| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric and young adult patients aged 1 to 25 years with first-line NCI high-risk (HR) B-cell acute lymphoblastic leukemia (B-ALL) who are in CR1 with minimal residual disease (MRD) positive (MRD ≥ 0.01%) at the end of consolidation (EOC) therapy by central laboratory assessment. |
|
| E.1.1.1 | Medical condition in easily understood language |
| High-risk B-cell acute lymphoblastic leukemia |
|
| 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 | 20.0 |
| 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 | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10063621 |
| E.1.2 | Term | Acute lymphoblastic leukaemia recurrent |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To evaluate efficacy of tisagenlecleucel therapy as measured by the 5 years disease-free survival (DFS) rate by investigator assessment. |
|
| E.2.2 | Secondary objectives of the trial |
- Proportion of patients who are disease free without allogeneic SCT at 1 year
- Overall survival (OS)
- Proportion of patients achieving MRD-negative CR or CRi at month 3 post-tisagenlecleucel infusion
- Proportion of patients in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
- Tisagenlecleucel manufacturing success rate in patients ≥1 year and <3 years
- Impact of tisagenlecleucel on health-related Quality of Life (QoL) measures
- Impact of tisagenlecleucel on neurocognitive measures
- Safety of tisagenlecleucel therapy
- Prevalence and incidence of immunogenicity to tisagenlecleucel and its impact on efficacy, safety and cellular kinetics
- Characterize in vivo cellular kinetic profile of tisagenlecleucel transgene and CD3+ CAR-positive viable T cells including second infusion
- Evaluate the relationship between B-cell and transgene persistence
- Evaluate dose-exposure-response relationship |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. CD19 expressing B-cell Acute Lymphoblastic Leukemia
2. De novo NCI HR B-ALL who received 1st line treatment and are at MRD ≥ 0.01% at EOC. EOC bone marrow MRD will be collected prior to screening and will be assessed by multi-parameter flow cytometry using central laboratory analysis.
3. Age 1 to 25 years at the time of screening
4. Lansky (age <16 years) or Karnofsky (age ≥16 years) performance status ≥60% at screening
5. Adequate organ function during the screening period
• Renal function based on age/gender as described in the protocol
• ALT ≤5 times ULN for age
• AST ≤5 times ULN for age
• Total bilirubin <2 mg/dL (for Gilbert’s Syndrome patients total bilirubin <4 mg/dL)
• Adequate pulmonary function defined as
- no or mild dyspnea (≤ Grade 1)
- oxygen saturation of > 90% on room air
• Adequate cardiac function defined as LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram or MUGA within 6 weeks of screening
6. Prior induction and consolidation chemotherapy allowed, as decribed in the protocol
7. Signed written informed consent and assent forms, if applicable, must be obtained prior to any study procedures
8. Must meet the institutional criteria to undergo leukapheresis
9. Once all other eligibility criteria are confirmed, must have a leukapheresis product of non-mobilized cells received and accepted by the manufacturing site.
NOTE: Leukapheresis product will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other clinical eligibility criteria is received.
Other protocol-defined inclusion criteria may apply. |
|
| E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following criteria:
1. M3 marrow (≥ 25% blasts by morphologic criteria) at the completion of first-line induction therapy
2. M2 (i.e. ≥ 5% blasts by morphologic criteria) or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia at the time of enrollment.
3. Philadelphia chromosome positive (Ph+) ALL
4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone
5. Prior tyrosine kinase inhibitor therapy
6. Subjects with concomitant genetic syndromes associated with bone marrow failure states: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down syndrome will not be excluded.
7. Patients with Burkitt’s lymphoma/leukemia (i.e. patients with mature B-ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation).
8. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
9. Has had treatment with any prior anti-CD19 therapy
10. Treatment with any prior gene or engineered T cell therapy
11. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to tisagenlecleucel infusion)
12. Presence of active or prior hepatitis B or C as indicated by serology. Serology must be repeated, if the interval between testing at screening and tisagenlecleucel infusion exceeds 8 weeks.
13. Human Immunodeficiency Virus (HIV) positivity as indicated by serology. Serology must be repeated, if the interval between testing at screening and tisagenlecleucel infusion exceeds 8 weeks.
14. Subject had an investigational medicinal product within the last 30 days prior to screening
NOTE: Investigational therapies must not be used at any time while on study until the first relapse following CTL019 infusion.
15. If subjects are taking any of the medications defined in the protocol, their infusion (including a second infusion) must be delayed until the medications have been stopped (details according to in the protocol):
a. Medications to be stopped > 72 hours prior to tisagenlecleucel infusion: Therapeutic systemic doses of steroids.
b. Medications to be stopped at least 1 week prior to tisagenlecleucel infusion:
• 6-thioguanine, asparginase (non-pegylated), vincristine, 6-mercaptopurine, and intrathecal methotrexate
c. Medications to be stopped at least 2 weeks prior to tisagenlecleucel infusion:
• Anthracyclines and cytarabine
• Intravenous methotrexate.
• Radiotherapy: Non-CNS site of radiation
d. Medications to be stopped at least 4 weeks prior to tisagenlecleucel infusion: Pegylated-asparaginase
e. Medications/Therapy to be stopped at least 8 weeks prior to tisagenlecleucel infusion:
• Radiotherapy: Cranial radiation (for CNS 3 patient) therapy
16. Pregnant or nursing (lactating) women
NOTE: Female study participants of reproductive potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis, lymphodepletion and prior to tisagenlecleucel infusion.
17. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective method of contraception while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests. Highly effective contraception are detailed in the protocol.
Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child bearing potential.
18. Sexually active males must use a condom during intercourse while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm for the time period specified above.
Other protocol-defined exclusion criteria may apply. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| 5-year DFS rate. DFS is defined as the time from tisagenlecleucel infusion to morphologic relapse, occurrence of secondary malignancy or death due to any cause, whichever occurs first. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| After tisagenlecleucel infusion, efficacy will be assessed at Day 28, then every 3 months for the first year, every 6 months for the second year, then yearly until the EOS. Relapse and survival will be captured every 3 months throughout the study. |
|
| E.5.2 | Secondary end point(s) |
- Proportion of patients who are disease free without allogeneic SCT at 1 year
- OS, i.e. the time from date of tisagenlecleucel infusion to the date of death due to any reason
- Proportion of patients achieving MRD-negative CR or CRi at month 3 post-tisagenlecleucel infusion
- Proportion of patients in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
- Proportion of patients who have tisagenlecleucel product successfully manufactured (meet all release criteria) over the total number of patients enrolled for the age ≥ 1 year and < 3 years at respective time points
- PedsQL 4.0 and EuroQol EQ-5D in patients ≥ age 8 years; change from baseline
- Cogstate computerized cognitive battery age standardized scores (5 tests: psychomotor function (DET), attention (IDN), working memory (ONB), visual learning (OCL) and executive function (GML) (in patients ≥ age 6 years)
- Evaluation of adverse events, vital signs, laboratory and other parameters.
- Prevalence and incidence of pre-existing and treatment induced immunogenicity
- Pre-existing and treatment induced immunogenicity on clinical response, cellular kinetics (Cmax, AUC0-28d, Clast) and safety
- Tisagenlecleucel transgene levels by qPCR in blood, bone marrow, and CSF if available
- Expression of tisagenlecleucel detected by flow cytometry in blood and bone marrow
- Cmax, Tmax, AUCs and other relevant cellular kinetic parameters in blood, bone-marrow, and CSF if available
- B-cell recovery time and transgene levels over time
- Dose-exposure-response relationship:
• Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationships with dose
• Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationship with relevant exposure parameters (e.g. AUC and Cmax)
• Cellular kinetic parameters and relationship with dose
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Subjects achieving CR or CRi at 1 year post infusion without SCT, overall survival, subjects achieving MRD negative CR or CRi at month 3 post infusion |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient Reported Outcomes and Cogstate Neurocognitive Assessment in patients |
|
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 15 |
| 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 |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
| The study will end when approximately 80% of the all treated patients have been followed for at least 5 years or have DFS events, whichever occurs first (estimated in approximately 8 years after first patient first treatment (FPFT)). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| 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 | 8 |
| 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 |
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