HOVON 161: A phase II non-inferiority study comparing point-of-care produced CAR T-cell to commercial CAR T-cells in patients with relapsed/refractory Non-Hodgkin Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Universitair Medisch Centrum Groningen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Oct 2022 → ongoing

Decision date (initial)

2024-10-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-511979-15-00

EudraCT number

2021-000937-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To compare progression free survival (PFS) of patients randomized to investigational point-of-care (PoC) ARI-0001 CAR T-cells versus PFS of patients randomized to commercial standard-of-care (SoC) (axicabtagene ciloleucel (Axi-cel, Yescarta)) CAR T-cells in patients with R/R DLBCL.

Secondary objectives 10

1. To evaluate response rates (ORR and CR).
2. To evaluate safety and toxicity of ARI-0001 and Axi-cel.
3. To assess overall survival (OS).
4. To evaluate quality of life (QoL).
5. To assess costs associated with both treatment regimens (ARI-0001 vs Axi-cel).
6. To evaluate CAR T-cell expansion, persistence, and T-cell characteristics in both treatment arms (ARI-0001 vs Axi-cel).
7. To evaluate PoC CAR T-cell production characteristics (e.g. number of viable T-cells, transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)), including the functional characteristics (e.g. potency tests) between the different production sites.
8. To evaluate the association of the functional characteristics (e.g. potency tests) of the CAR T-cell products (ARI-0001 CAR T-cells) with CAR T-cell expansion, persistence, adverse events, response rates and progression free survival.
9. To assess the proportion of successful batches between the different production sites.
10. To evaluate the number of days between leukapheresis and infusion of CAR T-cells (vein-to-vein time).

Conditions and MedDRA coding

relapsed/refractory Non-Hodgkin Lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. Histologically confirmed DLBCL and associated subtypes, defined by WHO 2016 classification: DLBCL not otherwise specified (NOS), High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements with DLBCL histology (DHL/THL) and FL3B, T-cell/histocyte rich B-cell lymphoma, Primary mediastinal B-cell lymphoma, transformed lymphoma (transformed follicular) and refractory after 1st line systemic therapy or have a relapse after 12 months of finishing first line therapy or have R/R after at least 2 lines of systemic therapy
2. Age ≥ 18 years.
3. Eastern Cooperative Oncology Group (ECOG)/WHO performance status 0-2.
4. Secondary central nervous system (CNS) involvement is allowed however, then he/she must have no signs or symptoms of CNS involvement that would hamper adequate ICANS assessment.
5. Estimated life expectancy of >3 months other than primary disease.
6. Patients of child-bearing or child-fathering potential must be willing to practice birth control from the time of enrollment on this study and for four months after receiving the preparative regimen.
7. Signed and dated informed consent before conduct of any trial-specific procedure.
8. Patient is capable of giving informed consent.
9. Approval by the Dutch CAR T-cell TumorBoard for lymphoma

Exclusion criteria 22

1. Absolute neutrophil count (ANC) <1.0x109/L.
2. Platelet count <50x109/L.
3. Absolute lymphocyte count <0.1x109/L.
4. Primary CNS lymphoma.
5. Known history of infection with hepatitis C or B virus unless treated and confirmed to be polymerase chain reaction (PCR) negative.
6. Active HIV infection with detectable viral load or CD4 T-cell count below 0.20x109/L.
7. Known history or presence of seizure activities or on active anti- seizure medications within the previous 12 months.
8. Known history of CVA within prior 12 months.
9. Unstable neurological deficits.
10. Known history or presence of autoimmune CNS disease, such as multiple sclerosis, optic neuritis or other immunologic or inflammatory disease.
11. Active systemic autoimmune disease for which immunnosupressive therapy is required.
12. Presence of CNS disease that, in the judgment of the investigator, may impair the ability to evaluate neurotoxicity, baseline dementia that would interfere with therapy or monitoring, determined using mini-mental status exam at baseline.
13. Active systemic fungal, viral or bacterial infection.
14. Clinical heart failure with New York Heart Association class ≥2 or Left Ventricular Ejection Fraction (LVEF) <40%.
15. Resting oxygen saturation <92% on room air.
16. Liver dysfunction as indicated by total bilirubin, AST and/or ALT >5 x institutional ULN, unless directly attributable to the lymphoma or Gilbert disease.
17. GFR <40 mL/min calculated according to the modified formula of Cockcroft and Gault or by direct urine collection.
18. Pregnant or breast-feeding woman.
19. Active other malignancy requiring treatment.
20. Medical condition requiring prolonged use of systemic immunosuppressives with exception of prednisolone <10 mg/day.
21. History of severe immediate hypersensitivity reaction against any drug or its Ingredients/ impurities that is scheduled to be given during trial participation e.g. as part of the mandatory lymphodepletion protocol, premedication for infusion, or rescue medication/salvage therapies for treatment related toxicities.
22. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS from date of IMP infusion (if applicable).

Secondary endpoints 14

1. PFS from date of randomization.
2. Safety and toxicity assessment of ARI-0001 CAR T-cells and Axi-cel per AE reporting classified according to CTCAE Version 5 and CRS and ICANS classified according to the ASTCT criteria.
3. Overall response rate (ORR, sum of complete response [CR] and partial response [PR]), as well as CR, PR, SD and PD/relapse at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells.
4. Expansion, phenotype and persistence of ARI-0001 CAR T-cells in both treatment arms.
5. Best overall response (BOR) rate at 4 weeks, 12 weeks, 6, 12 and 24 months after infusion of CAR T-cells.
6. Duration of response (DOR).
7. OS from date of randomization, and from date of CAR T-cell infusion (if applicable).
8. Patient Reported Outcome/Quality of Life (PRO/QOL).
9. CAR T-cell expansion, persistence, and T-cell characteristics in both treatment arms (ARI-0001 vs Axi-cel).
10. PoC CAR T-cell production characteristics (e.g. number of viable T-cells, transduction efficiency, T-cell subsets (activated T-cells, memory T-cells)), including the functional characteristics (e.g. potency tests) between the different production sites.
11. The association of the functional characteristics (e.g. potency tests) of the CAR T-cell products (ARI-0001 CAR T-cells) with CAR T-cell expansion, persistence, adverse events, response rates and progression free survival.
12. Proportion of successful batches between the different production sites.
13. Number of days between leukapheresis and infusion of CAR T-cells (vein-to-vein time).
14. Fludarabine pharmacokinetics.

Investigational products

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

Test 1

Comparator 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Universitair Medisch Centrum Groningen

Sponsor organisation

Universitair Medisch Centrum Groningen

Address

Hanzeplein 1

City

Groningen

Postcode

9713 GZ

Country

Netherlands

Scientific contact point

Organisation

Universitair Medisch Centrum Groningen

Contact name

M. Breems

Public contact point

Organisation

Universitair Medisch Centrum Groningen

Contact name

M. Breems

Third parties 4

Locations

1 EU/EEA country · 7 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 13 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