| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Hematological disorders (ALL; AML; Non-Hodgkin lymphoma; Myelodysplastic syndromes; Congenital immune deficiencies; Severe aplastic anemia; Fanconi anemia; Osteopetrosis; Selected cases of hemoglobinopathies) |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLGT |
| E.1.2 | Classification code | 10018849 |
| E.1.2 | Term | Haematological disorders NEC |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
This is a Phase I/II extension study evaluating the safety and feasibility of BPX-501 T cells infused after partially matched, related, T cell-depleted HSCT in pediatric patients. The purpose of this clinical trial is to determine whether BPX-501 infusion can enhance immune reconstitution in those patients with hematologic disorders, with the potential for reducing the severity and duration of severe acute GVHD, thereby improving overall survival. The trial will also evaluate the treatment of GVHD by the infusion of dimerizer drug (rimiducid), activating the safety gene, in those subjects who present with GVHD who do not respond to standard of care treatment.
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| E.2.2 | Secondary objectives of the trial |
This study will look at how long the patient remains disease free following the transplantation, and how many patients relapse.
To look at how many patients have recovery in the number blood cells called neutrophils and platelets.
To assess transplant/graft failure.
To assess graft versus host disease (GVHD)severity, how often GVHD occurs and the time it takes to recover following infusion of AP1903.
To assess the infection complications.
To assess time to recovery of patient’s immunity.
To look at the duration of hospital admission.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patient Inclusion Criteria:
1. Males or females
2. Age ≤ 18 years and ≥ 1 month (<1 month upon approval by Sponsor)
3. Life expectancy > 10 weeks
4. Patients deemed clinically eligible for allogeneic stem cell transplantation.
5. Patients may have failed a prior allograft.
6. Patients with life-threatening acute leukemia (high-risk Acute Lymphoblastic leukemia (ALL) in 1st Complete remission (CR), ALL in 2nd CR, high-risk Acute Myeloid leukemia (AML) in 1st CR, AML in 2nd CR). Morphological CR must be documented and minimal residual disease measurement before transplantation is recommended.
7. Non-malignant disorders deemed curable by allogenic transplantation:
a. primary immune deficiencies,
b. severe aplastic anemia not responding to immune suppressive therapy,
c. osteopetrosis,
d. selected cases of erythoid disorders, such as β0 β0 thalassemia major, sickle cell disease, Diamond-Blackfan anemia,
e. congenital/hereditary cytopenia, including Fanconi Anemia before any clonal malignant evolution (Myelodysplastic syndrome (MDS), AML).
Note: subjects will be eligible if they meet either item 6 or 7.
8. Lack of suitable conventional donor (Human Leucocyte Antigene (HLA) identical sibling or HLA phenotypically identical relative or 9-10/10 unrelated donor evaluated using high resolution molecular typing) or presence of rapidly progressive disease not permitting time to identify an unrelated donor
9. A minimum genotypic identical match of 5/10 is required
10. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA- DRB1 and HLA-DQB1.
11. Lansky/Karnofsky score > 50
12. Signed written informed consent by the patient or the patient's parent or guardian for patients who are minors
Donor Inclusion criteria:
1. Eligible donors include 5/10 HLA identical relative, including but not limited to biological parents, siblings, or half-siblings. Matching will be determined by class I and class II DNA typing. The donor of the BPX-501 T cells must be the HSCT donor.
2. Donor age must be > 18 and < 65 years.
3. The donor should be sufficiently healthy not to be at increased risk from the mobilization procedure.
4. Should more than one “equally” MHC compatible donor be identified, other selection criteria may include natural killer cell (NK) alloreactivity, NK cell KIR-Haplotype, B-content for B-haplotype donors, size of the NK alloreactive subset, gender, age, CMV status, health status and body weight of donor. The physician treating the subject will make the final decision.
5. Donors must meet the selection criteria as defined by the European Directive 2006/17/CE and according to the FACT-JACIE International Standards and local regulations for donor selection.
6. The donor must have been informed of the investigational nature of the BPX-501 product and have signed an informed consent form that they will undergo a second pheresis procedure.
7. Donor must have adequate peripheral venous access for leukapheresis or must agree to placement of a central venous catheter.
8. The collection of donor T cells to be transduced with the suicide gene will be performed before the mobilization procedure with G-CSF in order to avoid any potential negative influence of this cytokine on function of genetically modified T cells.
9. Signed informed consent
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| E.4 | Principal exclusion criteria |
Patient Exclusion criteria:
1. Greater than grade II acute GVHD or chronic extensive GVHD due to a previous allograft at the time of inclusion
2. Patient receiving an immunosuppressive treatment for GVHD treatment due o a previous allograft at the time of inclusion
3. Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 ml / min)
4. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction <40%)
5. Current uncontrolled clinically active infectious disease (including positive HIV serology or viral RNA
6. Serious concurrent uncontrolled medical disorder
7. Pregnant or breast feeding female patient
8. Lack of parents'/guardian's informed consent
Donor exclusion criteria
1. Evidence of active infection (including urinary tract infection, or upper respiratory tract infection) or viral hepatitis exposure (on screening), unless HBs Ab+ and HBV DNA negative.
2. Factors which place the donor at increased risk for complications from leukapheresis or G-CSF therapy (e.g., autoimmune disease, sickle cell trait, symptomatic coronary artery disease requiring therapy, previous thrombotic events).
3. Pregnancy at the time of normal leukapheresis for the T cells and at the time of the mobilization for the stem cell allograft collection.
4. Breastfeeding at the time of mobilization
Sponsor will be notified of any AEs (infections, etc.) occurring in the donor between the leukapheresis and stem cell apheresis. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I dose escalation summary
Nine subjects were treated according to a 3+3 dose escalation design. Cohorts 1-3 subjects received 0.2 X106 BPX-501 T cells/kg, 0.5 X 106 BPX-501 T cells/kg, and 1 X 106 BPX-501 T cells/kg, respectively. No DLTs were observed and the study then continued at the highest tested dose, namely 1 X 106 BPX-501 T cells/kg. No related AEs or SAEs were reported. There were no dose-limiting toxicities. All 9 subjects showed evidence of BPX-501 T cells. Subjects experienced Grade II skin-only GvHD which resolved without treatment with rimiducid.
The Phase II extension study will evaluate the 1x106 BPX-501 T cells/kg dose for both malignant and non-malignant diseases.
Phase II primary end-points
Event-Free Survival at 180 days (events include TRM (or NRM for malignant patients), severe GvHD (acute Grade 2-4 organ or extensive GvHD) and life threatening infections (Grade 4)
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 24 months post-transplant |
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| E.5.2 | Secondary end point(s) |
TRM (non-malignant) or NRM (malignant) at 100 and 180 days.
Cumulative incidence and severity of acute (grade 2-4) and chronic GVHD at 180 days.
Time to resolution of acute or chronic GVHD after administration of rimiducid.
Immune reconstitution as determined by T cell subsets at day 180:
a) Absolute CD3 count
b) Absolute CD4 count
c) Absolute CD8 count
Time to immune reconstitution.
Disease Free/cGVHD survival at 180 days.
Disease status of each specific disease indication at 180 days:
a) Primary immune disorders as determined by CD3 T cell count >500 cells/ul and lower normal levels of IgA and IgM at 180 days.
b) Haemoglobinopathies as determined by incidence of RBC transfusion dependence and haemoglobin of >8.5 g/dL at 180 days.
c) Fanconi Anemia as determined by RBC >3,000,000 cells/ul, neutrophil count determined by 1500 cells/ul and >150,000 platelet counts at 180 days.
d) Leukemia as determined by PFS at 180 days. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| For a period of 15 years. |
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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 | Yes |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| 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 | No |
| 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 | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 4 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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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| The study will evaluate overall survival and disease free survival for all patients enrolled at 24 months after transplantation. The study will be closed after the completion of the 15 years of follow-up. |
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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 | 15 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 15 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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