Study of efficacy and safety of tisagenlecleucel in HR B-ALL EOC MRD positive patients

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Pediatric, Patients

Age range

0-17 years, 18-64 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Apr 2019 → ongoing

Decision date (initial)

2024-03-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

ORG-100003908

External identifiers

EU CT number

2023-508081-15-00

EudraCT number

2017-002116-14

ClinicalTrials.gov

NCT03876769

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Pharmacodynamic

• 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 )

Secondary objectives 12

1. To assess the proportion of subjects who are disease free without allogeneic SCT at 1 year
2. To assess DFS censoring for new anticancer therapy, including SCT (i.e., the effect of tisagenlecleucel on DFS if new anticancer therapy is not available)
3. To assess the proportion of subjects achieving MRD negative CR or CRi at month 3 post-tisagenlecleucel infusion
4. To assess the proportion of subjects in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
5. To assess the tisagenlecleucel manufacturing success rate in subjects ≥1 year and < 3 years
6. To assess the impact of tisagenlecleucel on health-related Quality of Life (QoL) measures
7. To assess the impact of tisagenlecleucel on neurocognitive measure
8. To assess the safety of tisagenlecleucel therapy
9. To assess the prevalence and incidence of immunogenicity to tisagenlecleucel and its impact on efficacy, safety and cellular kinetics
10. To characterize in vivo cellular kinetic profile (levels, persistence) of tisagenlecleucel transgene and CD3+ CAR-positive viable T cells including second infusion
11. To evaluate the relationship between B-cell and transgene persistence
12. To evaluate dose-exposure-response relationship

Conditions and MedDRA coding

High-risk B-cell acute lymphoblastic leukemia

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-001654-PIP01-14

Plan to share IPD

Yes

IPD plan description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. CD19 expressing (in peripheral blood or bone marrow by flow cytometry) B-cell Acute Lymphoblastic Leukemia
2. 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
3. Age 1 to 25 years at the time of screening
4. Lansky (age < 16 years) or Karnofsky (age ≥ 16 years) performance status ≥ 60% at screening
5. 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
6. 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
7. Signed written informed consent and assent forms, if applicable, must be obtained prior to any study procedures
8. Must meet the institutional criteria to undergo leukapheresis
9. 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 18

1. M3 marrow (≥ 25% blasts by morphologic criteria) at the completion of first-line induction therapy
2. 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
3. Philadelphia chromosome positive (Ph+) ALL
4. Hypodiploid: less than 44 chromosomes and/or DNA index < 0.81, or other clear evidence of a hypodiploid clone
5. Prior tyrosine kinase inhibitor therapy
6. 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.
7. 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)
8. Prior malignancy, except carcinoma in situ of the skin or cervix treated with curative intent and with no evidence of active disease
9. Has had treatment with any prior anti-CD19 therapy
10. Treatment with any prior gene or engineered T cell therapy
11. Clinically significant active infection confirmed by clinical evidence, imaging, or positive laboratory tests (e.g., blood cultures, PCR for DNA/RNA, etc.)
12. Presence of active hepatitis B or C (for detailed criteria see Appendix 3)
13. Human Immunodeficiency Virus (HIV) positivity as indicated by serology
14. 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
15. 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
16. 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
17. 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.
18. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. 4-year OS rate. OS defined as the time from date of first tisagenlecleucel infusion to the date of death due to any reason
2. 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 endpoints 12

1. Proportion of subjects who are disease free without allogeneic SCT at 1 year
2. 5-year DFS rate censoring for new anticancer therapy, including SCT, while in remission
3. Proportion of subjects achieving MRD negative CR or CRi at month 3 post-tisagenlecleucel infusion
4. Proportion of subjects in CR or CRi with persistent B-cell aplasia over time post tisagenlecleucel infusion
5. 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
6. 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
7. 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)
8. Evaluation of adverse events, vital signs, laboratory and other parameters
9. • 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
10. • 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
11. B-cell recovery time and transgene levels over time
12. • 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel

Postcode

4056

Country

Switzerland

Scientific contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Public contact point

Organisation

Novartis Pharma AG

Contact name

Novartis Pharma Arzneimittel GmbH

Third parties 25

Locations

8 EU/EEA countries · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 141 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications