E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed or refractory indolent B-cell Non-Hodgkin Lymphoma (NHL)
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E.1.1.1 | Medical condition in easily understood language |
A cancer of B-cells, a type of white blood cell responsible for producing antibodies |
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 24.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10016895 |
E.1.2 | Term | Follicle centre lymphomas diffuse predominantly small cell |
E.1.2 | System Organ Class | 10016895 - Follicle centre lymphomas diffuse predominantly small cell |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10076596 |
E.1.2 | Term | Marginal zone lymphoma |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029460 |
E.1.2 | Term | Nodal marginal zone B-cell lymphoma |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to evaluate the efficacy of JCAR017 in subjects with relapsed/refractory (r/r) follicular lymphoma (FL) and marginal zone lymphoma (MZL) |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are:
-To evaluate other measures of efficacy
-To evaluate the safety of JCAR017
-To characterize the pharmacokinetic (PK) profile of JCAR017
-To evaluate the Health-Related-Quality of Life (HRQoL) using preselected primary domains of interest in the EORTC QLQ-C30 (global health/QoL, physical functioning, cognitive functioning, fatigue, pain) and FACT-LymS (lymphoma specific symptoms)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject has FL (Grade 1, 2, or 3a) or MZL histologically confirmed within 6 months of screening, as assessed by local pathology.
2. Subject must have relapsed or refractory disease, as assessed by the investigator.
3. Subject must have measurable disease as follows:
a. For FL subjects (Cohorts 1, 2, and 3), PET-positive disease with at least one PET-positive lesion and at least one measurable nodal or extranodal lesion greater than 1.5 cm in the long axis (refer to protocol, Appendix G)
b. MZL subjects (Cohort 4) with PET non-avid disease should have at least one measurable nodal lesion greater than 2.0 cm in the long axis (PET-positive disease is not required for MZL) - refer to protocol, Appendix G
4. Subject must have received the following, depending on cohort assignment:
a. Cohort 1 (4L+ r/r FL): received at least 3 prior lines of systemic therapy. At least one of these lines must be a combination which included an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent. Prior HSCT is permitted as a prior line of therapy. A group of 4L+ double-refractory subjects will be enrolled in this cohort (refer to protocol section 4.2).
b. Cohort 2 (3L r/r FL): received 2 prior lines of systemic therapy. At least one of these lines must be a combination which included an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent. Prior HSCT is permitted as a prior line of therapy.
c. Cohort 3 (2L r/r FL): received 1 prior line of combination systemic therapy, which included an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent. A group of POD24 subjects, defined as having progressive disease within 24 months of diagnosis and have received treatment within 6 months of the original FL diagnosis, will be enrolled to this cohort. The 2L subjects that do not meet this POD24 definition must instead meet one of the modified GELF criteria (NCCN, 2019) as outlined in protocol section 4.2, number 5.
d.Cohort 4 (3L+ r/r MZL): received at least 2 prior systemic therapies, including at least one line of combination systemic therapy, therapy with an anti-CD20 antibody (eg, rituximab, obinutuzumab) and an alkylating agent, or relapsed after HSCT. Splenectomy for Splenic MZL (SMZL) is considered as a line of therapy. Antibiotics for extranodal MZL (ENMZL) are not considered as a prior line of therapy.
5. Cohort 3 (2L r/r FL) subjects must meet at least one criterion of the modified GELF criteria listed below (a-d) (NCCN, 2019) if they do not meet criteria of POD24 (having progression of disease within 24 months from diagnosis and must have received treatment for FL within 6 months of diagnosis):
a. Symptoms attributable to FL (not limited to B symptoms)
b. Threatened end-organ function; OR cytopenia secondary to lymphoma; OR bulky
disease (single mass > 7 cm or 3 or more masses > 3 cm)
c. Splenomegaly
d. Steady progression over at least 6 months
6. Subject is ≥ 18 years of age the time of signing the informed consent form (ICF).
7. Subjects who have received previous CD19-targeted therapy must have CD19-positive lymphoma confirmed on a biopsy since completing the prior CD19-targeted therapy
8. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
9. Subject has adequate organ function.
10. Subject has adequate vascular access for leukapheresis procedure.
11. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals for at least 1 year following lymphodepleting chemotherapy.
12. Females of childbearing potential (FCBP) subjects must:
a. Have 2 negative pregnancy tests as verified by the Investigator (one negative serum beta-human chorionic gonadotropin [ß-hCG] pregnancy test result at screening, and within 7 days prior to the first dose of lymphodepleting chemotherapy).
b. Either commit to true abstinence from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, effective contraception without interruption.
c. Agree to abstain from breastfeeding during study participation and for at least 12 months following lymphodepleting chemotherapy.
13 Male subjects must:
a. Practice true abstinence (which must be reviewed on a monthly basis) or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential for 12 months after lymphodepleting chemotherapy even if he has undergone a successful vasectomy.
Refer to protocol section 4.2 for list of inclusion criteria |
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E.4 | Principal exclusion criteria |
1. Evidence or history of composite DLBCL and FL, or of transformed FL. Subjects with World Health Organization (WHO) sub-classification of duodenal-type FL
2. Any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study based on investigator’s judgement.
3. Any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study based on investigator’s judgement.
4. Any condition that confounds the ability to interpret data from the study based on investigator’s judgement.
5. Central nervous system (CNS)-only involvement by malignancy (note: subjects with secondary CNS involvement are allowed on study).
6. History of another primary malignancy that has not been in remission for at least 2 years For specific exceptions, see protocol section 4.3
7. Previous treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis.
8. Prior CAR T-cell or other genetically-modified cell therapy.
9. History of or active human immunodeficiency virus (HIV).
10. Active hepatitis B or active hepatitis C.
11. Uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.
12. Active autoimmune disease requiring immunosuppressive therapy.
13. Presence of acute or chronic graft-versus-host disease (GVHD).
14. History of specific cardiovascular conditions within the past 6 months prior to signing the ICF (see protocol section 4.3).
15. History or presence of clinically relevant central nervous system (CNS) pathology not related to disease under study. (see protocol section 4.3)
16. Subject is a pregnant or nursing (lactating) woman.
17. Subject has an intolerance to dimethyl sulfoxide (DMSO) and/or dextran
18. Progressive vascular tumor invasion, thrombosis, or embolism
19. Venous thrombosis or embolism not managed on a stable regimen of anticoagulation
20. Subject has received or undergone the following (See section 4.3 for additional details).
a. Therapeutic doses of corticosteroids (defined as >20 mg/day prednisone or equivalent) within 7 days prior to unstimulated leukapheresis.
b. Cytotoxic chemotherapeutic agents that are not considered lymphotoxic and intrathecal chemotherapy must be stopped > 7 days prior to unstimulated leukapheresis
c. Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide > 300 mg/m2, ifosfamide, bendamustine) 2 weeks prior to unstimulated leukapheresis.
d. Experimental agents within 4 weeks prior to signing the ICF unless no response or PD is documented on the experimental therapy
e. Ibrutinib, lenalidomide and PI3Ki within 3 half-lives prior to unstimulated leukapheresis
f. Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017 infusion
g. Donor lymphocyte infusion (DLI) within 6 weeks prior to JCAR017 infusion
h. Radiation within 6 weeks of leukapheresis.
i. Systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to JCAR017 infusion.
j. Allo-HSCT within 90 days of leukapheresis.
Refer to protocol section 4.3 for list of inclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate (ORR) as assessed by PET-CT (FL) or CT (MZL) using “The Lugano Classification”.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
-Complete response rate (CRR) as assessed by PET-CT (FL) or CT (MZL) using “The Lugano Classification”.
-Duration of Response (DOR) if Best Overall Response (BOR) is CR, as assessed by PET-CT and/or CT using “The Lugano Classification”.
-Duration of Response (DOR) as assessed by PET-CT and/or CT using “The Lugano Classification”.
-Progression Free Survival (PFS) as assessed by PET-CT and/or CT using “The Lugano Classification”.
-Overall Survival (OS)
-Safety
-Pharmacokinetics (PK)
-Health-related quality of life (HRQoL)
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 60months for all secondary endpoints EXCEPT HRQoL - which is up to 24 months. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Potential predictive biomarkers |
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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.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 14 |
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 |
Canada |
Japan |
United States |
Austria |
France |
Germany |
Italy |
Spain |
Sweden |
United Kingdom |
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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 Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, the date when the last subject enters the LTFU study, or the date of receipt of the last data point from the last subject that is required for primary, secondary, and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 6 |