E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The medical condition under investigation is childhood precursor B acute lymphoblastic leukaemia (ALL). |
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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 | LLT |
E.1.2 | Classification code | 10000844 |
E.1.2 | Term | Acute lymphoblastic leukaemia |
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 |
1. To evaluate the feasibility and safety of adoptive transfer of CD19ζ chimaeric receptor transduced donor-derived EBV-specific cytotoxic T-lymphocytes (EBV-CTL) in patients with high-risk or relapsed B cell precursor acute lymphoblastic leukaemia (BCP-ALL) after allogeneic HSCT.
2. To determine the biological effect of infusion of CD19ζ-transduced EBV-CTL on residual leukaemia as assessed by MRD quantification in the bone marrow.
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E.2.2 | Secondary objectives of the trial |
3. To determine the survival of CD19ζ-transduced EBV-CTL in vivo.
4. To determine the in vitro activity of circulating T cells after adoptive immunotherapy against CD19+ve targets.
5. To determine if vaccination with irradiated EBV-specific LCL post immunotherapy improves in vivo survival and expansion of CD19ζ-transduced EBV-CTL.
6. To determine relapse rate and disease-free survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Pre-emptive arm
Children (18 years or younger) with CD19+ precursor B cell ALL fulfilling one of the following criteria who are undergoing an allogeneic stem cell transplant from an EBV-seropositive donor at one of the participating centers will be eligible for entry into the trial and EBV CTL generation:
In first remission, if at least one of the following criteria are met:
• t(9;22) and prednisone poor response or not in molecular remission (BCR-ABL/ABL ratio > 0.02%) pre-HSCT or
• Infant ALL age < 6 months at diagnosis with MLL gene rearrangement and either presenting wcc >300 x 10*9/L or poor steroid early response (i.e circulating blast count >1x10*9/L following 7 day steroid pre-phase of Interfant 06) or
• Resistant disease (> 30% blasts at end of induction treatment day 28-33) in subsequent morphological CR or
• High level bone marrow MRD (> 1 in 1000) at week 12 ALL-BFM 2000/AIEOP BFM ALL 2009/EORTC 58951 protocols, week 12-15 of FRALLE A or at week 14 of UKALL2010
Relapsed patients if at least one of the following criteria are met:
• Very early (< 18 months from diagnosis) bone marrow or extramedullary relapse in second CR or
• Early (within 6 months of finishing therapy) isolated bone marrow relapse with bone marrow MRD > 1 in 100 at day 35 of reinduction in second CR or
• Early (within 6 months of finishing therapy) bone marrow or combined relapse with high level bone marrow MRD (> 1 in 1000) at the end of consolidation therapy (week 12-13 UKALL R3/INTREALL and COOPRALL protocols, prior to protocol M in BFM relapse protocol ((ALL-REZ BFM 2002)) and after Protocol II-IDA in AIEOP LLA Rec 2003).
These patients have a high (> 50%) risk of relapse and will be monitored for evidence of MRD in bone marrow aspirates (monthly for months 1-6, 6 weekly months 7.5-12 post HSCT) for the first year post-transplant. Patients who become MRD +ve in the marrow at a level ≥ 5 x 10-4 but are in haematological remission will be eligible to be treated pre-emptively with CD19zeta transduced CTL.
Prophylaxis arm
Any patient (≤ 18 years) with precursor B-ALL relapsing in the bone marrow (either isolated or combined) after myeloablative allogeneic HSCT who achieves morphological remission after re-induction and who is a candidate for second HSCT at one of the participating sites is eligible to receive CD19zeta transduced CTL prophylactically
- Stem cell donors must be EBV sero-positive and HLA-matched (10/10) or a single antigenic/allelic (9/10) mismatch with the recipient.
- Patients must have a life expectancy of at least 12 weeks.
- Patients must have Karnofsky score of >60% if ≥ 10 years old or Lansky performance score of greater than 60 if < 10 years old (see Appendix 2 of protocol).
- Patients must have transduced donor-derived EBV-specific CTLs with ≥15% expression of CD19ζ determined by flow-cytometry which meet the specified release criteria.
- Patients or legal guardians must sign an informed consent indicating that they are aware this is a research trial and have been told of its possible benefits and toxic side effects.
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E.4 | Principal exclusion criteria |
Patients with CD19 negative precursor B cell ALL
Patients transplanted from an EBV seronegative or > single antigenic/allelic HLA-mismatched donor.
Patients with active acute GVHD overall Grade ≥2 (Seattle criteria) or significant chronic GVHD requiring systemic steroids at the time of scheduled infusion of transduced CTL will be excluded from infusion of transduced CTL until the patient is GVHD-free and off steroids.
Patients with pre-existing severe lung disease (FEV1 or FVC < 50% predicted) pre-HSCT or an oxygen requirement of >28% O2 supplementation or active pulmonary infiltrates on chest X-ray at the time scheduled for transduced CTL infusion will be excluded.
Patients with a serum bilirubin greater than 3 times the upper limit of normal or an AST or ALT greater than 5 times the upper limit of normal will be excluded.
Patients with a serum creatinine greater than 3 times upper limit of normal will be excluded.
Patients with an active severe intercurrent infection at the time of transduced CTL infusion may be excluded (if present consult with Chief investigator).
Patients in whom transduced donor-derived EBV-specific CTLs do not meet release criteria will be excluded from receiving transduced CTL.
Patients who are serologically positive for Hepatitis B, C or HIV pre-HSCT will be excluded.
Female patients of childbearing age with a positive pregnancy test.
In addition, patients with severe allergy to gentamicin will be excluded from receiving vaccination with irradiated donor-derived BLCL.
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Toxicity attributable to transfer of CD19-zeta transduced CTL:
(a) Incidence of grade 3-5 toxicity (graded by the NCI Common Terminology Criteria for Adverse Events, v4.0) attributable to transfer of CD19-zeta transduced CTL within 12 weeks of infusion.
(b) Incidence of significant (Grade II-IV) and severe (Grade III-IV) acute GVHD before day 100 (graded by Seattle criteria) and limited/extensive chronic GVHD between day 100-365.
(c) Incidence of hypogammaglobulinaemia after CD19-zeta CTL transfer at day 100, 6 months and 1 year post-HSCT
2. Biological efficacy as assessed by effect of CD19-zeta transduced CTL on Minimal Residual Disease levels in the bone marrow in the first year post- transduced CTL infusion
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E.5.2 | Secondary end point(s) |
3. Persistence and frequency of circulating CD19ζ transduced CTL in the peripheral blood of recipients after adoptive transfer as assessed by flow cytometry and quantitative real-time PCR.
4. In vitro anti-leukaemic response of circulating PBMC post adoptive transfer of CD19ζ transduced CTL using interferon-γ ELISPOT assays after stimulation with CD19+ve targets
5. Relapse rate, disease-free survival and overall survival at 1 and 2 years after adoptive immunotherapy with CD19ζ-transduced EBV-CTL. |
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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 | Yes |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
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 | 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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The end of the trial will be 10 years after last patient receives infusion of CD19ζ transduced EBV-CTL, at which point ‘declaration of end of trial’ form will be submitted to participating regulatory authorities and ethical committees, as required.
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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 | 12 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 12 |
E.8.9.2 | In all countries concerned by the trial months | 6 |