Summary:
The primary objective of this study is to compare safety and efficacy of a haploidentical T-cell depleted HSCT and adjunctive treatment with ATIR101 versus a haploidentical T cell replete HSCT with post-transplant administration of high dose cyclophosphamide (PTCy) in patients with a hematologic malignancy. An additional objective of the study is to compare the effect of the two treatments on quality of life.

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Acute Lymphoblastic Leukemia Myelodysplastic Syndrome Biological: ATIR101 Drug: Cyclophosphamide Procedure: T-cell depleted HSCT from a related, haploidentical donor Procedure: T-cell replete HSCT from a related, haploidentical donor Phase 3

Detailed Description:

Study CR-AIR-009 is a Phase III randomized controlled multicenter open-label study comparing two parallel groups. After signing informed consent, a total of 250 patients will be randomized in a 1:1 fashion to receive either a T-cell depleted hematopoietic stem cell transplantation (HSCT; CD34 selection) from a related, haploidentical donor, followed by ATIR101 infusion, or a T-cell replete HSCT, followed by a high dose of post-transplant cyclophosphamide (PTCy).

Randomization will use minimization to balance treatment groups with respect to underlying disease (AML, ALL, or MDS), Disease Risk Index (DRI; intermediate risk, high risk, or very high risk) and center. A stochastic treatment allocation procedure will be used so that the treatment assignment is random for all patients entered in the study.

Patients randomized in the ATIR101 group will receive a single ATIR101 dose of 2×10E6 viable T-cells/kg between 28 and 32 days after the HSCT. Patients randomized in the PTCy group will receive cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT. All patients will be followed up for at least 24 months post HSCT.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 250 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: A Phase III, Multicenter, Randomized Controlled Study to Compare Safety and Efficacy of a Haploidentical HSCT and Adjunctive Treatment With ATIR101, a T-lymphocyte Enriched Leukocyte Preparation Depleted ex Vivo of Host Alloreactive T-cells, Versus a Haploidentical HSCT With Post-transplant Cyclophosphamide in Patients With a Hematologic Malignancy
Actual Study Start Date : November 29, 2017
Estimated Primary Completion Date : February 2021
Estimated Study Completion Date : February 2021


Arm Intervention/treatment
Experimental: ATIR101
T-cell depleted HSCT from a related, haploidentical donor, followed by IV infusion with ATIR101 at a single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT
Biological: ATIR101
ATIR101 is a T-lymphocyte enriched leukocyte preparation depleted ex vivo of host alloreactive T-cells using photodynamic treatment; single dose of 2×10E6 viable T-cells/kg body weight between 28 and 32 days after the HSCT (intravenous infusion)

Procedure: T-cell depleted HSCT from a related, haploidentical donor
T-cell depleted graft prepared from peripheral blood stem cells using the CD34+ cell selection method; infused after a total body irradiation (TBI) or non-TBI conditioning regimen

Active Comparator: PTCy
T-cell replete HSCT from a related, haploidentical donor, followed by IV infusion of post-transplant cyclophosphamide (PTCy) 50 mg/kg/day at 3 and 4/5 days after the HSCT
Drug: Cyclophosphamide
High dose post-transplant cyclophosphamide 50 mg/kg/day at 3 and 4/5 days after the HSCT (powder for intravenous infusion)

Procedure: T-cell replete HSCT from a related, haploidentical donor
T-cell replete (full, non-manipulated) graft prepared from either bone marrow or peripheral blood stem cells; infused after a total body irradiation (TBI) or non-TBI conditioning regimen




Primary Outcome Measures :
  1. Graft-versus-host disease-free, relapse-free survival (GRFS) [ Time Frame: Through study completion, at least two years post HSCT ]
    Time from randomization until grade III/IV acute GVHD, chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs first


Secondary Outcome Measures :
  1. Overall survival (OS) [ Time Frame: Through study completion, at least two years post HSCT ]
    Time from randomization until death from any cause

  2. Progression-free survival (PFS) [ Time Frame: Through study completion, at least two years post HSCT ]
    Time from randomization until relapse, disease progression, or death, whichever occurs first

  3. Relapse-related mortality (RRM) [ Time Frame: Through study completion, at least two years post HSCT ]
    Time from randomization to death due to disease relapse or disease progression

  4. Transplant-related mortality (TRM) [ Time Frame: Through study completion, at least two years post HSCT ]
    Time from randomization to death due to causes other than disease relapse or disease progression


Other Outcome Measures:
  1. Immune reconstitution [ Time Frame: Through study completion, at least two years post HSCT ]
    Time to CD3+ > 0.2×10E9/l in peripheral blood (at two consecutive measurements; time to first measurement)

  2. Cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host-disease (GVHD) [ Time Frame: Through study completion, at least two years post HSCT ]
  3. Cumulative incidence of moderate/severe chronic GVHD [ Time Frame: Through study completion, at least two years post HSCT ]
  4. Cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment [ Time Frame: Through study completion, at least two years post HSCT ]
  5. Duration of GVHD episodes [ Time Frame: Through study completion, at least two years post HSCT ]
  6. Cumulative incidence of NCI CTCAE grade 2-5 and grade 3-5 infections [ Time Frame: Until 2 years after the HSCT ]
    Viral, fungal, and bacterial infections

  7. Cumulative incidence of NCI CTCAE grade 3-5 adverse events [ Time Frame: Until 2 years after the HSCT ]
    Viral, fungal, and bacterial infections

  8. FACT-BMT total score (change from screening) [ Time Frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) ]
    Quality of life: Foundation for the Accreditation of Cellular Therapy - Bone Marrow Transplantation questionnaire (FACT-BMT)

  9. SF-36 total score (change from screening) [ Time Frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) ]
    Quality of life: Short Form 36-item health survey (SF-36)

  10. MDASI total score (change from screening) [ Time Frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) ]
    Quality of life: MD Anderson Symptom Inventory (MDASI)

  11. EQ-5D-5L (change from screening) [ Time Frame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT) ]
    Quality of life: EQ-5D-5L



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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Any of the following hematologic malignancies:

    • Acute myeloid leukemia (AML) in first cytomorphological remission (with < 5% blasts in the bone marrow) with Disease Risk Index (DRI) intermediate or above, or in second or higher cytomorphological remission (with < 5% blasts in the bone marrow)
    • Acute lymphoblastic leukemia (ALL) in first or higher remission (with < 5% blasts in the bone marrow)
    • Myelodysplastic syndrome (MDS): transfusion-dependent (requiring at least one transfusion per month), or intermediate or higher Revised International Prognostic Scoring System (IPSS-R) risk group
  • Clinical justification of allogeneic stem cell transplantation where a suitable HLA matched sibling or unrelated donor is unavailable in a timely manner
  • Availability of a related haploidentical donor with one fully shared haplotype and 2 to 4 mismatches at the HLA-A, -B, -C, and -DRB1 loci of the unshared haplotype, as determined by high resolution human leukocyte antigen (HLA)-typing
  • Karnofsky Performance Status (KPS) ≥ 70%
  • Male or female, age ≥ 18 years and ≤ 70 years. Patients aged ≥ 65 years must have a Sorror score ≤ 3
  • Patient weight ≥ 25 kg and ≤ 130 kg
  • Availability of a donor aged ≥ 16 years and ≤ 75 years who is eligible according to local requirements and regulations. Donors aged < 16 years are allowed if they are the only option for an HSCT, if they are permitted by local regulations, and if the IRB/IEC approves participation in the study.
  • For females of childbearing potential who are sexually active and males who have sexual contact with a female of childbearing potential: willingness to use of reliable methods of contraception (oral contraceptives, intrauterine device, hormone implants, contraceptive injection or abstinence) during study participation
  • Given written informed consent (patient and donor)

Exclusion Criteria:

  • Diagnosis of chronic myelomonocytic leukemia (CMML)
  • Availability of a suitable HLA-matched sibling or unrelated donor in a donor search
  • Prior allogeneic hematopoietic stem cell transplantation
  • Diffusing capacity for carbon monoxide (hemoglobin corrected DLCO) < 50% predicted
  • Left ventricular ejection fraction < 45% (evaluated by echocardiogram or MUGA scan)
  • Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 2.5 × upper limit of normal (CTCAE grade 2)
  • Creatinine clearance < 50 ml/min (calculated or measured)
  • Positive pregnancy test or breastfeeding of patient or donor (women of childbearing age only)
  • Estimated probability of surviving less than 3 months
  • Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide)
  • Known hypersensitivity to cyclophosphamide or any of its metabolites
  • Any contraindication for GVHD prophylaxis with mycophenolate mofetil, cyclosporine A, or tacrolimus
  • Known presence of HLA antibodies against the non-shared donor haplotype
  • Positive viral test of the patient or donor for human immunodeficiency virus (HIV)-1, HIV-2, hepatitis B virus (HBV), hepatitis C virus (HCV), Treponema pallidum, human T-lymphotropic virus (HTLV)-1 (if tested), HTLV-2 (if tested), West Nile virus (WNV; if tested), or Zika virus (if tested)
  • Any other condition that, in the opinion of the investigator, makes the patient or donor ineligible for the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02999854


Contacts
Contact: Andrew Sandler, MD +31 20 2405250 clinicaltrials@kiadis.com

Locations
Belgium
Universitair Ziekenhuis Antwerpen Recruiting
Antwerp, Belgium, 2650
Principal Investigator: Wilfried Schroyens, MD         
Algemeen Ziekenhuis Sint-Jan Recruiting
Brugge, Belgium, 8000
Principal Investigator: Dominik Selleslag, MD         
Institut Jules Bordet Recruiting
Brussels, Belgium, 1000
Principal Investigator: Philippe Lewalle, MD         
Universitair Ziekenhuis Gasthuisberg Recruiting
Leuven, Belgium, 3000
Principal Investigator: Johan Maertens, MD         
Centre Hospitalier Universitaire de Liège Recruiting
Liège, Belgium, 4000
Principal Investigator: Yves Beguin, Prof MD         
Canada, Quebec
Maisonneuve-Rosemont Hospital Recruiting
Montreal, Quebec, Canada, H1T 2M4
Principal Investigator: Denis Claude Roy, Prof MD         
Croatia
University Hospital Centre Zagreb Recruiting
Zagreb, Croatia, 10000
Contact: Radovan Vrhovac, Prof MD         
Germany
University Hospital Frankfurt, Goethe University Not yet recruiting
Frankfurt, Germany
Principal Investigator: Gesine Bug, MD         
University Medical Center Mainz Recruiting
Mainz, Germany, 55131
Principal Investigator: Eva Maria Wagner, MD         
Ludwig-Maximilians-University Hospital of Munich-Grosshadern Not yet recruiting
Munich, Germany, 81377
Contact: Johanna Tischer, Prof MD         
Universitätsklinikum Würzburg Recruiting
Würzburg, Germany, 97080
Principal Investigator: Götz-Ulrich Grigoleit, MD         
Italy
Milano Hospital, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico Not yet recruiting
Milano, Italy, 20122
Contact: Francesco Onida, Prof MD         
Fondazione IRCCS Policlinico San Matteo Not yet recruiting
Pavia, Italy, 27100
Contact: Paolo Bernasconi, MD         
Portugal
Faculdade de Medicina da Universidade de Lisboa Recruiting
Lisboa, Portugal, 1649-028
Principal Investigator: João Forjaz de Lacerda, Prof MD         
Spain
University Hospital Barcelona Vall d' Hebron Recruiting
Barcelona, Spain, 08035
Principal Investigator: David Valcarcel         
Hospital Puerta de Hierro Majadahonda Recruiting
Madrid, Spain, 28220
Principal Investigator: Rafael Duarte, MD         
Servicio de Hematología Hospital, Universitari I politècnic La Fe Recruiting
Valencia, Spain, 46026
Principal Investigator: Jose Luis Piñana, MD         
United Kingdom
Heartlands Hospital Not yet recruiting
Birmingham, United Kingdom, B9 5SS
Principal Investigator: Bhuvan Kishore, MD         
St James University Hospital Not yet recruiting
Leeds, United Kingdom, LS9 7TF
Principal Investigator: Maria Gilleece, MD         
Royal Liverpool University Hospital Not yet recruiting
Liverpool, United Kingdom, L7 8XP
Principal Investigator: Amit Patel, MD         
Hammersmith Hospital Recruiting
London, United Kingdom, W12 0HS
Principal Investigator: Eduardo Olavarria, MD         
Manchester Royal Infirmary Not yet recruiting
Manchester, United Kingdom, M13 9WL
Principal Investigator: Eleni Tholouli, MD         
Sponsors and Collaborators
Kiadis Pharma
Investigators
Principal Investigator: Denis Claude Roy, Prof MD Research Center and Cellular Therapy Laboratory, Maisonneuve-Rosemont Hospital (Montreal, Canada)
Principal Investigator: Stephan Mielke, Prof MD Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital (Stockholm, Sweden)

Responsible Party: Kiadis Pharma
ClinicalTrials.gov Identifier: NCT02999854     History of Changes
Other Study ID Numbers: CR-AIR-009
2016-004672-21 ( EudraCT Number )
First Posted: December 21, 2016    Key Record Dates
Last Update Posted: September 11, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Kiadis Pharma:
Haploidentical stem cell transplantation
Graft-versus-host disease
Immune reconstitution
Alloreactive T-cells
Photodynamic treatment
Hematologic malignancy
Transplant-related mortality
Overall survival
GRFS
GVHD

Additional relevant MeSH terms:
Leukemia
Leukemia, Myeloid, Acute
Myelodysplastic Syndromes
Preleukemia
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Leukemia, Lymphoid
Neoplasms by Histologic Type
Neoplasms
Leukemia, Myeloid
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists