| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric and adolescents patients with CD19positive r/r mature B-cell NHL who have relapsed after one or more prior therapies or are primary refractory. |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | HLGT |
| E.1.2 | Classification code | 10025320 |
| E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
| E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
|
| 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 |
| Evaluate the efficacy of tisagenlecleucel therapy as measured by ORR and determined by local investigator assessments in subjects with aggressive r/r B-cell NHL. |
|
| E.2.2 | Secondary objectives of the trial |
1-Evaluate the duration of response (DOR)
2-Evaluate event free survival (EFS)
3-Evaluate relapse free survival (RFS)
4-Evaluate progression free survival (PFS)
5-Evaluate overall survival (OS)
6-Evaluate the safety of tisagenlecleucel therapy
7-Characterize the in vivo cellular kinetics (levels, expansion, persistence) of tisagenlecleucel cells into target tissues (blood, bone marrow, lymph nodes, cerebral spinal fluid and other tissues if available), as measured by qPCR in relation to safety and efficacy.
8-Characterize the presence of pre-existing and treatment induced immunogenicity and impact on cellular kinetics and response
9-Assess the proportion of subjects who proceed to transplant post-tisagenlecleucel therapy until end of study.
10-Retrospective assessment of potential CRS predictive models considering also data from other CTL019 trials
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Signed informed consent and assent forms if applicable must be obtained prior to participation in the study.
2.Histologically confirmed (local evaluation) mature B-cell non-Hodgkin lymphoma (B-cell NHL) including the following subtypes; Burkitt Lymphoma and Burkitt Leukemia (L3 B-ALL) (BL), Diffuse Large B-Cell Lymphoma (DLBCL), Primary Mediastinal B-Cell Lymphoma (PMBCL), Gray Zone lymphoma (GZL), and Follicular Lymphoma (FL).
a. Note: Patients with B-cell NHL associated with Nijmegen breakage
syndrome will be allowed.
b. Sufficient formalin-fixed, paraffin-embedded (FFPE) tumor sample
must be available for correlative analyses. A recent tumor sample
obtained for the purpose of the study must be submitted, however if not clinically feasible, an archival tumor biopsy from the most recent relapse or other historical sample may be submitted instead. Excisional biopsies should be submitted wherever possible; in cases where this is not possible a core needle biopsy is allowed. Fine needle aspiration (FNA) is not suitable.
3. Patients ≤25 years of age and weighing at least 6 kg at the time of
screening.
4.Patients who have relapsed after one or more prior therapies (can
include allogeneic and autologous hematopoietic stem cell transplant) or are primary refractory (have not achieved a CR or PR after the first line of therapy).
5. Measurable disease by radiological criteria in all patients at the time of screening. Patients with Burkitt leukemia who don't meet radiological criteria must have bone marrow involvement of >25%.
6. Karnofsky (age ≥16 years) or Lansky (age <16 years) performance
status ≥60.
7. Adequate bone marrow reserve without transfusions defined as:
a. Absolute neutrophil count (ANC) >1000/mm3
b. Platelets ≥50000//mm3
c. Hemoglobin ≥8.0 g/dl
Note: These criteria do not apply for subjects with Burkitt leukemia.
8. Adequate organ function:
a.a serum creatinine (sCR) based on gender/age as described in detail
the protocol
b.AST (aspartate aminotransferase) and ALT (alanine aminotransferase) ≤5 times the upper limit of normal (ULN) for age.
c.Bilirubin <1.5 x ULN (for Gilbert's Syndrome patients total bilirubin <4 mg/dL).
d.Adequate pulmonary function
i.Oxygen saturation of >91% on room air.
ii.No or mild dyspnea (≤Grade 1)
9.Must have a leukapheresis material of non-mobilized cells accepted for manufacturing. Note: Leukapheresis material 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 |
1.Prior gene therapy or engineered T cell therapy
2.Prior treatment with any anti-CD19 therapy
3.Allogeneic hematopoietic stem cell transplant (HSCT) <3 months prior to screening and ≤4 months prior to infusion
4.Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease (GVHD) in patients who received prior allogeneic HSCT.
5.Prior diagnosis of malignancy other than study indication, and not disease free for 5 years
6.Clinically significant active infection confirmed by clinical evidence,
imaging, or positive laboratory tests (e.g., blood cultures, PCR for
DNA/RNA, etc.)
7. Presence of active hepatitis B or C as indicated by serology. Repeat serology is required if the interval between serology performed at
screening and tisagenlecleucel infusion exceeds 8 weeks.
8.Human Immunodeficiency Virus (HIV) positive test. Repeat serology is required if the interval between serology performed at screening and tisagenlecleucel infusion exceeds 8 weeks
9.Active neurological autoimmune or inflammatory disorders not related to B cell NHL (e.g., Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
10.Active CNS involvement by malignancy. Note: Patients with history of CNS disease that have been effectively treated will be eligible.
11.Patients with B-cell NHL in the context of post-transplant
lymphoproliferative disorders (PTLD) associated lymphomas.
12.Patients with concomitant genetic syndromes associated with bone marrow failure status such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Note: Patients with Down syndrome will not be excluded.
13. Known hypersensitivity to the excipients of tisagenlecleucel or to any other drug product as advised for administration in the study protocol (e.g. lymphodepleting agents, tocilizumab).
14.Cardiac disorder defined as:
a.Cardiac or cardiac repolarization abnormality, including any of the
following:
i.History of myocardial infarction (MI), angina pectoris, or coronary
artery bypass graft (CABG) within 6 months prior to starting study
treatment
ii.Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block
(e.g., bifascicular block, Mobitz type II and third degree AV block)
b.LVEF <45% as determined by ECHO or MRA or MUGA
c.NYHA functional class III or IV
15.Subjects enrolled in this study are not permitted to participate in
additional parallel investigational drug or device studies
16.Pregnant or nursing (lactating) women.
Note: Women of child-bearing potential must have a negative serum
pregnancy test performed at screening, within 24 hours prior to
leukapheresis, within 24 hours prior to lymphodepletion Serum or urine, within 24 hours prior to tisagenlecleucel infusion and at EOS.
17. Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, unless they are using
highly effective methods of contraception from enrollment into this
study through at least 12 months after the tisagenlecleucel infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests. qPCR test results will be available upon request.
18. Sexually active males who do not agree to use a condom during
intercourse from enrollment through at least 12 months after the
tisagenlecleucel infusion and until CAR-T cells are no longer present by
qPCR on two consecutive tests. qPCR test results will be available upon
request.Note: 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) |
| Overall response rate (ORR), which includes complete response (CR) and partial response (PR) determined by local investigator assessments. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1-DOR
2-EFS
3-RFS
4-PFS
5-OS
6- Physical examination, vital signs, adverse events, , laboratory abnormalities, performance status and as applicable physical development
7- Cellular kinetics parameters and/or other relevant parameters in peripheral blood, bone marrow, lymph nodes, cerebrospinal fluid and other tissues as appropriate, month 3 response, safety endpoint (CRS grade).
8-Levels of pre-existing and treatment induced immunogenicity, cellular kinetic parameters, and efficacy (Month 3 response)
9-Number of subjects that proceed to SCT after tisagenlecleucel infusion until EOS will be described
10-Assess the ability for early prediction of cytokine release syndrome utilizing clinical and biomarker data |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | 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) | 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 | 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 | 19 |
| 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 |
| Australia |
| Austria |
| Canada |
| Denmark |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| 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 (EOS) assessments for each subject is completed within 2 weeks of a subject's premature withdrawal of consent or when all infused and evaluable subjects with aggressive B-cell NHL have completed Month 24 evaluation or discontinued early. A final Clinical Study Report (CSR) will be produced once all subjects complete the study. |
|
| 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 | 4 |
| E.8.9.1 | In the Member State concerned days | 7 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| 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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