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)

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

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.

Study Overview

• Status: Terminated
• Conditions: Acute Myeloid Leukemia; Acute Lymphoblastic Leukemia; Myelodysplastic Syndrome
• Intervention / Treatment: Biological: ATIR101; Procedure: T-cell depleted HSCT from a related, haploidentical donor; Drug: Cyclophosphamide; Procedure: T-cell replete HSCT from a related, haploidentical donor

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
• Enrollment (Actual): 63
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Antwerp, Belgium, 2650
    • Universitair Ziekenhuis Antwerpen
  • Brugge, Belgium, 8000
    • Algemeen Ziekenhuis Sint-Jan
  • Brussels, Belgium, 1000
    • Institut Jules Bordet
  • Leuven, Belgium, 3000
    • Universitair Ziekenhuis Gasthuisberg
  • Liège, Belgium, 4000
    • Centre Hospitalier Universitaire de Liege
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H1T 2M4
      • Maisonneuve-Rosemont Hospital
• Croatia
  • Zagreb, Croatia, 10000
    • University Hospital Centre Zagreb
• France
  • Paris, France, 75475
    • APHP Hospital Saint Louis
• Germany
  • Frankfurt, Germany
    • University Hospital Frankfurt, Goethe University
  • Mainz, Germany, 55131
    • University Medical Center Mainz
  • Munich, Germany, 81377
    • Ludwig-Maximilians-University Hospital of Munich-Grosshadern
  • Würzburg, Germany, 97080
    • Universitatsklinikum Wurzburg
• Israel
  • Haifa, Israel, 3109601
    • Rambam Medical Center
  • Jerusalem, Israel, 91120
    • Hadassah Medical Center & Hadassah Hospital Ein Karem
  • Tel Aviv, Israel, 6423906
    • Sourasky Medical Center & Tel Aviv University
  • Tel-Hashomer, Israel, 5265601
    • Chaim Sheba Medical Center
• Italy
  • Milano, Italy, 20122
    • Milano Hospital, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Academisch Ziekenhuis Maastricht
• Portugal
  • Lisboa, Portugal, 1649-028
    • Faculdade de Medicina da Universidade de Lisboa
• Spain
  • Barcelona, Spain, 08035
    • University Hospital Barcelona Vall d' Hebron
  • Madrid, Spain, 28220
    • Hospital Puerta de Hierro Majadahonda
  • Sevilla, Spain, 41013
    • UGC Hematología y Hemoterapia
  • Valencia, Spain, 46026
    • Servicio de Hematología Hospital, Universitari I politècnic La Fe
• Sweden
  • Stockholm, Sweden, SE-141 86
    • Karolinska University Hospital
• United Kingdom
  • Birmingham, United Kingdom, B9 5SS
    • Heartlands Hospital
  • Leeds, United Kingdom, LS9 7TF
    • St James University Hospital
  • Liverpool, United Kingdom, L7 8XP
    • Royal Liverpool University Hospital
  • London, United Kingdom, W12 0HS
    • Hammersmith Hospital
  • Manchester, United Kingdom, M13 9WL
    • Manchester Royal Infirmary
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope National Medical Center
    • La Jolla, California, United States, 92037-0698
      • Moores UC San Diego Cancer Center
    • Los Angeles, California, United States, 90095
      • UCLA Center for Health Sciences
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Kansas
    • Westwood, Kansas, United States, 66205
      • University of Kansas Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-1274
      • University of Michigan
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • New York, New York, United States, 10021
      • Weill Cornell Medical College
    • Stony Brook, New York, United States, 11794
      • Stony Brook University Hospital
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Graft-versus-host Disease-free, Relapse-free Survival (GRFS)	Defined as the time until acute GVHD grade III/IV, chronic GVHD requiring systemic treatment, relapse, or death, whichever occurs first. Kaplan-Meier estimates (percentage of participants) of GRFS were calculated at 24 months post HSCT.	24 months post-HSCT

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time from HSCT until death from any cause. Kaplan-Meier estimates (percentage of participants) of OS were calculated at 24 months post HSCT.	24 months post-HSCT
Progression-free Survival (PFS)	Defined as the time from HSCT until relapse, disease progression, or death, whichever occurs first. Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT.	24 months post-HSCT
Relapse-related Mortality (RRM)	Time from randomization to death due to disease relapse or disease progression	Through study completion, at least two years post HSCT
Transplant-related Mortality (TRM)	Defined as death due to causes other than disease relapse or progression, or other causes which are unrelated to the transplantation procedure (e.g. accident, suicide). Kaplan-Meier estimates (percentage of participants) of PFS were calculated at 24 months post HSCT.	24 months post-HSCT

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immune Reconstitution	Time to CD3+ > 0.2×10E9/l in peripheral blood (at two consecutive measurements; time to first measurement)	Through study completion, at least two years post HSCT
Cumulative Incidence of Grade II-IV and Grade III-IV Acute Graft-versus-host-disease (GVHD)		Through study completion, at least two years post HSCT
Cumulative Incidence of Moderate/Severe Chronic GVHD		Through study completion, at least two years post HSCT
Cumulative Incidence of Chronic GVHD Requiring Systemic Immunosuppressive Treatment		Through study completion, at least two years post HSCT
Duration of GVHD Episodes		Through study completion, at least two years post HSCT
Cumulative Incidence of NCI CTCAE Grade 2-5 and Grade 3-5 Infections	Viral, fungal, and bacterial infections	Until 2 years after the HSCT
Cumulative Incidence of NCI CTCAE Grade 3-5 Adverse Events	Viral, fungal, and bacterial infections	Until 2 years after the HSCT
FACT-BMT Total Score (Change From Screening)	Quality of life: Foundation for the Accreditation of Cellular Therapy - Bone Marrow Transplantation questionnaire (FACT-BMT)	Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
SF-36 Total Score (Change From Screening)	Quality of life: Short Form 36-item health survey (SF-36)	Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
MDASI Total Score (Change From Screening)	Quality of life: MD Anderson Symptom Inventory (MDASI)	Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
EQ-5D-5L (Change From Screening)	Quality of life: EQ-5D-5L	Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)

Collaborators and Investigators

• Sponsor: Kiadis Pharma
• Investigators: Principal Investigator: Stephan Mielke, Prof MD, Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital (Stockholm, Sweden); Principal Investigator: Denis Claude Roy, Prof MD, Research Center and Cellular Therapy Laboratory, Maisonneuve-Rosemont Hospital (Montreal, Canada)

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 29, 2017
• Primary Completion (ACTUAL): November 9, 2021
• Study Completion (ACTUAL): December 17, 2021

Study Registration Dates

• First Submitted: December 19, 2016
• First Submitted That Met QC Criteria: December 19, 2016
• First Posted (ESTIMATE): December 21, 2016

Study Record Updates

• Last Update Posted (ACTUAL): May 24, 2022
• Last Update Submitted That Met QC Criteria: April 28, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: GVHD; Graft-versus-host disease; Overall survival; Hematologic malignancy; Immune reconstitution; Haploidentical stem cell transplantation; Alloreactive T-cells; Photodynamic treatment; Transplant-related mortality; GRFS
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Leukemia, Lymphoid; Myelodysplastic Syndromes; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Cyclophosphamide
• Other Study ID Numbers: CR-AIR-009; 2016-004672-21 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No