| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or refractory (r/r) CD19+ B-Cell Acute Lymphoblastic Leukemia (B-ALL) and 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 | 20.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| 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 | 10063625 |
| E.1.2 | Term | Acute lymphoblastic leukemia 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 |
Primary Objectives
Phase 1b:
The primary objective of the Phase 1b is to identify the recommended Phase 2 dose (RP2D) of JCAR017 in pediatric subjects with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL).
Phase 2:
The primary objective of Phase 2 is to evaluate the efficacy of JCAR017 in the following disease cohorts:
- Cohort 1 (r/r B-ALL): Overall response rate (ORR) defined as proportion of subjects with a complete response (CR) or complete response with incomplete blood count recovery (CRi) on Day 28 that must be confirmed on Day 56
- Cohort 2 (minimal residual disease [MRD]+ B-ALL): MRD- rate defined as proportion of subjects with a MRD- response on Day 28 that must be confirmed on Day 56
- Cohort 3 (r/r B-cell non-Hodgkin lymphoma [B-NHL] (diffuse large B-cell lymphoma [DLBCL], Burkitt lymphoma [BL] or primary mediastinal large B-cell lymphoma [PMBCL])): ORR defined as proportion of subjects with a CR or partial response (PR) on Day 28. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives for Phase 1b and Phase 2 are:
- Evaluate the feasibility of manufacturing JCAR017 measured by the percentage of product generated successfully (Phase 1b only)
- Evaluate ORR in the non-selected dose from Phase 1b
- Evaluate safety and tolerability assessments during 24 months after JCAR017 infusion
- To further evaluate efficacy by assessing the duration of response (DOR), relapse-free survival (RFS), event-free survival (EFS), and overall survival (OS) during 24 months after JCAR017 infusion
- Evaluate the percentage of r/r B-ALL subjects who achieve CR or CRi with no MRD detected in bone marrow (BM) (<0.01% by a validated assay) assessed during 24 months after JCAR017 infusion
- Assess the percentage of subjects who achieve a response after JCAR017 infusion and then proceed to hematopoietic stem cell transplant (HSCT)
- Characterize the pharmacokinetic (PK) profile of JCAR017 assessed during 24 months after JCAR017 infusion |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Phase 1b: Subject < 18 years of age and weighs ≥ 12 kg (for subjects receiving a dose of 0.5x10^6 JCAR017 CAR+ T cells/kg) or ≥ 6 kg (for subjects receiving a dose of 1x10^6 JCAR017 CAR+ T cells/kg) at the time of signing the informed consent form (ICF)/informed assent form (IAF).
Phase 2: Subject ≤ 25 years of age and weighs ≥ 12 kg (if RP2D is 0.5 x 10^6 JCAR017 CAR+ T cells/kg) or ≥ 6 kg (if RP2D is 1 x 10^6 JCAR017 CAR+ T cells/kg) at the time of signing the ICF/IAF.
2. Subject (when applicable, parental/legal representative) must understand and voluntarily provide permission to the ICF/IAF prior to conducting any study-related assessments/procedures.
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. Evidence of CD19 expression via flow cytometry (peripheral blood or bone marrow) or immunohistochemistry (bone marrow biopsy)
6. Subject has a Karnofsky score of ≥ 50 (subjects ≥ 16 years of age) or a Lansky score ≥ 50 (subjects < 16 years of age).
7. Phase 1b: Subjects with r/r B-ALL, defined as morphological evidence of disease in BM (5% or greater lymphoblast by morphology) and either of the following:
First or greater marrow relapse, or
Any marrow relapse after allogeneic HSCT, or
Primary refractory defined as not achieving a CR or a CRi after 2 or more separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1 cycle of standard chemotherapy for relapsed leukemia), or
Ineligible for allogeneic HSCT
Note: Subjects will be included regardless of MRD status.
Phase 2: Subjects with one of the following:
Cohort 1: r/r B-ALL, defined as morphological evidence of disease in BM (5% or greater lymphoblast by morphology) and either:
First or greater marrow relapse, or
Any marrow relapse after allogeneic HSCT, or
Primary refractory defined as not achieving a CR or a CRi after 2 or more separate induction regimens (or chemo-refractory as not achieving CR/CRi after 1 cycle of standard chemotherapy for relapsed leukemia), or
Ineligible for allogeneic HSCT.
Cohort 2: MRD+ B-ALL, defined as:
< 5% lymphoblasts by morphology
MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM cells after two lines of therapy.
Cohort 3: r/r B-NHL, defined as measurable disease after 1 or more lines of chemotherapy and/or having failed HSCT or being ineligible for HSCT.
8. Subjects with Philadelphia chromosome positive ALL are eligible if they are intolerant to or have failed one or more lines of tyrosine-kinase inhibitor (TKI) therapy or if TKI therapy is contraindicated.
9. Adequate organ function, defined as:
Adequate BM function to receive LD chemotherapy as assessed by the Investigator.
Subject with adequate renal function, which is defined as:
Creatinine clearance calculated using the Schwartz formula, (Schwartz, 1976) or radioisotope glomerular filtration rate (GFR) > 70 mL/min/1.73 m2.
Alanine aminotransferase (ALT) ≤ 5 x upper limit of normal (ULN) and total bilirubin < 2.0 mg/dL (or < 3.0 mg/dL for subjects with Gilbert’s syndrome or
lymphomatous infiltration of the liver).
Adequate pulmonary function, defined as ≤ Grade 1 dyspnea according to Common Toxicity Criteria for Adverse Events (CTCAE) and oxygen saturation (SaO2) ≥ 92% on room air.
Adequate cardiac function, defined as left ventricular ejection fraction (LVEF) ≥ 40% as assessed by echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 4 weeks prior to leukapheresis.
10. 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 while receiving as well as within 12 months after the JCAR017 infusion and until CAR T cells are no longer present by qPCR on 2 consecutive tests, whichever occurs last.
12. Female children of childbearing potential (FCCBP) and females of childbearing potential (FCBP) must:
Have two negative pregnancy tests as verified by the Investigator (one negative serum beta human chorionic gonadotropin [ß-hCG] pregnancy test result at screening and one negative serum pregnancy test within 48 hours prior to the first dose of LD chemotherapy). Subjects must agree to have another pregnancy test performed 90 days post JCAR017 infusion. This applies even if the subject practices true abstinence** from heterosexual contact.
** True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
See section 4.2 of the protocol for further 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 places the subject at unacceptable risk if he/she were to participate in the study.
3. Subject has any condition that confounds the ability to interpret data from the study.
4. Subject with a history of another primary malignancy that has not been in remission for at least 2 years prior to enrollment.
5. Subjects who have received previous CD19-targeted therapy must have CD19-positive disease confirmed since completing the prior CD19-targeted therapy.
6. Prior CAR T cell or other genetically-modified T cell therapy.
7. Subject with a previous history of or active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV) infection.
8. 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.
9. Subject has presence of acute or chronic graft-versus-host disease (GVHD).
10. Subject with active autoimmune disease requiring immunosuppressive therapy.
11. Subject has cardiac disorders (CTCAE version 4.03 Grade 3 or 4) within the past 6 months.
12. Subject with a concomitant genetic syndrome, with the exception of Down’s syndrome.
13. Subject with active CNS disease and significant neurological deterioration. Subjects with CNS-2 or CNS-3 involvement are eligible provided they are asymptomatic and do not have significant neurological deterioration and, in the opinion of the study investigator, the CNS disease burden can be controlled until JCAR017 infusion.
14. Subject with a history or presence of clinically relevant CNS pathology such as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease, cerebellar disease, organic brain syndrome, or psychosis.
15. Subject is pregnant or nursing.
16. Subject has used the following:
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, ifosfamide, bendamustine) within 2 weeks prior to leukapheresis.
Experimental agents within 4 weeks prior to leukapheresis unless no response or 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 antitumor 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 PD in irradiated lesions or have additional non-irradiated lesions to be eligible. Radiation to a single lesion, if additional non-irradiated, measurable lesions are present, is allowed up to 2
weeks prior to leukapheresis.
Allogeneic HSCT within 90 days prior to leukapheresis. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1b
Recommended Phase 2 dose (RP2D). Identify pharmacokinetic (PK), and number of subjects experiencing a dose-limiting toxicity (DLT).
Phase 2 - Cohort 1
(relapsed/refractory [r/r] B-cell acute lymphoblastic leukemia [B-ALL]): Overall response rate (ORR). Percentage of subjects achieving a confirmed complete response (CR) or complete response with incomplete blood count recovery (CRi)
Phase 2 - Cohort 2
(MRD+ BALL): Minimal residual disease (MRD) negative (MRD-) rate. Percentage of subjects achieving a confirmed MRD negative rate
Phase 2 - Cohort 3
(r/r B-cell non-Hodgkin lymphoma [BNHL]): Overall response rate (ORR). Percentage of subjects achieving CR or partial response (PR)
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1b
Up to 28 days after JCAR017 infusion
Phase 2 - Cohort 1
Day 28 and must be confirmed on Day 56
Phase 2 - Cohort 2
Day 28 and must be confirmed on Day 56
Phase 2 - Cohort 3
Day 28 |
|
| E.5.2 | Secondary end point(s) |
1. Safety - Type, frequency, and severity of adverse events (AEs), including serious adverse events (SAEs) and laboratory abnormalities
2. Feasibility of manufacturing JCAR017 (Phase 1b only) - Percentage of JCAR017 product generated successfully
3. Overall response rate (ORR) in the non-selected dose from Phase 1b - Percentage of subjects achieving a confirmed CR or CRi
4. Duration of response (DOR) - Time from first response until progressive disease (PD), disease relapse, or death from any cause, whichever occurs first
5. Relapse-free survival (RFS) - Time from first response to documentation of PD, disease relapse, or death due to any cause, whichever occurs first
6. Event-free survival (EFS) - Time from JCAR017 infusion to PD, disease relapse, start of a new anticancer therapy, or death from any cause, whichever occurs first
7. Overall survival (OS) - Time from JCAR017 infusion to time of death due to any cause
8. MRD response rate (non-selected RP2D cohort in Phase 1b and Cohort 1 in Phase 2 only) - Percentage of subjects achieving a CR or CRi and a negative MRD bone marrow
9. Rate of hematopoietic stem cell transplant (HSCT) after response to JCAR017 infusion - Percentage of subjects who achieve a response after JCAR017 infusion and then proceed to HSCT
10. Pharmacokinetics (PK) - Maximum concentration (Cmax), time to peak concentration (Tmax), area under the curve (AUC), including maximum expansion and duration of persistence of JCAR017 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timeframe for secondary endpoints:
1, 4, 5, 6, 7, 8, 9 and 10. During 2 years after JCAR017 infusion
2. During Part A (leukapheresis and JCAR017 generation)
3. On Day 28 and must be confirmed on Day 56 |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| dose confirmation for use in phase 2 |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| To identify the recommended Phase 2 dose (RP2D) of JCAR017 in pediatric subjects |
|
| 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 |
| Belgium |
| France |
| Germany |
| Italy |
| Spain |
| 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 completing the post-treatment period 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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