Study of efficacy and safety of tisagenlecleucel in HR B-ALL EOC MRD positive patients
- Conditions
- High-risk B-cell acute lymphoblastic leukemia
- Registration Number
- 2023-508081-15-00
- Lead Sponsor
- Novartis Pharma AG
- Brief Summary
• To evaluate the efficacy of tisagenlecleucel therapy as measured by the overall survival (OS)
• To evaluate the efficacy of tisagenlecleucel therapy as measured by the disease-free survival (DFS) without censoring for new anticancer therapy, including SCT, by investigator assessment (i.e combined effect of tisagenlecleucel and possible subsequent therapy on DFS )
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Ongoing, recruitment ended
- Sex
- Not specified
- Target Recruitment
- 23
CD19 expressing (in peripheral blood or bone marrow by flow cytometry) B-cell Acute Lymphoblastic Leukemia
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
Age 1 to 25 years at the time of screening
Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60% at screening
Adequate organ function during the screening phase: • Renal 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 • Adequate liver function defined as: • ALT ≤ 5 times ULN for age • AST ≤ 5 times ULN for age • Total bilirubin < 2 mg/dL (for Gilbert’s Syndrome subjects total bilirubin < 4 mg/dL) • Adequate pulmonary function defined as: • no or mild dyspnea (≤ Grade 1) • oxygen saturation of > 90% on room air • Adequate 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
Prior induction and consolidation chemotherapy allowed: • 1st 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). • Additional (augmented) chemotherapy such as clofarabine and ifosfamide added to induction/consolidation therapy prior to enrollment, leukapheresis, or infusion are not allowed • Subject 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
Signed written informed consent and assent forms, if applicable, must be obtained prior to any study procedures
Must meet the institutional criteria to undergo leukapheresis
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.
M3 marrow (≥ 25% blasts by morphologic criteria) at the completion of first-line induction therapy
Treatment with any prior gene or engineered T cell therapy
Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
Presence of active hepatitis B or C (for detailed criteria see Appendix 3)
Human Immunodeficiency Virus (HIV) positivity as indicated by serology
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
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. Medications to be stopped > 72 hours prior to tisagenlecleucel infusion: • Therapeutic systemic doses of steroids. However, the following physiological replacement doses of steroids are allowed: < 12 mg/m2/day hydrocortisone or equivalent b. Medications to be stopped at least 1 week prior to tisagenlecleucel infusion: • 6-thioguanine, asparaginase (non-pegylated), vincristine, 6-mercaptopurine, and intrathecal methotrexate c. Medications to be stopped at least 2 weeks prior to tisagenlecleucel infusion: • Anthracyclines and cytarabine • Intravenous methotrexate. • Radiotherapy: Non-CNS site of radiation d. Medications to be stopped at least 4 weeks prior to tisagenlecleucel infusion: • Pegylated-asparaginase e. Medications/Therapy to be stopped at least 8 weeks prior to tisagenlecleucel infusion: • Radiotherapy: Cranial radiation (for CNS 3 subjects) therapy
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
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: • Total 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 • Female 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 • Male 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 • Use 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.
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.
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
Philadelphia chromosome positive (Ph+) ALL
Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone
Prior tyrosine kinase inhibitor therapy
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.
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)
Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
Has had treatment with any prior anti-CD19 therapy
Study & Design
- Study Type
- Not specified
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method 4-year OS rate. OS defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason 4-year OS rate. OS defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason
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 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
- Secondary Outcome Measures
Name Time Method Proportion of subjects who are disease free without allogeneic SCT at 1 year Proportion of subjects who are disease free without allogeneic SCT at 1 year
5-year DFS rate censoring for new anticancer therapy, including SCT, while in remission 5-year DFS rate censoring for new anticancer therapy, including SCT, while in remission
Proportion of subjects achieving MRD negative CR or CRi at month 3 post-tisagenlecleucel infusion Proportion of subjects achieving MRD negative CR or CRi at month 3 post-tisagenlecleucel infusion
Proportion of subjects in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion Proportion of subjects in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
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 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
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 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
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) 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)
Evaluation of adverse events, vital signs, laboratory and other parameters Evaluation of adverse events, vital signs, laboratory and other parameters
• Prevalence and incidence of pre-existing and treatment induced immunogenicity • Pre-existing and treatment induced immunogenicity on clinical response, cellular kinetics (Cmax, AUC0-29d, Clast) and safety • Prevalence and incidence of pre-existing and treatment induced immunogenicity • Pre-existing and treatment induced immunogenicity on clinical response, cellular kinetics (Cmax, AUC0-29d, Clast) and safety
• Tisagenlecleucel transgene levels by qPCR in blood, bone marrow, and CSF if available • Expression of tisagenlecleucel detected by flow cytometry in blood and bone marrow • Cmax, Tmax, AUCs and other relevant cellular kinetic parameters in blood, bone-marrow, and CSF if available • Tisagenlecleucel transgene levels by qPCR in blood, bone marrow, and CSF if available • Expression of tisagenlecleucel detected by flow cytometry in blood and bone marrow • Cmax, Tmax, AUCs and other relevant cellular kinetic parameters in blood, bone-marrow, and CSF if available
B-cell recovery time and transgene levels over time B-cell recovery time and transgene levels over time
• Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationships with dose • Response 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) • Cellular kinetic parameters and relationship with dose • Response endpoints (e.g. DFS, OS, Month 3 response) and key safety events (e.g. CRS, neurological events, cytopenias) and relationships with dose • Response 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) • Cellular kinetic parameters and relationship with dose
Trial Locations
- Locations (10)
Universitair Ziekenhuis Gent
🇧🇪Gent, Belgium
Rigshospitalet
🇩🇰Copenhagen Oe, Denmark
Robert Debre University Hospital
🇫🇷Paris, France
Ospedale Pediatrico Bambino Gesu'
🇮🇹Rome, Italy
Fondazione IRCCS San Gerardo Dei Tintori
🇮🇹Monza, Italy
Sant Joan De Deu Barcelona Hospital
🇪🇸Esplugues De Llobregat, Spain
Queen Silvia Childrens Hospital - Sahlgrenska University Hospital - Vastra Gotalandsregionen
🇸🇪Gothenburg, Sweden
Karolinska University Hospital
🇸🇪Huddinge, Sweden
Prinses Maxima Centrum voor Kinderoncologie B.V.
🇳🇱Utrecht, Netherlands
Oslo University Hospital HF
🇳🇴Oslo, Norway
Universitair Ziekenhuis Gent🇧🇪Gent, BelgiumTessa KerreSite contact+3292402069Tessa.kerre@ugent.beBarbara De MoerlooseSite contact+3293326417Barbara.demoerloose@uzgent.be