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

Acute Myeloid Leukemia Clinical Trial

— HATCY  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT02999854
• Other study ID #: CR-AIR-009
• Secondary ID: 2016-004672-21
• Status: Terminated
• Phase: Phase 3
• Start date: November 29, 2017
• Est. completion date: December 17, 2021

Study information

• Verified date: April 2022
• Source: Kiadis Pharma
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 63
• Est. completion date: December 17, 2021
• Est. primary completion date: November 9, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Acute Myeloid Leukemia
• Leukemia
• Myelodysplastic Syndrome
• Myelodysplastic Syndromes
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

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)

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 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
• 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

Locations

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

Sponsors (1)

Lead Sponsor	Collaborator
Kiadis Pharma

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Croatia,  France,  Germany,  Israel,  Italy,  Netherlands,  Portugal,  Spain,  Sweden,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	Cumulative Incidence of Moderate/Severe Chronic GVHD		Through study completion, at least two years post HSCT
Other	Cumulative Incidence of Chronic GVHD Requiring Systemic Immunosuppressive Treatment		Through study completion, at least two years post HSCT
Other	Duration of GVHD Episodes		Through study completion, at least two years post HSCT
Other	Cumulative Incidence of NCI CTCAE Grade 2-5 and Grade 3-5 Infections	Viral, fungal, and bacterial infections	Until 2 years after the HSCT
Other	Cumulative Incidence of NCI CTCAE Grade 3-5 Adverse Events	Viral, fungal, and bacterial infections	Until 2 years after the HSCT
Other	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)
Other	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)
Other	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)
Other	EQ-5D-5L (Change From Screening)	Quality of life: EQ-5D-5L	Through study completion (Month 3, 6, 12, 24, 36, 48 post HSCT)
Primary	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	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
Secondary	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
Secondary	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
Secondary	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