Phase 2, Open-Label Study Evaluating Axi-Cel as a 2nd line therapy in patients with Relapsed/Refractory aggressive B-NHL who are ineligible to Autologous Stem Cell Transplantation

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Lysarc

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

12 Feb 2021 → ongoing

Decision date (initial)

2024-05-06

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513659-34-00

EudraCT number

2020-001868-28

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the complete metabolic response (CMR) at 3 months from Axi-cel infusion (without additional anticancer therapy) based on investigator disease assessment

Secondary objectives 1

1. To evaluate efficacy and safety of Axi-cel infusion (without additional anticancer therapy) with respect to secondary efficacy endpoints.

Conditions and MedDRA coding

Relapsed/Refractory aggressive B-NHL

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Signed written Informed Consent Form
2. Patient who understands and speaks one of the country official languages
3. Histologically proven relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (B-NHL) of the following histology at relapse: diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma (HGBL), follicular lymphoma Grade 3B per WHO 2016 classification and Primary mediastinal B-cell lymphomas. Indolent B-NHL who transformed into aggressive B-NHL and were previously treated with R-CHOP are eligible
4. Tumoral tissue (at diagnosis or relapse) available for central pathology review, exploratory endpoints and ancillary studies
5. Positron-emission tomography (PET)-positive disease
6. Patients must have received adequate first-line therapy including at a minimum: o An anti-CD20 monoclonal antibody (rituximab or obinutuzumab), and LYSARC ALYCANTE EudraCT#: 2020􀇦001868􀇦28 Confidential, do not disclose without prior agreement Protocol version 4.0 dated 02/Feb/2023 EN-SOP-PM-11-Temp-01-protocol template-v8.0 effective date: 24/06/2019 Page 7/100 o CHOP or CHOP-like chemotherapy Note: CHOP-like chemotherapy corresponds to ACVBP or EPOCH or COPADEM. Dose-reduced CHOP (i.e. miniCHOP) is excluded except for dose-reductions of vincristin due to peripheral neuropathy. Patients who have received additional drugs in combination with CHOP or CHOP-like regimen are eligible.
7. Relapsed or refractory disease after first-line chemoimmunotherapy (full dose of R-CHOP or R-CHOP-like regimen), documented by PET-scan: o Relapsed disease defined as complete remission to first-line therapy followed by biopsy proven disease relapse within 12 months from end of first-line therapy. Patients who received first line of R-CHOP or obinutuzumab-CHOP for an indolent B-NHL who relapse as transformed aggressive B-NHL within a year from the end of first-line therapy are eligible. o Refractory disease defined as: Progressive disease (PD) during first-line therapy Stable disease (SD) as best response after at least 4 cycles of firstline therapy (e.g. 4 cycles of R-CHOP) Partial response (PR) as best response after at least 6 cycles, and biopsy-proven residual disease
8. At least 2 weeks must have elapsed since any prior systemic cancer therapy at the time the patient provides consent
9. Patients must be autologous stem cell transplantation (ASCT)-ineligible as defined by: o Patient deemed ineligible for high-dose chemotherapy and ASCT based on physician’s assessment o AND at least one of the following criteria: Age ≥ 65 years or Age ≥ 18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI – Appendix 09) score ≥3 or Age ≥ 18 years and prior ASCT (as 1st line consolidation)
10. Patients must meet CAR-T-eligible as defined by: o Patient deemed eligible for CAR T-cells therapy by the CAR-T physician o AND all the following criteria: ECOG performance status of 0, 1 or 2 Adequate vascular access for leukapheresis procedure (either peripheral or central venous line) Absolute neutrophil count (ANC) ≥ 1 G/L Platelets ≥ 75 G/L Absolute lymphocyte count ≥ 0,1 G/L Creatinine clearance (as estimated by Cockcroft Gault or MDRD) ≥ 40 mL/min Serum alanine aminotransferase/aspartate aminotransferase (ALT/AST) ≤ 2.5xULN Total bilirubin ≤ 26 μmol/L, except in patients with Gilbert’s syndrome Cardiac ejection fraction ≥ 45% Baseline oxygen saturation ≥ 92% on room air
11. Females of childbearing potential must have a negative serum or urine pregnancy test (females who have undergone surgical sterilization or who have been postmenopausal for at least 12 months are not considered to be of childbearing potential)

Exclusion criteria 21

1. Patients who received more than one prior line of systemic therapy
2. Patients who are intolerant to first-line therapy or who received suboptimal firstline therapy, including dose-reduced R-CHOP (“R-miniCHOP”), and those who discontinued prematurely first-line therapy due to toxicity are not eligible (except for dose-reductions or discontinuation of vincristin due to peripheral neuropathy)
3. Prior CD19 targeted therapy
4. Patients with cardiac atrial or cardiac ventricular lymphoma involvement
5. Requirement for urgent therapy due to tumor mass effects, such as bowel obstruction or blood vessel compression
6. Patient with clinically significant pleural effusion
7. History of another primary malignancy that has not been in remission for at least 2 years (except for nonmelanoma skin cancer or carcinoma in situ (eg, cervix, bladder, breast)). A maintenance treatment is not allowed.
8. Patients with detectable Central Nervous System (CNS) lymphoma. Patients with a history of CNS lymphoma but no active CNS disease (after systematic MRI and lumbar puncture) at the time of enrollment will be eligible.
9. History or presence of non-malignant CNS disorder, such as seizure disorder requiring anti-convulsive therapy, cerebellar disease, or any autoimmune disease with CNS involvement disease
10. Active hepatitis B or hepatitis C infection at the time of screening Active Hepatitis B Virus (HBV) infection defined as: - HBs Ag positive - HBs Ag negative, anti-HBs antibody positive and/or anti-HBc antibody positive with detectable viral DNA
11. Positive serology of human immunodeficiency virus (HIV) and syphilis at the time of screening
12. Uncontrolled systemic fungal, bacterial, viral or other infection despite appropriate antibiotics or other treatment at the time of leukapheresis or Axicel administration
13. History of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association, cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease
14. History of autoimmune disease requiring systemic immunosuppression and/or systemic disease modifying agents within the last year
15. History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest computed tomography (CT) scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed.
16. History of severe immediate hypersensitivity reaction to tocilizumab or any of the agents used in this study
17. History of severe immediate hypersensitivity reaction attributed to aminoglycosides, cyclophosphamide and fludarabine
18. Treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment or anticipation of need for such a vaccine during the course of the study
19. Women of childbearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of chemotherapy on the fetus or infant. Patients of either sex who are not willing to practice birth control from the time of consent during treatment and for at least 6 months after conditioning chemotherapy dosing or axicabtagene ciloleucel dosing, whichever is later
20. In the investigator’s judgment, the patient is unlikely to complete all protocolrequired study visits or procedures, including follow-up visits, or comply with the study requirements for participation
21. Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. CMR at 3 months based on investigator disease assessment according to PET-scan using the Lugano Response Criteria

Secondary endpoints 11

1. CMR at 3 months from Axi-cel infusion (without additional anticancer therapy) determined by central imaging review (using the Lugano Response Criteria)
2. Event-free survival (EFS) at 3, 6 and 12 months from leukapheresis based on investigator disease assessment. EFS is defined as the time between leukapheresis and: o any event preventing Axi-cel infusion if Axi-cel is never infused, or o death, disease progression, or instauration of a new lymphoma therapy for lymphoma progression after Axi-cel infusion.
3. EFS at 3, 6 and 12 months from leukapheresis based on central imaging review. EFS is defined as the time between leukapheresis and: o any event preventing Axi-cel infusion if Axi-cel is never infused, or o death, disease progression, or instauration of a new lymphoma therapy for lymphoma progression after Axi-cel infusion.
4. Modified EFS (mEFS) at 6 and 12 months from leukapheresis based on investigator assessment and central imaging review. mEFS is defined as the time between leukapheresis and: o any event preventing Axi-cel infusion if Axi-cel is never infused, or o death, disease progression, or instauration of a new lymphoma therapy for lymphoma progression after Axi-cel infusion or failure to achieve a CMR at 6 and 12 months post-CAR infusion.
5. Best objective response (complete and partial metabolic response)
6. Duration of response (DOR)
7. Progression-free survival (PFS) from Axi-cel infusion
8. Overall survival (OS) from leukaphaeresis and Axi-cel infusion
9. DOR, PFS, OS at 2 years and 3 years
10. Safety of Axi-cel
11. Health-related Quality of life (EORTC QLQ-C30, EQ-5D-5L and QLQ-NHLHG29)

Investigational products

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

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Lysarc

Sponsor organisation

LYSARC

Address

2d Lyon Sud Batiment

City

Pierre Benite Cedex

Postcode

69495

Country

France

Scientific contact point

Organisation

LYSARC

Contact name

Anne VIOLA

Public contact point

Organisation

LYSARC

Contact name

Anne VIOLA

Locations

1 EU/EEA country · 19 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 14 files

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

Application history

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