E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paediatric/young adult patients with B-cell acute lymphoblastic leukaemia who are chemo-refractory, relapsed after allogeneic SCT, or are otherwise ineligible for allogeneic SCT. |
|
E.1.1.1 | Medical condition in easily understood language |
Paediatric/young adult patients with a recurrent form of B-cell acute lymphoblastic leukaemia. |
|
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 |
This expanded treatment protocol (ETP) will provide pediatric/young adult patients with relapsed or refractory B-cell ALL the opportunity to be treated with CTL019 after the closure of the Novartis single-arm phase II clinical trial (Study CCTL019B2202) and to collect additional safety information. |
|
E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy of CTL019 therapy as measured by complete remission rate, which includes CR and CR with incomplete blood count recovery (CRi).
- Evaluate the percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment.
- Evaluate the percentage of patients who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment.
- Evaluate the duration of remission.
- Evaluate the relapse-free survival.
- Evaluate the event-free survival.
- Evaluate the overall survival.
- Evaluate the response at Day 28 +/- 4 days.
- Evaluate the impact of baseline tumor burden on response.
- Evaluate the quality of response using minimal residue disease assessments.
- Describe the prevalence and incidence of immunogenicity to CTL019.
- Characterize the in vivo cellular kinetic profile of CTL019 cells in the blood.
- Evaluate the relationship between exposure to CTL019 with CRS grades.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this program have to meet all of the following criteria:
1. Relapsed or refractory B-cell ALL in pediatric or young adult patients
2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry with adequate organ function.
3. Adequate organ function as defined in the protocol.
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at Screening
5. Life expectancy > 12 weeks.
6. Age < 26 years of age at the time of Screening.
7. Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at Screening.
8. Patients previously treated with blinatumomab who have detectable leukemia and documented CD19+ expression (via flow cytometry) and confirmed absence of CD19- leukemic blasts at Screening may be included.
9. Signed written informed consent form (ICF) and assent form if applicable must be obtained prior to any study procedures
10. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored leukapheresis product.
11. Once all other eligibility criteria are confirmed, must have a leukapheresis product of nonmobilized 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 eligibility criteria is received.
Other protocol-defined inclusion criteria may apply. |
|
E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Isolated extra-medullary disease relapse.
2. Patients 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.
3. Patients with Burkitt's lymphoma/leukemia.
4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
5. Prior treatment with any gene therapy product.
6. Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with linatumomab
who fulfill inclusion criterion no. 8.
7. Presence of active or prior hepatitis B or C as indicated by serology (for detailed criteria see Appendix 2 of main protocol). Serology must be repeated, if the interval between testing at Screening and CTL019 infusion exceeds 8 weeks.
8. HIV positivity as indicated by serology. Serology must be repeated, if the interval between testing at Screening and CTL019 infusion exceeds 8 weeks.
9. Presence of grade 2 to 4 acute or extensive chronic graft versus host disease (GVHD).
10. Active CNS involvement by malignancy.
11. Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.
12. Previous or concurrent malignancy (exceptions defined in the protocol)
13. Intolerance to the excipients of the CTL019 cell product (i.e. dimethyl sulfoxide).
14. Cardiac or cardiac repolarization abnormality.
15. Patients enrolled in this study are not permitted to participate in additional parallel investigational drug or device studies.
16. Patient has an investigational medicinal product within the last 30 days prior to screening.
17. The following medications are excluded:
a. Steroids,
b. Allogeneic cellular therapy,
c. GVHD therapies,
d. Chemotherapy,
e. CNS disease prophylaxis,
f. Radiotherapy,
g. Anti-T cell antibodies.
18. Pregnant or nursing (lactating) women.
19. Women of child-bearing potential
20. Sexually active males must use a condom during intercourse while taking study treatment and for at least 12 months after the CTL019
infusion and until CAR T cells are no longer present by qPCR on 2 consecutive tests.
Other protocol-defined exclusion criteria may apply. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Evaluate the safety of CTL019 therapy. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The endpoint is assessed throughout the 12 months study duration. |
|
E.5.2 | Secondary end point(s) |
- Percentage of patients who achieve complete remission or complete remission with incomplete blood count recovery (i.e. CR or CRi) during the 6 months after CTL019 infusion.
- Percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment.
- Percentage of patients who achieve CR or CRi and then proceed to SCT while in remission prior to Month 6 response assessment.
- Duration of remission.
- Relapse-free survival.
- Event-free survival.
- Overall survival.
- Response at Day 28 +/- 4 days.
- Impact of baseline tumor burden on response.
- Quality of response using MRD assessments.
- Safety: type, frequency and severity of adverse events, laboratory abnormalities, vital signs, ECGs, pulse oximetry, echocardiogram and B-cell levels.
- Describe the prevalence and incidence of immunogenicity to CTL019.
- Characterize the in vivo cellular kinetic profile (levels, persistence, trafficking) of CTL019 cells in the blood.
- Evaluate the relationship between exposure to CTL019 with CRS grades.
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
The endpoints are assessed throughout the 12 months study duration. |
|
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 | 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) | 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) | No |
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 | No |
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 | 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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Austria |
Belgium |
Canada |
France |
Germany |
Italy |
Japan |
Norway |
Spain |
|
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
|
The end of study is defined as the last patient's last visit (LPLV) which is the last patient's Month 12 evaluation or the time of premature withdrawal. The EOS is anticipated to occur around Quarter 3, 2020.
Semiannual & annual evaluations will be performed for up to 15 years on all patients under a separate LTFU protocol (i.e. CCTL019A2205B). All patients who either complete this study or prematurely discontinue from this study will be enrolled in the LTFU protocol. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | 16 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 0 |