E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Transplant-eligible relapsed or refractory (R/R) aggressive B-cell Non Hodgkin Lymphoma (B-NHL) |
|
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 |
|
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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10029593 |
E.1.2 | Term | Non-Hodgkin's lymphoma NOS |
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 | 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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to compare the efficacy in subjects treated with JCAR017 versus subjects treated according to standard of care (SOC) defined as event-free survival (EFS). |
|
E.2.2 | Secondary objectives of the trial |
The key secondary objectives are to compare the efficacy in subjects treated with JCAR017 versus subjects treated according to SOC defined as complete response rate (CRR), progression-free survival (PFS) and overall survival (OS).
- To compare other parameters of efficacy, defined as duration of response (DOR), overall response rate (ORR), PFS on next line of treatment (PFS-2)
- To compare efficacy rates (EFS, PFS, OS) at 6, 12 and 24 and 36 months after randomization
- To compare the safety defined as type and frequency of adverse events (AEs), serious adverse events (SAEs), and laboratory abnormalities
- To compare the safety and efficacy in clinical, histological and molecular subgroups
- To compare health-related quality of life (HRQoL)
- To compare hospital resource utilization (HRU)
- To describe the rate of completion of high dose chemotherapy (HDCT) and hematopoietic stem cell transplant (HSCT)
- To assess the response 3 months after-HSCT |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years and ≤ 75 years of age at the time of signing the ICF. 2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted. 3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements. 4. ECOG performance status ≤ 1. 5. Histologically proven DLBCL NOS (de novo or transformed FL), high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (double/triple-hit lymphoma [DHL/THL]) , primary mediastinal (thymic) large B-cell lymphoma (PMBCL), T cell/histiocyte-rich large B-cell lymphoma (THRBCL), or follicular lymphoma grade 3B. Enough tumor material must be available for confirmation by central pathology. If archival sample is before most recent relapse or no or insufficient archival sample is available, a new tumor biopsy is mandated to confirm diagnosis. Note: Subjects with secondary CNS involvement are eligible. Subject selection must consider clinical risk factors for severe AEs and alternative treatment options. Subjects should only be enrolled if the Investigator assesses that the potential benefit outweighs the risk for the subject.6. Refractory (SD, PD, PR or CR with relapse before 3 months) or relapsed (CR with relapse on or after 3 months) within 12 months from CD20 antibody and anthracycline containing firstline therapy. Note: The time of relapse is calculated from the date of the first disease assessment confirming a CR obtained with firstline treatment for disease under study, to the date of first assessment demonstrating a relapse. 7. [18F] FDG PET positive lesion per Lugano criteria at screening. 8. Adequate organ function, defined as: Adequate bone marrow function as assessed by the Investigator; Serum creatinine < 1.5 x age-adjusted ULN or creatinine clearance > 45 mL/min (eGFR by Cockcroft Gault; see Appendix D for calculation); ALT ≤ 5 x ULN and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert's syndrome orlymphomatous infiltration of the liver); Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to CTCAE and oxygen saturation (SaO2) ≥ 92% on room air and FEV1 ≥ 50%; Adequate cardiac function, defined as LVEF ≥ 40% as assessed by ECHO or MUGA performed within 4 weeks of randomization. 9. Adequate vascular access for leukapheresis. 10. Subjects must agree to not donate blood, organs, sperm or semen, and egg cells for usage in other individuals while receiving as well as within 12 months after the JCAR017 infusion and until CART cells are no longer present by qPCR on 2 consecutive tests, whichever occurs last. 11. Females of CBP must: Have a neg. pregnancy test as verified by the Investigator prior to starting study therapy. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact; 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. Contraception methods must include 1 highly effective and 1 additional effective (barrier) method of contraception from screening until at least 12 months after the JCAR017 infusion and until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever is later (Arm B) and until 12 months after the last chemotherapy (Arm A); Agree to abstain from breastfeeding during study participation and for at least 3 months after the last dose of JCAR017 or until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever is later. Note: Highly effective methods are defined as those that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. The following are examples of highly effective and additional effective methods of contraception: IUD, Hormonal (birth control pill, injections, implants), Tubal ligation, Partner's vasectomy, Male condom (additional effective method), Diaphragm (additional effective method), Cervical cap (additional effective method). 12. Male subjects must: 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 while participating in the study, during dose interruptions and for 12 months after the JCAR017 infusion even if he has undergone a successful vasectomy and until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever occurs last (Arm B) and for 12 months after the last chemotherapy (Arm A). * True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. |
|
E.4 | Principal exclusion criteria |
1. Subject has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from participating in the study.
2. Subject has any condition including the presence of laboratory abnormalities, which would place the subject at unacceptable risk if participating in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subjects not eligible for hematopoietic stem cell transplantation (HSCT).
5. Subjects planned to undergo allogeneic stem cell transplantation.
6. Subjects with primary cutaneous large B-cell lymphoma, EBV (Epstein-Barr virus) positive DLBCL of the elderly and Burkitt lymphoma
7. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been free of the disease for ≥ 2 years with the exception of the following noninvasive malignancies:
- Basal cell carcinoma of the skin
- Squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix
- Carcinoma in situ of the breast
- Incidental histologic finding of prostate cancer (T1a or T1b using the TNM [tumor, nodes, metastasis] clinical staging system) or prostate cancer that is curative.
- Other completely resected stage 1 solid tumor with low risk for recurrence
8. Treatment with any prior gene therapy product
9. Subjects who have received previous CD19-targeted therapy.
10. History of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
11. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment.
12. Active autoimmune disease requiring immunosuppressive therapy.
13. History of any one of the following cardiovascular conditions within the past 6 months prior to signing the ICF: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease.
14. History or presence of clinically relevant central nervous system (CNS) pathology such as epilepsy, seizure, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
15. Tumor invasion of venous or arterial vessels.
16. Deep venous thrombosis (DVT)/ Pulmonary embolism (PE) within 3
months prior to leukapheresis, and/or DVT/ PE that requires ongoing
therapeutic levels of anti-coagulation.
17. Pregnant or nursing (lactating) women.
18. Use of the following:
- Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to unstimulated leukapheresis. Physiologic replacement, topical, and inhaled steroids are permitted.
- Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below)and intrathecal (IT) chemotherapymust be stopped ≥ 7 days prior to unstimulated leukapheresis.
- Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide, ifosfamide, bendamustine) 2 weeks prior to unstimulated leukapheresis.
- Experimental agents within 4 weeks prior to signing the ICF unless no response or progressive disease (PD) is documented on the experimental therapy and at least 3 half-lives have elapsed prior to unstimulated leukapheresis.
- Immunosuppressive therapies within 4 weeks prior to unstimulated leukapheresis (eg, calcineurin inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin, thalidomide, immunosuppressive antibodies such as anti-tumor necrosis factor [TNF], anti-IL-6, or anti-IL-6R).
- Radiation within 4 weeks prior to signing the ICF. Subjects must have progressive disease in irradiated lesions or have additional non-irradiated, PET-positive lesions to be eligible. Radiation to a single lesion, if additional non-irradiated, measurable PETpositive lesions are present, is allowed up to 2 weeks prior to unstimulated leukapheresis.
- Systemic immunostimulatory agents (including but not limited to
interferon and IL-2) within 6 weeks or 5 half-lives of the drug,
whichever is shorter, prior to JCAR017 infusion. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Event-free survival (EFS):
Time from randomization to death from any cause, progressive disease (PD), failure to achieve complete response (CR) or partial response (PR) by 9 weeks post-randomization, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 3 years post-randomization |
|
E.5.2 | Secondary end point(s) |
1. Complete response rate (CRR):
Percentage of subjects achieving a complete response (CR) according to the Lugano Classification (Cheson, 2014) assessed by the IRC.
2. Progression-free survival (PFS):
Time from randomization to PD, or death from any cause, whichever occurs first.
3. Overall survival (OS):
Time from randomization to time of death due to any cause.
Secondary Efficacy:
1. Overall response rate (ORR):
Percentage of subjects achieving an objective response of partial response (PR) or better.
2. Duration of response (DOR):
Time from first response to disease progression, start of new antineoplastic therapy due to efficacy concerns or death from any cause.
3. PFS-2:
Time from randomization to second objective disease progression or death from any cause, whichever is first.
4. EFS rate
Percentage of subjects free of any PFS event at fixed timepoints
5. PFS rate
Percentage of subjects free of any PFS event at fixed timepoints
6. OS rate
Percentage of subjects alive at fixed timepoints
See protocol for additional study endpoints |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key Secondary Efficacy:
1 and 2 - Up to 3 years post-randomization
3 - Up to last subject last visit
Secondary Efficacy:
1, 2, 3 - Up to 3 years post-randomization
4, 5, 6 - At 6, 12 and 24 and 36 months post-randomization |
|
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 | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
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 | Yes |
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 | Yes |
E.8.2.3.1 | Comparator description |
Immunochemotherapy followed by HDCT and HSCT |
|
E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 16 |
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 |
France |
Germany |
Italy |
Japan |
Netherlands |
Spain |
Sweden |
Switzerland |
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 End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or 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 pre-specified in the protocol, whichever is the later date. |
|
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 | 1 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |