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 1

• Conditions: Patients with a hematologic malignancy (AML, ALL, or MDS) who are eligible for a haploidentical HSCT; MedDRA version: 20.0Level: LLTClassification code 10000845Term: Acute lymphoblastic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10059044Term: Allogeneic peripheral hematopoietic stem cell transplantSystem Organ Class: 10042613 - Surgical and medical procedures; MedDRA version: 20.0Level: PTClassification code 10027703Term: Mismatched donor bone marrow transplantation therapySystem Organ Class: 10042613 - Surgical and medical procedures; MedDRA version: 20.0Level: PTClassification code 10000880Term: Acute myeloid leukaemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10028533Term: Myelodysplastic syndromeSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2016-004672-21-GB
• Lead Sponsor: Kiadis Pharma Netherlands B.V.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2017-02-06
• Last Update Posted: 4 December 2018

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 250

Inclusion Criteria

1. 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 IPSS-R risk group)
2. Clinical justification of allogeneic stem cell transplantation where a suitable HLA matched sibling or unrelated donor is unavailable in a timely manner.
3. 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 HLA-typing
4. Karnofsky Performance Status (KPS) = 70%
5. Male or female, age = 18 years and = 70 years. Patients aged = 65 years must have a Sorror score = 3
6. Patient weight = 25 kg and = 130 kg
7. 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.
8. For females of childbearing potential27 who are sexually active and males who have sexual contact with a female of childbearing potential: willingness to use reliable methods of contraception (oral contraceptives, intrauterine device, hormone implants, contraceptive injection or abstinence) during study participation
9. Given written informed consent (patient and donor)
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 237
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 13

Exclusion Criteria

1. Diagnosis of chronic myelomonocytic leukemia (CMML)
2. Availability of a suitable HLA-matched sibling or unrelated donor in adonor search
3. Prior allogeneic hematopoietic stem cell transplantation
4. Diffusing capacity for carbon monoxide (hemoglobin corrected DLCO) < 50% predicted
5. Left ventricular ejection fraction < 45% (evaluated byechocardiogram or MUGA scan)
6. AST and/or ALT > 2.5 × ULN (CTCAE grade 2)
7. Creatinine clearance < 50 ml/min (calculated or measured)
8. Positive pregnancy test or breastfeeding of patient or donor (womenof childbearing age only)
9. Estimated probability of surviving less than 3 months
10. Known allergy to any of the components of ATIR101 (e.g., dimethyl sulfoxide)
11. Known hypersensitivity to cyclophosphamide or any of itsmetabolites
12. Any contraindication for GVHD prophylaxis with mycophenolatemofetil, cyclosporine A, or tacrolimus
13. Known presence of HLA antibodies against the non-shared donorhaplotype
14. Positive viral test of the patient or donor for HIV-1, HIV-2, HBV28,HCV28, Treponema pallidum, HTLV-1 (if tested), HTLV-2 (if tested), WNV (if tested), or Zika virus (if tested)
15. Any other condition that, in the opinion of the investigator, makes the patient or donor ineligible for the study

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: The 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.;Secondary Objective: Not applicable;Primary end point(s): The primary endpoint of the study is GVHD-free, relapse-free survival (GRFS). GRFS is defined as time from randomization until grade III/IV acute graft-versus-host disease (GVHD), chronic GVHD requiring systemic immunosuppressive treatment, disease relapse, or death, whichever occurs first. This endpoint captures both safety and efficacy.;Timepoint(s) of evaluation of this end point: Throughout the study (no fixed timepoint)

Secondary Outcome Measures

Name	Time	Method
Secondary end point(s): Overall survival (safety and efficacy)<br>Progression-free survival (efficacy)<br>Relapse-related mortality (efficacy)<br>Transplant-related mortality (safety and efficacy)<br>;Timepoint(s) of evaluation of this end point: Throughout the study (no fixed timepoint)