Efficacy and safety of tisagenlecleucel in adult patients with refractory or relapsed follicular lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Novartis Pharma AG

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

25 Jan 2019 → 28 May 2025

Decision date (initial)

2024-02-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-508127-13-00

EudraCT number

2017-004385-94

ClinicalTrials.gov

NCT03568461

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Others, Therapy, Safety, Efficacy, Pharmacokinetic

Evaluate the efficacy of tisagenlecleucel therapy as measured by CRR determined by IRC

Secondary objectives 6

1. 1. Evaluate the efficacy of tisagenlecleucel as measured by additional efficacy measures, including ORR, DOR, PFS and OS
2. 2. Evaluate safety of tisagenlecleucel
3. 3. Characterize the in vivo cellular kinetics (levels, expansion, persistence) of tisagenlecleucel transduced cells into target tissues (blood, bone marrow, and other tissues if available) and CD3+ tisagenlecleucel cells in peripheral blood, summarized by clinical response
4. 4. Characterize the incidence and prevalence of tisagenlecleucel immunogenicity (humoral and cellular)
5. 5. Characterize the impact of pre-existing and treatment induced immunogenicity (cellular and humoral) on cellular kinetics, efficacy and safety
6. 6. Describe the effect of tisagenlecleucel therapy on Patient reported outcomes (PRO)

Conditions and MedDRA coding

Adult patients with refractory or relapsed follicular lymphoma

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1. Written informed consent prior to any screening procedures
2. 2. ≥18 years of age at the time of ICF signature
3. 3. FL (Grade 1, 2, 3A) confirmed histologically by central pathology review before tisagenlecleucel infusion.
4. 4. FL meeting one of the following criteria: • Refractory to a second line or later line of systemic therapy (including an anti-CD20 antibody and an alkylating agent) or relapsed within 6 months after completion of a second line or later line of systemic therapy • Relapsed during anti-CD20 antibody maintenance (following at least two lines of therapies as above) or within 6 months after maintenance completion • Relapsed after autologous HSCT
5. 5. Radiographically measurable disease at screening defined as: • At least one nodal lesion greater than 20 mm in the long axis, regardless of the length of the short axis AND/OR • Extranodal lesions (outside lymph node or nodal mass, including liver and spleen) greater than 10 mm in long AND short axis
6. 6. ECOG performance status that is either 0 or 1 at screening
7. 7. Patients must meet the following laboratory values without transfusion at screening: • Absolute neutrophil count (ANC) ≥ 1,000/mm3 (≥ 1×109/L) • Absolute lymphocyte count (ALC) > 300/mm3 (> 0.3×109/L) • Absolute number of CD3+ T cells > 150/mm3 (> 0.15×109/L) • Platelets ≥ 50 000/mm3 (≥ 50×109/L) • Hemoglobin ≥ 8.0 g/dl (≥ 4.9 mmol/L) • A serum creatinine of ≤1.5 times ULN or eGFR ≥ 60 mL/min/1.73 m2 • Alanine aminotransferase (ALT)/ Aspartate aminotransferase (AST) ≤ 5 times the Upper Limit of Normal (ULN) • Total bilirubin (TBIL) ≤ 1.5 times ULN (with the exception of patients with Gilbert’s syndrome. Patients with Gilbert’s syndrome may be included if their total bilirubin is ≤ 3.0 times ULN and direct bilirubin ≤ 1.5 times ULN
8. 8. Adequate pulmonary function defined as: • No or mild dyspnea (≤ Grade 1) • Oxygen saturation measured by pulse oximetry > 90% on room air
9. 9. Must have a leukapheresis product of non-mobilized cells accepted for manufacturing

Exclusion criteria 18

1. 1. Evidence of histologic transformation
2. 2. Follicular Lymphoma Grade 3B
3. 3. Prior anti-CD19 therapy
4. 4. Prior gene therapy
5. 5. Prior adoptive T cell therapy
6. 6. Prior allogeneic hematopoietic stem cell transplant
7. 7. Active CNS involvement by malignancy
8. 8. Active neurological autoimmune or inflammatory disorders (e.g. Guillain-Barre syndrome, Amyotrophic Lateral Sclerosis)
9. 9. Investigational medicinal product within the last 30 days or five half-lives (whichever is longer) prior to screening
10. 10. Presence of active or prior hepatitis B or C as indicated by serology. Serology must be repeated, if the interval between testing prior to lymphodepletion and tisagenlecleucel infusion exceeds 8 weeks
11. 11. Presence of HIV antibody. Serology must be repeated, if the interval between testing prior to lymphodepletion and tisagenlecleucel infusion exceeds 8 weeks
12. 12. Uncontrolled acute life threatening bacterial, viral or fungal infection (e.g. blood culture positive ≤ 72 hours prior to tisagenlecleucel infusion)
13. 13. Cardiac or cardiac repolarization abnormality, including any of the following: • History of myocardial infarction (MI), angina pectoris, or coronary artery bypass graft (CABG) within 6 months prior to starting study treatment • Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II and third degree AV block) • LVEF <45% as determined by ECHO or MRA or MUGA • NYHA functional class III or IV
14. 14. Previous or concurrent malignancy with the following exceptions: a. Adequately treated basal cell or squamous cell carcinoma (adequate wound healing is required prior to enrollment) b. In situ carcinoma of the cervix or breast, treated curatively and without evidence of recurrence for at least 3 years prior to enrollment c. A primary malignancy which has been completely resected and in complete remission for ≥ 3 years at the time of enrollment
15. 15. Pregnant or nursing (lactating) women NOTE: female study participants of reproductive potential must have a negative serum or urine pregnancy test performed within 24 hours before leukapheresis, lymphodepletion and prior to tisagenlecleucel infusion.
16. 16. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. Highly effective contraception methods include: • 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 • Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or 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 patients on the study, the vasectomized male partner should be the sole partner for that patient • 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 taking study treatment.
17. 17. Sexually active males must use a condom during intercourse while taking study treatment and for at least 12 months after the tisagenlecleucel infusion and until CAR T-cells are no longer present by qPCR on two consecutive tests. 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 for the time period specified above.
18. 18. Intolerance to the excipients of the tisagenlecleucel cell product.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 1. Complete response rate (CRR) determined by an Independent Review Committee (IRC) in the efficacy analysis set (EAS) based on Lugano 2014 classification response criteria (Cheson et al 2014).

Secondary endpoints 6

1. ORR, including complete response (CR) and partial response (PR) determined by IRC in the FAS based on Lugano 2014 classification. DOR, defined as time from CR/PR to relapse or death due to FL, based on IRC DOR for CR only, defined as time from CR to relapse or death due to FL, based on IRC. PFS, defined as time from tisagenlecleucel infusion to first documented disease progression or death due to any cause, based on IRC.OS, defined as time from tisagenlecleucel infusion to death due to any cause
2. Type, frequency and severity of adverse events and laboratory abnormalities
3. Summary of: -qPCR detected tisagenlecleucel transgene concentrations in peripheral blood, bone marrow and other tissues by time point and clinical response status. -cellular kinetic parameters: Cmax, Tmax, AUC0-28 and AUC0-84d, T1/2, and/or other relevant parameters in peripheral blood; bone marrow and other tissues by clinical response as appropriate -exposure and cellular kinetic parameters of CD3+ tisagenlecleucel cells in peripheral blood detected by flow cytometry
4. Summary of pre-existing and treatment induced immunogenicity (cellular and humoral) of tisagenlecleucel
5. Levels of pre-existing and treatment induced immunogenicity Cellular kinetic parameters (Cmax, AUCs, Tlast), concentration-time profile tisagenlecleucel by immunogenicity category (positive/negative) Efficacy (ORR, DOR, PFS) Safety (B-cell levels, CRS grades, neurologic events)
6. Summary scores of PRO measured by SF-36 version 2, EQ-5D-3L and FACT-Lym quality of life questionnaires

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 19

Locations

7 EU/EEA countries · 12 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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 23 files

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

Application history

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