LEDA: A Phase III Trial Comparing Tisagenlecleucel to Standard of Care (SoC) in Adult Participants With r/r Follicular Lymphoma

Sponsor

Novartis Pharmaceuticals (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05888493

Collaborator

(none)

108

Enrollment

Arms

64.2

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This trial will compare tisagenlecleucel to standard of care in adult participants with relapsed or refractory (r/r) follicular lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Follicular Lymphoma (FL)	Biological: Tisagenlecleucel Drug: Lenalidomide and rituximab (R2) in 28-day cycles for up to 12 cycles. Drug: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or prednisolone (R-CHOP) in 21-day cycles for 6 to 8 cycles Drug: Lymphodepleting chemotherapy Other: Corticosteroids and/or Radiation (Bridging therapy)	Phase 3

Detailed Description

The purpose of this phase III study is to verify the clinical benefit of tisagenlecleucel for the treatment of r/r FL by comparing the tisagenlecleucel treatment strategy to standard of care therapy in patients with r/r FL after two or more lines of systemic therapy, with progression-free survival (PFS) as the primary endpoint.

The primary objective is to demonstrate superiority of the tisagenlecleucel treatment strategy over standard of care (SOC) therapy with respect to progression-free survival (PFS) determined by blinded independent review committee (BIRC) based on the Lugano response criteria.

Participants randomized to Arm A (tisagenlecleucel treatment) will receive a single infusion of 0.6 to 6 x 10^8 CAR-positive viable T-cells.

Participants randomized to Arm B (Standard of Care) will receive R2 or R-CHOP based on investigator choice and this has to be determined prior to randomization.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

108 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Randomized, Open-label, Multi-center Phase III Trial Comparing Tisagenlecleucel to Standard of Care in Adult Participants With Relapsed or Refractory Follicular Lymphoma (FL)

Anticipated Study Start Date :

Aug 10, 2023

Anticipated Primary Completion Date :

May 31, 2028

Anticipated Study Completion Date :

Dec 16, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tisagenlecleucel Participants randomized to the tisagenlecleucel treatment strategy will receive a single infusion of 0.6 to 6 x 10^8 CAR-positive viable T-cells	Biological: Tisagenlecleucel Tisagenlecleucel is a solution for infusion of 0.6 to 6 x 10^8 CAR-positive viable T-cells taken intravenously (i.v.). Other Names: CTL019 Drug: Lymphodepleting chemotherapy Fludarabine (25 mg/m^2 intravenously [i.v.] daily for 3 doses) OR Cyclophosphamide (250 mg/m^2 i.v. daily for 3 doses starting with the first dose of fludarabine). OR Bendamustine 90 mg/m^2 i.v. daily for 2 days (If there was previous grade IV hemorrhagic cystitis with cyclophosphamide, or the participant demonstrated resistance to a previous cyclophosphamide-containing regimen) Other: Corticosteroids and/or Radiation (Bridging therapy) Corticosteroids and/or Radiation
Active Comparator: R2 or R-CHOP Participants randomized to Standard of Care treatment will receive either R2 or R-CHOP based on investigator choice of therapies, and this has to be determined prior to randomization.	Drug: Lenalidomide and rituximab (R2) in 28-day cycles for up to 12 cycles. Lenalidomide 20 mg daily on days 1-21 for up to 12 cycles Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-5 Other Names: R2 Drug: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or prednisolone (R-CHOP) in 21-day cycles for 6 to 8 cycles Rituximab 375 mg/m2 i.v. on day 1 Cyclophosphamide 750 mg/m2 i.v. day 1 Doxorubicin 50 mg/m2 i.v. day 1 Vincristine 1.4 mg/2 (capped at 2 mg) i.v. day 1 Prednisone or prednisolone 40 mg/m2 PO days 1-5 Other Names: R-CHOP

Arm

Intervention/Treatment

Experimental: Tisagenlecleucel

Participants randomized to the tisagenlecleucel treatment strategy will receive a single infusion of 0.6 to 6 x 10^8 CAR-positive viable T-cells

Biological: Tisagenlecleucel

Tisagenlecleucel is a solution for infusion of 0.6 to 6 x 10^8 CAR-positive viable T-cells taken intravenously (i.v.).

Other Names:

CTL019

Drug: Lymphodepleting chemotherapy

Fludarabine (25 mg/m^2 intravenously [i.v.] daily for 3 doses) OR Cyclophosphamide (250 mg/m^2 i.v. daily for 3 doses starting with the first dose of fludarabine). OR Bendamustine 90 mg/m^2 i.v. daily for 2 days (If there was previous grade IV hemorrhagic cystitis with cyclophosphamide, or the participant demonstrated resistance to a previous cyclophosphamide-containing regimen)

Other: Corticosteroids and/or Radiation (Bridging therapy)

Corticosteroids and/or Radiation

Active Comparator: R2 or R-CHOP

Participants randomized to Standard of Care treatment will receive either R2 or R-CHOP based on investigator choice of therapies, and this has to be determined prior to randomization.

Drug: Lenalidomide and rituximab (R2) in 28-day cycles for up to 12 cycles.

Lenalidomide 20 mg daily on days 1-21 for up to 12 cycles Rituximab 375 mg/m2 IV on days 1, 8, 15, and 22 of cycle 1 and day 1 of cycles 2-5

Other Names:

Drug: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone or prednisolone (R-CHOP) in 21-day cycles for 6 to 8 cycles

Rituximab 375 mg/m2 i.v. on day 1 Cyclophosphamide 750 mg/m2 i.v. day 1 Doxorubicin 50 mg/m2 i.v. day 1 Vincristine 1.4 mg/2 (capped at 2 mg) i.v. day 1 Prednisone or prednisolone 40 mg/m2 PO days 1-5

Other Names:

R-CHOP

Outcome Measures

Primary Outcome Measures

Progression-free survival (PFS) determined by blinded independent review committee (BIRC) [5 years]
Progression free survival (PFS) based on Lugano response criteria, defined as time from randomization to the first of the following events to occur: progressive disease (by BIRC) death from any cause

Secondary Outcome Measures

Complete response rate (CRR) as assessed by BIRC (Key Secondary) [5 years]
CRR: The proportion of participants with BOR of complete response (CR)
Overall response rate (ORR) by BIRC [5 years]
ORR: The proportion of participants with BOR of either CR or partial response (PR)
Overall survival (OS) [5 years]
OS: Time from randomization to date of death due to any cause
Time to next anti-lymphoma treatment (TTNT) [5 years]
TTNT: Time from randomization until start of new anticancer therapy or death due to any cause.
Duration of Response (DOR) [5 years]
Time from the date of first documented BIRC response of CR or PR to the date of first documented progression by BIRC or any cause of death
Pre-existing (prior to treatment) and treatment-induced anti-mCAR antibodies (humoral immunogenicity) [5 years]
Summarize percentage of patients with pre-existing and treatment-induced anti-mCAR antibodies, and relate the antibody responses with CAR expansion, efficacy, and safety endpoints.
Anti-mCAR, T cell response, as measured by IFNγ expression (cellular immunogenicity) [5 years]
Summarize cellular immunogenicity by pre-infusion and post-infusion timepoints, and correlate cellular immunogenicity signals with CAR expansion, efficacy, and safety endpoints.
CAR transgene levels, as measured by quantitative polymerase chain reaction (qPCR), in peripheral blood, bone marrow (and other tissues, if available) [5 years]
Summary of transgene levels by timepoints and by clinical responses, cellular kinetic parameters will be derived using non-compartmental analysis from time course of transgene levels and will be summarized by clinical responses.
Replication competent lentivirus (RCL) by VSV-g qPCR in participants receiving tisagenlecleucel [5 years]
This is to assess presence of (Replication competent lentivirus) RCL in participants receiving tisagenlecleucel by VSV-g qPCR

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Age ≥ 18 years at the date of signing the informed consent form.
Follicular lymphoma grade 1, 2, or 3A confirmed histologically after latest relapse (local assessment).
Relapsed or refractory disease after a second or later line of systemic therapy including an anti-CD20 antibody and an alkylating agent.
Disease that is both active on Positron emission tomography (PET) scan (defined as a score of 4 or 5 on the Deauville 5-point scale) and measurable on Computed tomography (CT) scan.
ECOG performance status of 0, 1 or 2 at screening.
Adequate hematologic, renal, hepatic and pulmonary organ function at screening.
Must meet the institutional criteria to undergo leukapheresis (unless historical leukapheresis is available).
Must be eligible for treatment with the selected standard of care regimen.

Exclusion Criteria:

Follicular lymphoma grade 3B or evidence of histologic transformation.
Prior treatment with anti-CD19 therapy, gene therapy, or adoptive T-cell therapy.
Active CNS involvement by malignancy.
Clinically significant active infection, presence of Human immunodeficiency virus (HIV) antibody or active hepatitis B or C.
Active neurological autoimmune or inflammatory disorders (e.g., Guillain-Barré syndrome).
Investigational medicinal product within the last 30 days or five half-lives (whichever is longer) prior to randomization.
Clinically significant cardiovascular conditions such as acute coronary syndrome, significant cardiac arrhythmias, heart failure or decreased LVEF.