Clinical trial NCT02999854: 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
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndrome
Keywords: Haploidentical stem cell transplantation
Graft-versus-host disease
Immune reconstitution
Alloreactive T-cells
Photodynamic treatment
Hematologic malignancy
Transplant-related mortality
Overall survival
GRFS
GVHD
Lead sponsor: Kiadis Pharma
Sponsor class: INDUSTRY
First posted: 2016-12-21
Enrollment: 63
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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

Primary outcomes:
measure: Graft-versus-host Disease-free, Relapse-free Survival (GRFS)
timeFrame: 24 months post-HSCT
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 24 months post-HSCT
measure: Progression-free Survival (PFS)
timeFrame: 24 months post-HSCT
measure: Relapse-related Mortality (RRM)
timeFrame: Through study completion, at least two years post HSCT
measure: Transplant-related Mortality (TRM)
timeFrame: 24 months post-HSCT
Other outcomes:
measure: Immune Reconstitution
timeFrame: Through study completion, at least two years post HSCT
measure: Cumulative Incidence of Grade II-IV and Grade III-IV Acute Graft-versus-host-disease (GVHD)
timeFrame: Through study completion, at least two years post HSCT
measure: Cumulative Incidence of Moderate/Severe Chronic GVHD
timeFrame: Through study completion, at least two years post HSCT
measure: Cumulative Incidence of Chronic GVHD Requiring Systemic Immunosuppressive Treatment
timeFrame: Through study completion, at least two years post HSCT
measure: Duration of GVHD Episodes
timeFrame: Through study completion, at least two years post HSCT
measure: Cumulative Incidence of NCI CTCAE Grade 2-5 and Grade 3-5 Infections
timeFrame: Until 2 years after the HSCT
measure: Cumulative Incidence of NCI CTCAE Grade 3-5 Adverse Events
timeFrame: Until 2 years after the HSCT
measure: FACT-BMT Total Score (Change From Screening)
timeFrame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
measure: SF-36 Total Score (Change From Screening)
timeFrame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
measure: MDASI Total Score (Change From Screening)
timeFrame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
measure: EQ-5D-5L (Change From Screening)
timeFrame: Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: La Jolla
country: United States
facility: Moores UC San Diego Cancer Center
state: California
city: Los Angeles
country: United States
facility: UCLA Center for Health Sciences
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: New York
country: United States
facility: Weill Cornell Medical College
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Stony Brook
country: United States
facility: Stony Brook University Hospital
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Antwerp
country: Belgium
facility: Universitair Ziekenhuis Antwerpen
city: Brugge
country: Belgium
facility: Algemeen Ziekenhuis Sint-Jan
city: Brussels
country: Belgium
facility: Institut Jules Bordet
city: Leuven
country: Belgium
facility: Universitair Ziekenhuis Gasthuisberg
city: Liège
country: Belgium
facility: Centre Hospitalier Universitaire de Liège
city: Montreal
country: Canada
facility: Maisonneuve-Rosemont Hospital
state: Quebec
city: Zagreb
country: Croatia
facility: University Hospital Centre Zagreb
city: Paris
country: France
facility: APHP Hospital Saint Louis
city: Frankfurt
country: Germany
facility: University Hospital Frankfurt, Goethe University
city: Mainz
country: Germany
facility: University Medical Center Mainz
city: Munich
country: Germany
facility: Ludwig-Maximilians-University Hospital of Munich-Grosshadern
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Haifa
country: Israel
facility: Rambam Medical Center
city: Jerusalem
country: Israel
facility: Hadassah Medical Center & Hadassah Hospital Ein Karem
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center & Tel Aviv University
city: Tel-Hashomer
country: Israel
facility: Chaim Sheba Medical Center
city: Milano
country: Italy
facility: Milano Hospital, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
city: Pavia
country: Italy
facility: Fondazione IRCCS Policlinico San Matteo
city: Maastricht
country: Netherlands
facility: Academisch Ziekenhuis Maastricht
city: Lisboa
country: Portugal
facility: Faculdade de Medicina da Universidade de Lisboa
city: Barcelona
country: Spain
facility: University Hospital Barcelona Vall d' Hebron
city: Madrid
country: Spain
facility: Hospital Puerta de Hierro Majadahonda
city: Sevilla
country: Spain
facility: UGC Hematología y Hemoterapia
city: Valencia
country: Spain
facility: Servicio de Hematología Hospital, Universitari I politècnic La Fe
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Birmingham
country: United Kingdom
facility: Heartlands Hospital
city: Leeds
country: United Kingdom
facility: St James University Hospital
city: Liverpool
country: United Kingdom
facility: Royal Liverpool University Hospital
city: London
country: United Kingdom
facility: Hammersmith Hospital
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
Study officials:
affiliation: Research Center and Cellular Therapy Laboratory, Maisonneuve-Rosemont Hospital (Montreal, Canada)
name: Denis Claude Roy, Prof MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital (Stockholm, Sweden)
name: Stephan Mielke, Prof MD
role: PRINCIPAL_INVESTIGATOR
References: