TISAGENLECLEUCEL for B-cell acute lymphoblastic leukemia|High-risk B-cell acute lymphoblastic leukemia

Inclusion criteria

• {"criterion_text":"- CD19 expressing (in peripheral blood or bone marrow by flow cytometry) B-cell Acute Lymphoblastic Leukemia"}
• {"criterion_text":"- De novo NCI HR B-ALL who received first-line treatment and are MRD ≥ 0.01% at EOC (HR defined by NCI criteria at the time of initial leukemia presentation as age ≥ 10 and/or WBC ≥ 50 x 109 cells/L). EOC bone marrow MRD will be collected prior to screening and will be assessed by multi-parameter flow cytometry using central laboratory analysis"}
• {"criterion_text":"- Age 1 to 25 years at the time of screening"}
• {"criterion_text":"- Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60% at screening"}
• {"criterion_text":"- Adequate organ function during the screening phase: •\tRenal function based on age/gender as follows: Age; 1 to < 2 years, Maximum Serum Creatinine =0.6(mg/dL) Age; 2 to < 6 years, Maximum Serum Creatinine =0.8(mg/dL) Age; 6 to < 10 years, Maximum Serum Creatinine =1.0(mg/dL) Age; 10 to < 13 years, Maximum Serum Creatinine =1.2(mg/dL) Age; 13 to < 16 years, Maximum Serum Creatinine =1.5(mg/dL) for male or 1.4(mg/dL) for female Age; ≥ 16 years, Maximum Serum Creatinine =1.7(mg/dL) for male or 1.4(mg/dL) for female •\tAdequate liver function defined as: •\tALT ≤ 5 times ULN for age •\tAST ≤ 5 times ULN for age •\tTotal bilirubin < 2 mg/dL (for Gilbert’s Syndrome subjects total bilirubin < 4 mg/dL) •\tAdequate pulmonary function defined as: •\tno or mild dyspnea (≤ Grade 1) •\toxygen saturation of > 90% on room air •\tAdequate cardiac function defined as LVSF ≥ 28% confirmed by echocardiogram or LVEF ≥ 45% confirmed by echocardiogram or MUGA during screening or within 6 weeks prior to screening"}
• {"criterion_text":"- Prior induction and consolidation chemotherapy allowed: •\t1st line subjects: ≤ 3 blocks of standard chemotherapy for first-line B-ALL, defined as 4-drug induction, Berlin-Frankfurt-Münster (BFM) consolidation or Phase 1b, and interim maintenance with high-dose methotrexate. Protocols that are allowed include the following: COG AALL0232 ([NCT00075725]), AALL1131 ([NCT02883049]) standard arm, COG AALL1732, European ALLTogether 1st line trial, Dana Farber Cancer Institute (DFCI) 16-001 (High Risk), Dutch Childhood Oncology Group (DCOG) ALL-11, European Organization for Research and Treatment of Cancer–Children’s Leukemia Group (EORTC-CLG) 58081 (variant 1), UKALL2011, or other comparable protocols if approved by Novartis (See Appendix 4 for approved regimens). •\tAdditional (augmented) chemotherapy such as clofarabine and ifosfamide added to induction/consolidation therapy prior to enrollment, leukapheresis, or infusion are not allowed •\tSubject should be enrolled (leukapheresis accepted by Novartis manufacturing) on study before the initiation of the third dose of high-dose methotrexate during interim maintenance therapy"}
• {"criterion_text":"- Signed written informed consent and assent forms, if applicable, must be obtained prior to any study procedures"}
• {"criterion_text":"- Must meet the institutional criteria to undergo leukapheresis"}
• {"criterion_text":"- Once all other eligibility criteria are confirmed, must have a leukapheresis product of non-mobilized 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 IRT confirmation of all other clinical eligibility criteria is received."}

Exclusion criteria

• {"criterion_text":"- M3 marrow (≥ 25% blasts by morphologic criteria) at the completion of first-line induction therapy"}
• {"criterion_text":"- Treatment with any prior gene or engineered T cell therapy"}
• {"criterion_text":"- Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)"}
• {"criterion_text":"- Presence of active hepatitis B or C (for detailed criteria see Appendix 3)"}
• {"criterion_text":"- Human Immunodeficiency Virus (HIV) positivity as indicated by serology"}
• {"criterion_text":"- Subject had an 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 relapse following tisagenlecleucel infusion"}
• {"criterion_text":"- If subjects are taking any of the following medications, their infusion (including a second infusion) must be delayed until the medications have been stopped according to the following: a.\tMedications to be stopped > 72 hours prior to tisagenlecleucel infusion: •\tTherapeutic systemic doses of steroids. However, the following physiological replacement doses of steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent b.\tMedications to be stopped at least 1 week prior to tisagenlecleucel infusion: •\t6-thioguanine, asparaginase (non-pegylated), vincristine, 6-mercaptopurine, and intrathecal methotrexate c.\tMedications to be stopped at least 2 weeks prior to tisagenlecleucel infusion: •\tAnthracyclines and cytarabine •\tIntravenous methotrexate. •\tRadiotherapy: Non-CNS site of radiation d.\tMedications to be stopped at least 4 weeks prior to tisagenlecleucel infusion: •\tPegylated-asparaginase e.\tMedications/Therapy to be stopped at least 8 weeks prior to tisagenlecleucel infusion: •\tRadiotherapy: Cranial radiation (for CNS 3 subjects) therapy"}
• {"criterion_text":"- Pregnant or nursing (lactating) women. NOTE: Women of child-bearing potential must have a negative serum pregnancy test performed within 24 hours before leukapheresis, lymphodepletion and prior to tisagenlecleucel infusion"}
• {"criterion_text":"- Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they agree to use highly effective methods of contraception from enrollment through at least 12 months after the tisagenlecleucel infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests. qPCR test results will be available upon request. Highly effective contraception methods include: •\tTotal abstinence (when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception •\tFemale sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six 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 •\tMale sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject •\tUse of oral, (estrogen and progesterone), injected or implanted hormonal methods of contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before enrollment into this study. Women are considered post-menopausal if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate history of vasomotor symptoms). Women are considered not of child-bearing potential if they are post-menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to enrolment on the study. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment, she is considered to be not of child-bearing potential. NOTE: If local regulations deviate from the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF."}
• {"criterion_text":"- Sexually active males must use a condom during intercourse while on the study, starting from interim maintenance during screening until at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. qPCR test results will be available upon request. A condom is required for all sexually active male participants to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner. In addition, male participants must not donate sperm as mentioned in Section 6.2.5. If local regulations are more stringent than the contraception methods listed above to prevent pregnancy, local regulations apply and will be described in the ICF."}
• {"criterion_text":"- M2 (i.e. ≥ 5% blasts by morphologic criteria) or M3 marrow or persistent extramedullary disease at the completion of first-line consolidation therapy or evidence of disease progression in the peripheral blood or new extramedullary disease prior to enrollment. Patients with previous CNS disease are eligible if there is no active CNS involvement of leukemia (defined as CNS-3 by NCCNv1 2018) at the time of screening"}
• {"criterion_text":"- Philadelphia chromosome positive (Ph+) ALL"}
• {"criterion_text":"- Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone"}
• {"criterion_text":"- Prior tyrosine kinase inhibitor therapy"}
• {"criterion_text":"- Subjects with concomitant genetic syndromes associated with bone marrow failure states: such as subjects with Fanconi anemia, Kostmann syndrome, Shwachman syndrome or any other known bone marrow failure syndrome. Subjects with Down syndrome will not be excluded."}
• {"criterion_text":"- Subjects with Burkitt’s lymphoma/leukemia (i.e. subjects with mature B-ALL, leukemia with B-cell [sIg positive and kappa or lambda restricted positivity] ALL, with FAB L3 morphology and /or a MYC translocation)"}
• {"criterion_text":"- Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease"}
• {"criterion_text":"- Has had treatment with any prior anti-CD19 therapy"}

Primary endpoints

• {"endpoint_text":"- 4-year OS rate. OS defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason","definition_or_measurement_approach":"Overall survival (OS) measured as time from date of first tisagenlecleucel infusion to date of death due to any cause; primary measure is the 4-year OS rate."}
• {"endpoint_text":"- 5-year DFS rate without censoring for new anticancer therapy, including SCT, while in remission. DFS, defined as the time from tisagenlecleucel infusion to morphologic relapse, occurrence of secondary malignancy or death due to any cause, whichever occurs first","definition_or_measurement_approach":"Disease-free survival (DFS) measured as time from tisagenlecleucel infusion to morphologic relapse, occurrence of secondary malignancy or death; primary measure is the 5-year DFS rate without censoring for subsequent anticancer therapy (including SCT)."}

Secondary endpoints

• {"endpoint_text":"- Proportion of subjects who are disease free without allogeneic SCT at 1 year","definition_or_measurement_approach":"Proportion (percentage) of subjects alive and disease-free at 1 year without having undergone allogeneic stem cell transplant."}
• {"endpoint_text":"- 5-year DFS rate censoring for new anticancer therapy, including SCT, while in remission","definition_or_measurement_approach":"5-year DFS measured censoring subjects at the time they receive new anticancer therapy (including SCT) while in remission."}
• {"endpoint_text":"- Proportion of subjects achieving MRD negative CR or CRi at month 3 post-tisagenlecleucel infusion","definition_or_measurement_approach":"Proportion of subjects with MRD-negative complete remission (CR) or CR with incomplete hematologic recovery (CRi) assessed at month 3 after infusion."}
• {"endpoint_text":"- Proportion of subjects in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion","definition_or_measurement_approach":"Proportion of subjects in CR/CRi who demonstrate persistent B-cell aplasia at specified post-infusion timepoints."}
• {"endpoint_text":"- Proportion of subjects who have tisagenlecleucel product successfully manufactured (meet all release criteria) over the total number of subjects enrolled for the age ≥ 1 year and < 3 years at respective time points","definition_or_measurement_approach":"Manufacturing success rate: proportion of enrolled subjects aged ≥1 and <3 years for whom tisagenlecleucel product met release criteria at specified time points."}
• {"endpoint_text":"- Pediatric Quality of Life Questionnaire (PedsQL) 4.0 and European Quality of Life Questionnaire (EuroQol) EQ-5D in subjects ≥ age 8 years; change from baseline","definition_or_measurement_approach":"Change from baseline in QoL scores (PedsQL 4.0 and EQ-5D) in subjects aged ≥8 years."}
• {"endpoint_text":"- Cogstate computerized cognitive battery age standardized scores (5 tests: psychomotor function (DET), attention (IDN), working memory (ONB), visual learning (OCL) and executive function (GML) (in subjects ≥ age 6 years)","definition_or_measurement_approach":"Age-standardized scores on Cogstate cognitive battery (5 tests) in subjects aged ≥6 years; change from baseline/timepoint assessments."}
• {"endpoint_text":"- Evaluation of adverse events, vital signs, laboratory and other parameters","definition_or_measurement_approach":"Safety assessments including collection and analysis of adverse events, vital signs, laboratory tests, and other safety parameters per protocol."}
• {"endpoint_text":"- •\tPrevalence and incidence of pre-existing and treatment induced immunogenicity •\tPre-existing and treatment induced immunogenicity on clinical response, cellular kinetics (Cmax, AUC0-29d, Clast) and safety","definition_or_measurement_approach":"Assessment of prevalence/incidence of anti-product immunogenicity (pre-existing and treatment-induced) and its relationship to clinical response, cellular kinetics (Cmax, AUC0-29d, Clast) and safety."}
• {"endpoint_text":"- •\tTisagenlecleucel transgene levels by qPCR in blood, bone marrow, and CSF if available •\tExpression of tisagenlecleucel detected by flow cytometry in blood and bone marrow •\tCmax, Tmax, AUCs and other relevant cellular kinetic parameters in blood, bone-marrow, and CSF if available","definition_or_measurement_approach":"Cellular kinetics: qPCR transgene levels in blood/BM/CSF, flow cytometry detection, and PK-like parameters (Cmax, Tmax, AUC) measured at specified timepoints."}
• {"endpoint_text":"- B-cell recovery time and transgene levels over time","definition_or_measurement_approach":"Time to B-cell recovery post-infusion and longitudinal transgene level measurements."}
• {"endpoint_text":"- •\tResponse endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationships with dose •\tResponse endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationship with relevant exposure parameters (e.g. AUC and Cmax) •\tCellular kinetic parameters and relationship with dose","definition_or_measurement_approach":"Analyses of response and key safety events in relation to dose and exposure parameters (AUC, Cmax) and evaluation of cellular kinetics vs dose."}

Norway

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

30-01-2026

Processing Time Days

718

Number Of Sites

1

Number Of Participants

3

Italy

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

02-02-2026

Processing Time Days

721

Number Of Sites

1

Number Of Participants

2

Sweden

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

28-01-2026

Processing Time Days

716

Number Of Sites

2

Number Of Participants

1

France

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

28-01-2026

Processing Time Days

716

Number Of Sites

1

Number Of Participants

3

Spain

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

02-02-2026

Processing Time Days

721

Number Of Sites

1

Number Of Participants

5

Netherlands

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

30-01-2026

Processing Time Days

718

Number Of Sites

1

Number Of Participants

6

Belgium

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

27-01-2026

Processing Time Days

715

Number Of Sites

2

Number Of Participants

1

Denmark

Earliest CTIS Part Ii Submission Date

12-02-2024

Latest Decision Or Authorization Date

26-01-2026

Processing Time Days

714

Number Of Sites

1

Number Of Participants

3

Primary sponsor

Full Name

Novartis Pharma AG

Organisation Type

Pharmaceutical company

Country Of Registered Address

Switzerland

Contract research organisations

Name

Icon Clinical Research Limited

Responsibilities

code 1

Name

Parexel International (IRL) Limited

Responsibilities

Ancillary Supplies; code 12

Name

IQVIA Limited

Responsibilities

code 1

Name

Syneos Health Inc.

Responsibilities

code 1

Third parties

• {"country":"Spain","full_name":"Rps Research Iberica S.L.","duties_or_roles":"code 1","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"Cellular Immunogenicity analysis; code 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"The Childrens Hospital Los Angeles","duties_or_roles":"MRD sample analysis; code 4","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"Sweden","full_name":"ApoEx AB","duties_or_roles":"code 14; Pharmaceutical control","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"code 1","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Cogstate Inc.","duties_or_roles":"Neurocognitive assessments","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Tjoapack Netherlands B.V.","duties_or_roles":"(Re) labelling IMP","organisation_type":"Pharmaceutical company"}
• {"country":"France","full_name":"Kayentis","duties_or_roles":"Patient Reported Outcome questionnaires","organisation_type":"Non-Pharmaceutical company"}
• {"country":"United States","full_name":"Labcorp Central Laboratory Services LP","duties_or_roles":"Lab kit supply, Sample management and processing of safety/ PK/biomarker and safety endpoint samples; code 4","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Opis S.r.l.","duties_or_roles":"TMF archive Activation sites activities","organisation_type":"Pharmaceutical company"}
• {"country":"Italy","full_name":"Phardis S.r.l.","duties_or_roles":"Local equipment storage","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Greenphire LLC","duties_or_roles":"US Patient reimbursement service","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Ireland","full_name":"Icon Clinical Research Limited","duties_or_roles":"code 1","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"DATAMAP-Gesellschaft fuer Datenmanagement Datenanalyse und Datenpraesentation mbH","duties_or_roles":"Biostats; statistical programming and analysis of the study data (for DMC as well as for primary and final CSR)","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Spain","full_name":"Syneos Health Clinical Spain S.L.","duties_or_roles":"code 1","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"code 3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Syneos Health Inc.","duties_or_roles":"code 1","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Alloga (Nederland) B.V.","duties_or_roles":"Distribution and destruction IMP","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Navigate Biopharma Services Inc.","duties_or_roles":"Sample analysis; code 4","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Sandoz B.V.","duties_or_roles":"IMP storage and destruction","organisation_type":"Pharmaceutical company"}
• {"country":"Spain","full_name":"IQVIA RDS Spain S.L.","duties_or_roles":"code 1","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"World Courier (U.K.) Limited","duties_or_roles":"Courier and Transport","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Labcorp Central Laboratory Services SARL","duties_or_roles":"Lab kit supply, Sample management and processing of safety/ PK/biomarker and safety endpoint samples; code 4","organisation_type":"Pharmaceutical company"}
• {"country":"Ireland","full_name":"Parexel International (IRL) Limited","duties_or_roles":"Ancillary Supplies","organisation_type":"Pharmaceutical company"}
• {"country":"Norway","full_name":"Oslo University Hospital HF","duties_or_roles":"MRD sample analysis; code 4","organisation_type":"Pharmaceutical company"}