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 | 100000012975 |
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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 | 100000012975 |
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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 not part of the program team.
2. For relapsed patients, CD19 tumor expression demonstrated in bone marrow or peripheral blood by flow cytometry within 3 months of program entry.
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. Signed written informed consent and assent forms if applicable must be obtained prior to
any program procedures.
9. Must meet the institutional criteria to undergo leukapheresis or have an acceptable, stored
leukapheresis product.
10. 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: such as patients with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Patients with Down Syndrome will not be excluded.
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. Has had treatment with any prior anti-CD19/anti-CD3 therapy, or any other anti-CD19 therapy.
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. Patient has an investigational medicinal product within the last 30 days prior to screening.
12. Pregnant or nursing (lactating) women. NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 48 hours before infusion.
13. Women of child-bearing potential (defined as all women physiologically capable of becoming pregnant) and all male participants, unless they are using highly effective methods of contraception for a period of 1 year after the CTL019 infusion. Highly effective contraception methods include:
a. Total abstinence (when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are NOT acceptable methods of contraception.
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. 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 hormone vaginal ring or transdermal hormone contraception.
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.
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.
Women who are not of reproductive potential (defined as either <11 years of age, Tanner Stage 1, post-menopausal for at least 24 consecutive months or have undergone hysterectomy, salpingotomy, and/or bilateral oophorectomy) are eligible without requiring the use of contraception. Women who are not yet of reproductive potential are to agree to use acceptable forms of contraception when they reach reproductive potential if within 1 year of CTL019 or if CAR cells are present in the blood by polymerase chain reaction (PCR). Acceptable documentation includes written or oral documentation communicated by clinician or clinician’s staff of one of the following:
- Demographics show age <11,
- Physical examination indicates Tanner Stage 1,
- Physician report/letter,
- Operative report or other source documentation in the patient record,
- Discharge summary,
- Follicle stimulating hormone measurement elevated into the menopausal range.
14. The following medications are excluded (more details are provided in the protocol):
a. Steroids,
b. Allogeneic cellular therapy,
c. GVHD therapies,
d. Chemotherapy,
e. CNS disease prophylaxis,
f. Radiotherapy,
g. Anti T-cell antibodies.
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) | 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.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
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. |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
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 |