E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Paediatric/young adult patients with B-cell acute lymphoblastic leukaemia who are chemo-refractory, relapsed after allogeneic SCT, or are otherwise ineligible for allogeneic SCT. |
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E.1.1.1 | Medical condition in easily understood language |
Paediatric/young adult patients with a recurrent form of B-cell acute lymphoblastic leukaemia. |
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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 | LLT |
E.1.2 | Classification code | 10063625 |
E.1.2 | Term | Acute lymphoblastic leukemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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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 | 10063621 |
E.1.2 | Term | Acute lymphoblastic leukaemia recurrent |
E.1.2 | System Organ Class | 100000004864 |
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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 |
This expanded treatment protocol (ETP) will provide pediatric/young adult patients with relapsed or refractory B-cell ALL the opportunity to be treated with CTL019 after the closure of the Novartis single-arm phase II clinical trial (Study CCTL019B2202) and to collect additional safety information. |
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E.2.2 | Secondary objectives of the trial |
- Evaluate the efficacy of CTL019 therapy as measured by complete remission rate, which includes CR and CR with incomplete blood count recovery (CRi).
- Evaluate the percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment.
- Evaluate the percentage of patients who achieve CR or CRi and then proceed to SCT while in remission before Month 6 response assessment.
- Evaluate the duration of remission.
- Evaluate the relapse-free survival.
- Evaluate the event-free survival.
- Evaluate the overall survival.
- Evaluate the response at Day 28 +/- 4 days.
- Evaluate the impact of baseline tumor burden on response.
- Evaluate the quality of response using minimal residue disease assessments.
- Describe the prevalence and incidence of immunogenicity to CTL019.
- Characterize the in vivo cellular kinetic profile of CTL019 cells in the blood.
- Evaluate the relationship between exposure to CTL019 with CRS grades.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this program have to meet all of the following criteria:
1. Relapsed or refractory B-cell ALL in pediatric or young adult patients:
a. Second or greater bone marrow relapse, OR
b. Any bone marrow relapse after allogeneic SCT and must be ≥ 6 months from SCT at the time of CTL019 infusion, OR
c. Primary refractory as defined by not achieving a CR after 2 cycles of a standard chemotherapy regimen or chemorefractory as defined by not achieving a CR after 1 cycle of standard chemotherapy for relapsed leukemia, OR
d. Patients with Philadelphia chromosome positive (Ph+) ALL are eligible if they are intolerant to or have failed 2 lines of tyrosine kinase inhibitor (TKI) therapy, or if TKI therapy is contraindicated, OR
e. Ineligible for allogeneic SCT because of:
- Comorbid disease,
- Other contraindications to allogeneic SCT conditioning regimen,
- Lack of suitable donor,
- Prior SCT,
- Declines allogeneic SCT as a therapeutic option after documented discussion about the role of SCT with a bone marrow transplantation physician who is not a member of the CTL019 study team.
2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of study entry. For relapsed or refractory patients previously treated with blinatumomab, CD19 tumor expression must be demonstrated (via flow cytometry) at Screening.
3. Adequate organ function defined as:
a. Renal function defined as: A serum creatinine based on age/gender as follows: Maximum Serum Creatinine (mg/dL) - Age/Male/Female: 1 to < 2 years/0.6/0.6; 2 to < 6 years/0.8/0.8; 6 to < 10 years/1.0/1.0; 10 to < 13 years/1.2/1.2; 13 to < 16 years/1.5/ 1.4; ≥ 16 years/1.7/1.4.
b. Alanine Aminotransferase (ALT) ≤ 5 times the upper limit of normal (ULN) for age.
c. Bilirubin < 2.0 mg/dL.
d. Must have a minimum level of pulmonary reserve defined as ≤ Grade 1 dyspnea and pulse oxygenation > 91% on room air.
e. Left Ventricular Shortening Fraction (LVSF) ≥ 28% confirmed by echocardiogram (ECHO), or Left Ventricular Ejection Fraction (LVEF) ≥ 45% confirmed by echocardiogram or Multiple Uptake Gated Acquisition (MUGA) within 7 days of screening.
4. Bone marrow with ≥ 5% lymphoblasts by morphologic assessment at screening.
5. Life expectancy > 12 weeks.
6. Age 3 years at the time of screening to age 21 years at the time of initial diagnosis.
7. Karnofsky (age ≥ 16 years) or Lansky (age < 16 years) performance status ≥ 50 at screening.
8. Patients previously treated with blinatumomab who have detectable leukemia and documented CD19+ expression (via flow cytometry) and confirmed absence of CD19- leukemic blasts at Screening may be included. In this case, at least 1-week washout period must be applied from last dose of blinatumomab to start of leukapheresis. Patients previously treated with blinatumomab with no detectable MRD (i.e. MRD negative demonstrated by leukemic blasts < 0.01%) will be excluded.
Note: blinatumomab must not be administered as a bridging therapy prior to CTL019 infusion while the patient is awaiting manufacture of CTL019
9. Signed written informed consent and assent forms if applicable must be obtained prior to any study procedures.
10. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored leukapheresis product.
11. Once all other eligibility criteria are confirmed, must have a leukapheresis product of nonmobilized cells received and accepted by the manufacturing site. Note: Leukapheresis product will not be shipped to or assessed for acceptance by the manufacturing site until documented confirmation of all other eligibility criteria is received.
Other protocol-defined inclusion criteria may apply. |
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E.4 | Principal exclusion criteria |
Exclusion Criteria:
1. Isolated extra-medullary disease relapse.
2. Patients with concomitant genetic syndrome
3. Patients with Burkitt's lymphoma/leukemia (i.e. patients with mature B-cell ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation).
4. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease.
5. Treatment with any prior gene therapy product.
6. Prior treatment with any anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy, except for patients pre-treated with blinatumomab who fulfill inclusion criterion no. 8.
7. Active or latent hepatitis B or active hepatitis C (test within 8 weeks of screening), or any uncontrolled infection at screening.
8. Human Immunodeficiency Virus (HIV) positive test within 8 weeks of screening.
9. Presence of grade 2 to 4 acute or extensive chronic graft-versus-host disease.
10. Active CNS involvement by malignancy, defined as CNS-3 per NCCN guidelines. Note: Patients with history of CNS disease that has been effectively treated will be eligible.
11. Uncontrolled acute life threatening bacterial, viral or fungal infection at Screening.
12. Previous or concurrent malignancy with the following exceptions:
a. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to study entry).
b. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to the study.
c. A primary malignancy which has been completely resected and in CR for ≥ 5 years.
13. Intolerance to the excipients of the CTL019 cell product (i.e. dimethyl sulfoxide).
14. Cardiac arrhythmia not controlled with medical management.
15. Patients enrolled in this study are not permitted to participate in additional parallel investigational drug or device studies.
16. Patient has an investigational medicinal product within the last 30 days prior to screening.
17. Pregnant or nursing (lactating) women.
18. The following medications are excluded:
a. Steroids;
b. Allogeneic cellular therapy;
c. GVHD therapies;
d. Chemotherapy;
e. CNS disease prophylaxis;
f. Radiotherapy;
g. Anti-T cell antibodies
19. Women of child-bearing potential and all male participants, unless they are using effective methods of contraception for a period of 1 year after the CTL019 infusion.
- Sexually active women must continue to use contraception for greater than 12 months after the CTL019 infusion and until CAR T cells are no longer present by quantitative PCR (q-PCR) on 2 consecutive tests.
- Sexually active males must use a condom during intercourse for 12 months after CTL019 infusion and until CAR T cells are no longer present by q-PCR on 2 consecutive tests, as they should not father a child in this period. A condom is required to be used also by vasectomized men (as well as during intercourse with a male partner) as white blood cells (WBCs) are a normal part of semen and transmission of CTL019 transduced cells may occur.
Effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient.
b. Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
c. Male sterilization (at least 6 months prior to screening). For female patients on the study the vasectomized male partner should be the sole partner for that patient.
d. BOTH of the following forms of contraception must be utilized:
- Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormonal vaginal ring or transdermal hormone contraception.
- Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/fil/cream/vaginal suppository.
e. Use of IUDs are excluded due to increased risks of infection and bleeding in this population. However, IUD inserted prior to consent may remain in place, and a second method of contraception is mandated.
Additionally, drugs that induce cytochrome P450 (CYP) enzymes can increase the clearance of sex hormones that are eluted by the IUD and reduce contraceptive efficacy, given the poly-pharmacy for these patients this presents a real risk of IUD failure and resultant conception.
f. In case of use of oral contraception, women must be stable on the same pill for a minimum of 3 months before taking study treatment.
Other protocol-defined exclusion criteria may apply. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Evaluate the safety of CTL019 therapy. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The endpoint is assessed throughout the 12 months study duration. |
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E.5.2 | Secondary end point(s) |
- Percentage of patients who achieve complete remission or complete remission with incomplete blood count recovery (i.e. CR or CRi) during the 6 months after CTL019 infusion.
- Percentage of patients who achieve CR or CRi at Month 6 without SCT between CTL019 infusion and Month 6 response assessment.
- Percentage of patients who achieve CR or CRi and then proceed to SCT while in remission prior to Month 6 response assessment.
- Duration of remission.
- Relapse-free survival.
- Event-free survival.
- Overall survival.
- Response at Day 28 +/- 4 days.
- Impact of baseline tumor burden on response.
- Quality of response using MRD assessments.
- Safety: type, frequency and severity of adverse events, laboratory abnormalities, vital signs, ECGs, pulse oximetry, echocardiogram and B-cell levels.
- Describe the prevalence and incidence of immunogenicity to CTL019.
- Characterize the in vivo cellular kinetic profile (levels, persistence, trafficking) of CTL019 cells in the blood.
- Evaluate the relationship between exposure to CTL019 with CRS grades.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The endpoints are assessed throughout the 12 months study duration. |
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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 | No |
E.6.7 | Pharmacodynamic | No |
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) | 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 | 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.8.3 |
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 | 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 |
Austria |
Belgium |
Canada |
France |
Germany |
Italy |
Japan |
Norway |
Spain |
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E.8.7 | Trial has a data monitoring committee | No |
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 study is defined as the last patient's last visit (LPLV) which is the last patient's Month 12 evaluation or the time of premature withdrawal. The EOS is anticipated to occur around Quarter 3, 2020.
Semiannual & annual evaluations will be performed for up to 15 years on all patients under a separate LTFU protocol (i.e. CCTL019A2205B). All patients who either complete this study or prematurely discontinue from this study will be enrolled in the LTFU protocol. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | |
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 | 3 |