E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult patients ≥ 18 years with relapsed or refractory DLBCL, having failed 2 or more lines of therapy and not eligible for HSCT |
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E.1.1.1 | Medical condition in easily understood language |
Lymphoma is a cancer of lymphocytes, a type of white blood cell. The study enrols adult patients with recurrence of a subtype of a lymphoma termed 'diffuse large B cell lymphoma'. |
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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 | HLT |
E.1.2 | Classification code | 10012819 |
E.1.2 | Term | Diffuse large B-cell lymphomas |
E.1.2 | System Organ Class | 100000004851 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10012818 |
E.1.2 | Term | Diffuse large 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 |
- Evaluate the efficacy of CTL019 therapy |
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E.2.2 | Secondary objectives of the trial |
- Evaluate safety of CTL019
- Evaluate time to response
- Evaluate duration of overall response (DOR)
- Evaluate event free survival (EFS)
- Evaluate progression free survival (PFS)
- Evaluate overall survival (OS)
- Evaluate efficacy and safety in histological and molecular subgroups
- Characterize the in vivo cellular PK profile
- Describe the prevalence and incidence of immunogenicity to CTL019
- Describe presence of RCL |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Written informed consent must be obtained prior to any screening procedures
2) Histologically confirmed DLBCL at last relapse (by central pathology review before enrolment).
3) Relapsed or refractory disease after ≥2 lines of chemotherapy, including rituximab and anthracycline, and either having failed autologous HSCT, or being ineligible for or not consenting to autologous HSCT
4) Measurable disease at time of enrollment
5) Life expectancy ≥12 weeks
6) ECOG performance status that is either 0 or 1 at screening
7) Adequate organ function:
- Renal function defined as: A serum creatinine of ≤1.5 x ULN OR eGFR ≥ 60 mL/min/1.73 m2
- Liver function defined as:
• ALT ≤ 5 times the ULN for age
• Bilirubin ≤ 2.0 mg/dl with the exception of patients with Gilbert–Meulengracht syndrome; patients with Gilbert-Meulengracht syndrome may be included if their total bilirubin is ≤ 3.0 x ULN and direct bilirubin ≤ 1.5 x ULN . Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air . Hemodynamically stable and LVEF ≥ 45% confirmed by echocardiogram or MUGA .
- Adequate bone marrow reserve without transfusions defined as:
• Absolute neutrophil count (ANC) > 1.000/mm3
• Absolute lymphocyte count (ALC) ≥ 300/mm3
• Platelets ≥ 50.000//mm3
• Hemoglobin > 8.0 g/dl .
8) Must have an apheresis product of non-mobilized cells accepted for manufacturing .
9) Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants must agree to use highly effective methods of contraception for at least 12 months following CTL019 infusion and until CAR T cells are no longer present by PCR on two consecutive tests |
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E.4 | Principal exclusion criteria |
1) Prior treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy
2) Treatment with any prior gene therapy product
3) Active CNS involvement by malignancy
4) Prior allogeneic HSCT
5 )Eligible for and consenting to autologous HSCT
6) Chemotherapy other than lymphodepleting chemotherapy within 2 weeks of infusion
7) Investigational medicinal product within the last 30 days prior to screening
Note: Investigational therapies must not be used at any time while on study until the first progression following CTL019 infusion
8) The following medications are excluded:
• Steroids: Therapeutic doses of steroids must be stopped > 72 hours prior to leukapheresis and > 72 hours prior to CTL019 infusion. However, the following physiological replacement doses of steroids are allowed: <6 – 12 mg/m2/day hydrocortisone or equivalent
• Immunosuppression: Any immunosuppressive medication must be stopped ≥ 2 weeks prior to leukapheresis and ≥ 2 weeks prior to CTL019 infusion. This could include check point inhibitors (monoclonal antibodies and small molecule modulators).
• Antiproliferative therapies other than lymphodepleting chemotherapy within two weeks of leukapheresis and 2 weeks prior to infusion
- Short acting drugs used to treat leukemia or lymphoma (e.g.
tyrosine kinase inhibitors, and hydroxyurea) must be stopped > 72 hour prior to leukapheresis and > 72 hours prior to CTL019 infusion
- Other cytotoxic drugs, including low dose daily or weekly
maintenance chemotherapy, must not be given within 2 weeks prior to leukapheresis and within 2 weeks prior to CTL019 infusion.
- Fludarabine may be associated with prolonged lymphopenia. This
should be taken into consideration when evaluating the optimal timing for leukapheresis
• Antibody use including anti-CD20 therapy within 4 weeks prior to infusion or 5 half-lives of the respective antibody, whichever is longer
• CNS disease prophylaxis must be stopped > 1 week prior to CTL019 infusion (e.g. intrathecal methotrexate)
9) Prior radiation therapy within 2 weeks of infusion
10) Active replication of or prior infection with latent hepatitis B or active hepatitis C (HCV RNA positive)
11) HIV positive patients
12) Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to infusion)
13) Unstable angina and/or myocardial infarction within 6 months prior to screening
14) Previous or concurrent malignancy with the following exceptions:
• Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry)
• In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study
• A primary malignancy which has been completely resected and in complete remission for ≥ 5 year
15) Pregnant or nursing (lactating) women
16) Intolerance to the excipients of the CTL019 cell product
17) Cardiac arrhythmia not controlled with medical management
18) Patients on oral anticoagulation therapy
19) Prior treatment with any adoptive T cell therapy
20) Patients with active neurological auto immune or inflammatory disorders (e.g. Guillain-Barré Syndrome, Amyotrophic Lateral Sclerosis)
Other protocol-related inclusion/exclusion may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Overall Response Rate(ORR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
monitored throughout the duration of the study (5 years) |
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E.5.2 | Secondary end point(s) |
- Number of participants with adverse evensts (AEs)
- Number of participants with serious adverse evensts (SAEs)
- Time to response (TTR)
- Duration of overall response (DOR)
- Event free survival (EFS)
- Progression free survival (PFS)
- Overall survival (OS)
- ORR, PFS, OS, EFS, DOR and AEs in histological and molecular subtypes
- Characterize the in vivo cellular PK profile (levels, persistence, trafficking) of CTL019 transduced cells into target tissues (blood, bone marrow, cerebral spinal fluid (CSF) and other tissues if available)
- Prevalence and Incidence of immunogenicity to CTL019
- RCL by VSV-g q-PCR |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
monitored throughout the duration of the study (5 years) |
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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 | 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.8.2.4 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Canada |
Japan |
United States |
Austria |
France |
Germany |
Italy |
Netherlands |
Norway |
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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
|
The end of study is defined as the last patients last visit (LPLV) which is the last patient’s Month 60 evaluation or the time of premature withdrawal. |
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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 | 6 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |