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

Phase 3

Terminated

Conditions: Acute Myeloid Leukemia
Acute Lymphoblastic Leukemia
Myelodysplastic Syndrome

Interventions: Biological: ATIR101
Drug: Cyclophosphamide
Procedure: T-cell depleted HSCT from a related, haploidentical donor
Procedure: T-cell replete HSCT from a related, haploidentical donor

Registration Number: NCT02999854

Lead Sponsor: 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.

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 63

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 & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
ATIR101	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
ATIR101	T-cell depleted HSCT from a related, haploidentical donor	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
PTCy	T-cell replete HSCT from a related, haploidentical donor	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
PTCy	Cyclophosphamide	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

Primary Outcome Measures

Name	Time	Method
Graft-versus-host Disease-free, Relapse-free Survival (GRFS)	24 months post-HSCT	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.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival (PFS)	24 months post-HSCT	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.
Overall Survival (OS)	24 months post-HSCT	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.
Relapse-related Mortality (RRM)	Through study completion, at least two years post HSCT	Time from randomization to death due to disease relapse or disease progression
Transplant-related Mortality (TRM)	24 months post-HSCT	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.

Trial Locations

Locations (42): Emory University
🇺🇸
Atlanta, Georgia, United States
Weill Cornell Medical College
🇺🇸
New York, New York, United States
City of Hope National Medical Center
🇺🇸
Duarte, California, United States
Moores UC San Diego Cancer Center
🇺🇸
La Jolla, California, United States
UCLA Center for Health Sciences
🇺🇸
Los Angeles, California, United States
Stanford University School of Medicine
🇺🇸
Stanford, California, United States
University of Kansas Cancer Center
🇺🇸
Westwood, Kansas, United States
Massachusetts General Hospital
🇺🇸
Boston, Massachusetts, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Stony Brook University Hospital
🇺🇸
Stony Brook, New York, United States
Oregon Health & Science University
🇺🇸
Portland, Oregon, United States
Universitair Ziekenhuis Antwerpen
🇧🇪
Antwerp, Belgium
Institut Jules Bordet
🇧🇪
Brussels, Belgium
Algemeen Ziekenhuis Sint-Jan
🇧🇪
Brugge, Belgium
Universitair Ziekenhuis Gasthuisberg
🇧🇪
Leuven, Belgium
Centre Hospitalier Universitaire de Liège
🇧🇪
Liège, Belgium
University Hospital Centre Zagreb
🇭🇷
Zagreb, Croatia
Maisonneuve-Rosemont Hospital
🇨🇦
Montreal, Quebec, Canada
Ludwig-Maximilians-University Hospital of Munich-Grosshadern
🇩🇪
Munich, Germany
Rambam Medical Center
🇮🇱
Haifa, Israel
APHP Hospital Saint Louis
🇫🇷
Paris, France
University Medical Center Mainz
🇩🇪
Mainz, Germany
University Hospital Frankfurt, Goethe University
🇩🇪
Frankfurt, Germany
Universitätsklinikum Würzburg
🇩🇪
Würzburg, Germany
Chaim Sheba Medical Center
🇮🇱
Tel-Hashomer, Israel
Sourasky Medical Center & Tel Aviv University
🇮🇱
Tel Aviv, Israel
Fondazione IRCCS Policlinico San Matteo
🇮🇹
Pavia, Italy
Hadassah Medical Center & Hadassah Hospital Ein Karem
🇮🇱
Jerusalem, Israel
Academisch Ziekenhuis Maastricht
🇳🇱
Maastricht, Netherlands
University Hospital Barcelona Vall d' Hebron
🇪🇸
Barcelona, Spain
Milano Hospital, Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
🇮🇹
Milano, Italy
Faculdade de Medicina da Universidade de Lisboa
🇵🇹
Lisboa, Portugal
Hospital Puerta de Hierro Majadahonda
🇪🇸
Madrid, Spain
UGC Hematología y Hemoterapia
🇪🇸
Sevilla, Spain
Servicio de Hematología Hospital, Universitari I politècnic La Fe
🇪🇸
Valencia, Spain
Karolinska University Hospital
🇸🇪
Stockholm, Sweden
St James University Hospital
🇬🇧
Leeds, United Kingdom
Heartlands Hospital
🇬🇧
Birmingham, United Kingdom
Hammersmith Hospital
🇬🇧
London, United Kingdom
Manchester Royal Infirmary
🇬🇧
Manchester, United Kingdom
Royal Liverpool University Hospital
🇬🇧
Liverpool, United Kingdom