| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| 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 determine the efficacy, defined as overall response rate (ORR), of JCAR017 in subjects with aggressive B-cell non-Hodgkin lymphoma. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and feasibility of administering JCAR017
- To evaluate ORR of JCAR017 in underlying chronic lymphocytic leukemia (CLL) in subjects with Richter’s transformation (Cohort 6)
- To evaluate other measures of efficacy of JCAR017 ( e.g., complete response rate [CRR], event-free survival [EFS], progression-free survival [PFS], overall survival [OS], duration of response [DOR])
- To characterize the pharmacokinetic (PK) profile of JCAR017 in the peripheral blood measured using qPCR detection for the JCAR017 vector sequence
- Describe changes in health-related quality of life using the European Organisation for Research and Treatment of Cancer – Quality of Life C30 questionnaire (EORTC QLQ-C30), the European Quality of Life-5 Dimensions health state classifier to 5 Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) "Additional concerns" scale |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject is ≥ 18 years of age at the time of signing the informed consent form (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. Investigator considers the subject is appropriate for adoptive T cell therapy.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (Cohort 1, 4, 5 or 6). Subjects not eligible for transplant (TNE) with ECOG performance status 0, 1 or 2 may be enrolled in Cohort 2 or 3 only, if they meet all other inclusion/exclusion criteria.
6. Subjects with one of the following:
• Cohort 1: Subjects with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B per WHO 2016 classification (Swerdlow, 2016), after ≥ 2 lines of therapy*, including an anthracycline and rituximab (or other CD20-targeted agent).
• Cohort 2: Transplant not eligible subjects with DLBCL NOS (de novo or tFL), high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B per WHO 2016 classification (Swerdlow, 2016), who failed first line therapy including an anthracycline and rituximab (or other CD-20-targeted agent).
- Transplant not eligible subjects will include those who are deemed ineligible for high-dose chemotherapy and HSCT due to age, performance status or comorbidity. At the very least, subjects have to meet one of the following criteria:
age ≥ 70 years, ECOG performance status ≥ 2, impaired pulmonary function (DLCO ≤ 60%), impaired cardiac function (LVEF < 50%), impaired renal function (CrCl < 60 mL/min) or impaired hepatic function (AST/ALT > 2x ULN, bilirubin > 2 mg/dL or cirrhosis Child-Pugh B or C).
- Subjects must fulfil all other in- and exclusion criteria
• Cohort 3: (Japan only): Subjects meeting eligibility criteria for either Cohort 1 or 2.
• Cohort 4: Subjects with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) who failed first line therapy*. Subjects may be screened at time of initial diagnosis and leukapheresis may be performed prior to initiation of first line therapy.
• Cohort 5: Subjects with PCNSL after ≥ 1 line of therapy, including high-dose methotrexate.
• Cohort 6: Subjects with Richter’s transformation after ≥ 1 line of therapy for Richter’s transformation.
* For subjects with transformed disease, the subject should have had at least 2 lines of systemic therapy for his/her transformed disease (ie, the DLBCL) for Cohort 1 and 1 line for Cohort 2 to be eligible. Lines of therapy do not include those given for a previously indolent condition (eg, follicular lymphoma). Subjects do NOT have to have anthracycline for their DLBCL if received for indolent disease.
Note: Subjects with secondary CNS lymphoma involvement may enroll in Cohorts 1 to 4 and 6; subjects with PCNSL are eligible for Cohort 5. Subject selection must consider clinical risk factors for severe adverse events (AEs) and alternative treatment options. Subjects should only be enrolled if the Investigator considers the potential benefit outweighs the risk for the subject.
7. Histological confirmation of diagnosis at last relapse. Enough tumor material must be available for central confirmation of diagnosis, otherwise a new tumor biopsy is mandated. NOTE: If the subject did not experience CR since last biopsy, the most recent biopsy will be considered adequate to participate in the trial. For subjects with PCNSL, at a minimum, corresponding pathology report is required if archival tumor material is not available and repeated biopsy not feasible.
8. For subjects with NHL and Richter’s transformed CLL: Subject must have positron emission tomography (PET)-positive disease as per Lugano Classification (Cheson, 2014).
9. For subjects with PCNSL: Subjects must have disease that is objectively measurable by International Workshop to Standardize Baseline Evaluation and Response Criteria in Primary Central Nervous System (CNS) Lymphoma (Abrey, 2005), cerebrospinal fluid (CSF) cytology (in case of leptomeningeal only disease), or vitreal aspiration cytology and/or retinal photographs (in case of ocular lymphoma if clinically indicated).
Please refer to protocol section 4.2 for other inclusion criteria |
|
| 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 with T cell rich/histiocyte rich large B-cell lymphoma (THRBCL), primary cutaneous large B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBCL), EBV positive DLBCL of the elderly and Burkitt lymphoma.
5. Subjects with prior history of malignancies, other than aggressive R/R NHL, unless the subject has been in remission for ≥ 2 years with the exception of the following non-invasive 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
6. Treatment with any prior gene therapy product.
7. Subjects who have received previous CD19-targeted therapy.
8. Previous history of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
9. Subjects with uncontrolled systemic fungal, bacterial, viral or other infection (including tuberculosis) despite appropriate antibiotics or other treatment at the time of leukapheresis or JCAR017 infusion.
10. Presence of acute or chronic graft-versus-host disease (GVHD).
11. Active autoimmune disease requiring immunosuppressive therapy.
12.History of any one of the following cardiovascular conditions within the past 6 months:
• Heart failure class III or IV as defined by the New York Heart Association (NYHA)
• Cardiac angioplasty or stenting
• Myocardial infarction
• Unstable angina
• Other clinically significant cardiac disease
13. History or presence of clinically relevant CNS pathology such as epilepsy, seizure, aphasia, stroke, cerebral edema, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.
14. Pregnant or nursing women.
15. Treatment with alemtuzumab within 6 months of leukapheresis, or treatment with fludarabine or cladribine within 3 months of leukapheresis
16. Use of the following (see Section 8.2 for full details):
• Therapeutic doses of corticosteroids (defined as > 20 mg/day prednisone or equivalent) within 7 days prior to leukapheresis or
72 hours prior to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are permitted.
• Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide ≤ 300 mg/m2) given after leukapheresis to maintain disease control must be stopped ≥ 7 days prior to LD chemotherapy.
• Cytotoxic chemotherapeutic agents that are not considered lymphotoxic (see below) within 1 week prior to leukapheresis. Oral anticancer agents, including lenalidomide and ibrutinib,are allowed if at least 3 half-lives have elapsed prior to leukapheresis.
• Lymphotoxic chemotherapeutic agents (eg, cyclophosphamide > 300 mg/m2, ifosfamide, bendamustine) within 2 weeks prior to leukapheresis.
• Experimental agents within 4 weeks prior to leukapheresis unless no response or progressive disease (PD) is documented on the experimental therapy and at least 3 half-lives have elapsed prior to leukapheresis.
• Immunosuppressive therapies within 4 weeks prior to leukapheresis and JCAR017 infusion (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).
• Donor lymphocyte infusions (DLI) within 6 weeks prior to JCAR017 infusion.
• Radiation within 6 weeks prior to leukapheresis. 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 PET-positive lesions are present, is allowed up to 2 weeks prior to leukapheresis.
• Allogenic HSCT within 90 days prior to leukapheresis.
• Prior hematopoietic stem cell transplant (only applicable to Cohort 2).
17. Tumor invasion of venous or arterial vessels
18. Deep venous thrombosis (DVT)/pulmonary embolism (PE) within 3 months of ICF siganture and/or DVT/PE that requires ongoing therapeutic levels of anti-coagulation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
- Non-Hodgkin lymphoma (NHL; including secondary central nervous system [CNS] involvement): Overall Response Rate (ORR)
Cohorts 1, 2, 3, 4 and 6
- Relapsed/refractory (r/r) primary central nervous system lymphoma (PCNSL): ORR
Cohort 5 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to 2 years after JCAR017 infusion |
|
| E.5.2 | Secondary end point(s) |
- Safety
- Underlying chronic lymphocytic leukemia (CLL) in subjects with Richter´s transformation: ORR Cohort 6
- Complete response rate (CRR)
- Event-free survival (EFS)
- Progression-free survival (PFS)
- Overall survival (OS)
- Duration of response (DOR)
- PK
- Patient-Reported Outcomes |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Up to 2 years after JCAR017 infusion
For overall survival (OS) - up to last subject last visit |
|
| 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 | 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| 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 | 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 |
| Austria |
| Belgium |
| Finland |
| France |
| Germany |
| Italy |
| Japan |
| Netherlands |
| Spain |
| Switzerland |
| United Kingdom |
|
| 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 completing the post-treatment follow-up of this study 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 18 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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