E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with hematologic malignancies who are eligible for an allogeneic stem cell transplantation but without the availability of an (according to the treating physician) suitable matched related or unrelated donor following a donor search. |
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E.1.1.1 | Medical condition in easily understood language |
Patients with an abnormal growth of cells rising through transformation of bone marrow derived cells that are eligible for HSCT, but have no suitable matched related family or unrelated donor. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028228 |
E.1.2 | Term | Multiple myeloma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10066110 |
E.1.2 | Term | T-cell lymphoblastic leukemia acute |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000886 |
E.1.2 | Term | Acute myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10028233 |
E.1.2 | Term | Multiple myeloma without mention of remission |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10028533 |
E.1.2 | Term | Myelodysplastic syndrome |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10028578 |
E.1.2 | Term | Myeloproliferative disorders (excl leukaemias) |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10025310 |
E.1.2 | Term | Lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000887 |
E.1.2 | Term | Acute myeloid leukemia in remission |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10000845 |
E.1.2 | Term | Acute lymphoblastic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008948 |
E.1.2 | Term | Chronic leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10009015 |
E.1.2 | Term | Chronic myeloid leukemia |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To study the effects of the administration of a donor lymphocyte preparation selectively depleted of host alloreactive T-cells (ATIR) to patients with hematologic malignancies on 6 months and 12 months TRM. |
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E.2.2 | Secondary objectives of the trial |
• To study the effects of ATIR on Overall Survival (OS).
• To study the effects of ATIR on the incidence and severity of acute GvHD.
• To study the effects of ATIR on the incidence and severity of chronic GvHD.
• To study the effects of ATIR on Progression Free Survival (PFS).
• To study the effects of ATIR on the incidence and severity of bacterial, viral or fungal infections.
• To study the effects of ATIR on immune reconstitution.
• To study the effects of ATIR on the health status of patients (including Quality of Life [QoL]). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must comply with the recipient inclusion and exclusion criteria mentioned below. These criteria must be assessed before patient apheresis.
Recipient Inclusion Criteria (any of the following)
Initially, both patients with primary and secondary indications are eligible for the trial. During the trial accrual may be limited to the primary indications based on a recommendation made by the Independent Data Monitoring Committee (IDMC).
• Acute Myeloid Leukemia (AML): AML in first remission with high risk features (secondary AML, FLT-3 mutation, complex karyotype, abn(3q), -5/5q-, -7/7q-, abn(12p), abn(17p), or other cytogenetic anomaly of similar poor prognosis, or need for 2 induction regimens to achieve a complete remission (CR)). All AML in second remission.
Group 1: Primary Indications
• Acute Lymphoblastic Leukemia (ALL): ALL in first remission with high-risk features (presenting leukocyte count > 30,000/mm3 for B-cell ALL or > 100,000/mm3 for T-cell ALL, karyotypes t(9;22), t(11;19), and t(4;11) biphenotypic leukemia, pro-B-ALL, late CR after induction therapy, rising MRD markers). All ALL in second remission.
• Myelodysplastic Syndrome (MDS): Transfusion-dependent MDS with low or intermediate-1 IPSS score, and all MDS with intermediate-2 or high IPSS score. Patients with more than 20% blasts in the marrow will be considered AML.
• Ph-positive chronic myeloid leukemia (CML): Patients with Ph-positive CML in first chronic phase who have failed (either resistant or intolerant) at least 2 tyrosine kinase inhibitors and any patient with the T315I mutation (irrespective of prior tyrosine kinase inhibitors).
Group 2: Secondary Indications
AML:
- All AML not belonging to Group 1 in subsequent remission or with evidence of chemo-sensitive disease or,
- Patients requiring 3 or more induction regimens to achieve a first remission or,
- Patients with AML in hematologic remission who relapsed more than 2 years after allogeneic stem cell transplantation.
• ALL: All ALL not belonging to Group 1 in subsequent remission or with evidence of chemo-sensitive disease. Patients with ALL in hematologic remission who relapsed more than 2 years after allogeneic stem cell transplantation.
• Non-Hodgkin Lymphoma (NHL): All high grade and low grade Non-Hodgkin lymphoma (other than CLL and MM) in 2nd or 3rd remission (at least PR) after standard of care treatments including autologous stem cell transplantation.
• Chronic Myeloid Leukemia (CML): Patients with accelerated phase CML or CML in second or later chronic phase.
• Multiple Myeloma (MM): Secretory MM with or without osteolytic lesions concurrently not featuring extramedullary disease responsive to prior autologous stem cell transplantation(s) or at least one standard of care treatment (defined as 50% reduction of paraprotein in serum/plasma and/or 75% reduction of paraprotein in urine).
• Chronic Lymphocytic Leukemia (CLL):
- CLL non-responsive or early relapsed (within 12 months) after a previous fludarabine- or equivalent purine-based regimen or,
- CLL relapsed (within 24 months) after purine analogue combination therapy or treatment of similar efficacy (i.e. autologous stem cell transplantation) or,
- CLL with p53 deletion/mutation (i.e. del 17p-) requiring treatment.
• CLL transformed to high grade lymphoma (Richter transformation) having demonstrated at least PR.
• MPS: Myeloproliferative disorders in transformation to acute leukemia or with progressive transfusion requirements or pancytopenia including atypical (Ph negative) chronic myeloid and neutrophilic leukemias, and progressing myelofibrosis. Patients with more than 20% blasts in the marrow will be considered AML.
Donor inclusion criteria:
• Male or female, age ≥ 18, ≤ 65 years.
• Ability to comprehend the investigational nature of the study and provide informed consent.
• Haploidentical family donor with 2 to 3 mismatches at the HLA-A, -B and/or -DR loci of the unshared haplotype.
• Male or female, age ≥ 16, ≤ 75 years.
• Donors must be fit to receive G-CSF and undergo apheresis (normal blood count, normotensive and no history of stroke).
• Donor must have Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.
• Donor must provide written informed consent.
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E.4 | Principal exclusion criteria |
Recipient exclusion criteria (any of the following):
• AML in 1st CR with good risk karyotypes: AML M3 (t15; 17), AML M4Eo (inv 16), AML t (8; 21).• MM featuring concurrent extramedullary disease or being non-responsive to prior therapy
• CML in blast crisis.
• CLL concurrently transformed into high-grade lymphoma and failing to demonstrate at least PR.
• NHL with concurrent bulky disease (≥ 5 cm).
• Diffusing Capacity for Carbon Monoxide (DLCO) < 40% predicted.
• Left ventricular ejection fraction < 40% (evaluated by echocardiogram or MUGA).
• AST/SGOT > 2.5 x ULN (CTCAE grade II v3.0).
• Bilirubin > 1.5 x ULN (CTCAE grade II v3.0).
• Creatinine > 1.5 x ULN (CTCAE grade II v 3.0).
• HIV positive (Recipients who are positive for hepatitis B (HBV), hepatitis C (HCV) or human T-cell lymphotropic virus (HTLV-I/II) are not excluded from participation).
• Positive pregnancy test for women of childbearing age.
• Prior haploidentical PBSC or cord blood transplantation.
• Less than 2 years from a prior allogeneic stem cell transplantation.
• Estimated probability of surviving less than three months.
• Major anticipated illness or organ failure incompatible with survival from transplant.
• Severe psychiatric illness or mental deficiency sufficiently severe as to make compliance with the transplant treatment unlikely and informed consent impossible.
• Known allergy to any of the components of ATIR (e.g., dimethyl sulfoxide).
• Any other condition which, in the opinion of the investigator, makes the patient ineligible for the study.
Donor exclusion criteria:
• Medically uncontrolled coronary heart disease.
• Myocardial infarction within the last 3 months.
• History of uncontrolled seizures.
• History of malignancy (except basal cell or squamous carcinoma of the skin, positive PAP smear and subsequent negative follow up).
• Positive test result for any of the mandatory viral tests in the applicable region, except for a positive cytomegalovirus (CMV) result, which does not lead to exclusion.
• Presence of a transmissible disease (such as HIV positive), a major illness, a suspected systemic dysfunction and/or an active inflammatory or autoimmune disorder.
• Female donors who are pregnant or nursing. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Incidence of TRM at 6 months and 12 months after the transplantation. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Incidence of TRM at 6 and 12 months after the transplantation. Time to TRM will be calculated from the date of receipt of the HSCT. |
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E.5.2 | Secondary end point(s) |
• Overall Survival (OS).
• Incidence and severity of acute and chronic GvHD.
• Progression free survival (PFS).
• The incidence, severity and duration of fungal, viral and bacterial infections occurring within the first year following HSCT.
• Immune reconstitution.
• To measure the health status of patients, the EQ-5D and the Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) will be used.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Patients will be assessed weekly for the first 100 days after the transplant. Patients will be assessed every month up to 6 months after the transplantation, every 2 months up to 12 months after the transplantation and subsequently every 3 months up to 24 months after the transplantation. Patients will be followed-up for 24 months to assess overall survival. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.6.13.1 | Other scope of the trial description |
Cellular therapy using haploidentiacl donor lymphocytes, selectively eliminated for alloreactive T cells through using the photosensitizing compound TH9402, resulting in the cellular product ATIR. |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
External control groups are described in detail in a separate protocol (CR-AIR-006). |
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E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 11 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
France |
Germany |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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A total of up to 70 patients are expected to be treated with ATIR™, in order to obtain at least 60 evaluable patients. Patients who die due to progression or replace prior to 6 or 12 months will not be considered evaluated and will be replaced. The trial ends when the last enrolled patient has completed the last follow up visit (24 months after the transplantation), or earlier if the last patient dropped out before the last follow up visit could be performed. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |