Study of Rapcabtagene autoleucel (YTB323) in adult patients with CLL/SLL, 3L+ DLBCL, r/r ALL and 1L HR LBCL

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

7 Aug 2020 → ongoing

Decision date (initial)

2024-08-05

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Novartis Pharma AG

External identifiers

EU CT number

2023-507062-34-00

EudraCT number

2018-004336-30

ClinicalTrials.gov

NCT03960840

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Therapy, Efficacy, Pharmacokinetic, Pharmacodynamic

Phase I:
The primary objective of the Phase I part of this study is to identify the Recommended Dose of rapcabtagene autoleucel and to characterize safety of rapcabtagene autoleucel as single agent in r/r DLBCL and r/r adult ALL, and to characterize the safety of rapcabtagene autoleucel in combination with ibrutinib in CLL/SLL. Another primary objective is to evaluate the feasibility of rapcabtagene autoleucel manufacturing process.
Phase II:
3L+ DLBCL: The primary objective is to demonstrate the antitumor activity of rapcabtagene autoleucel on complete disease response as assessed by local Investigator.
1L HR LBCL: The primary objective is to assess the antitumor activity of rapcabtagene autoleucel on complete disease response as assessed by local Investigator.

Secondary objectives 16

1. Phase I: CLL/SLL, 3L+ DLBCL and ALL: • Characterize the in vivo cellular kinetics of rapcabtagene autoleucel in peripheral blood, bone marrow and lymph nodes by qPCR.
2. Phase I: CLL/SLL, 3L+ DLBCL and ALL: • Characterize the incidence and prevalence of pre-existing and treatment-induced immunogenicity (cellular and humoral) of rapcabtagene autoleucel.
3. Phase I: CLL/SLL: • Assess the antitumor activity of rapcabtagene autoleucel in combination with ibrutinib in CLL/SLL as assessed by local investigator.
4. Phase I: 3L+ DLBCL and ALL: • Assess the antitumor activity of rapcabtagene autoleucel single agent in 3L+ DLBCL and r/r adult ALL as assessed by local investigator.
5. Phase I: ALL: • Assess the antitumor activity of rapcabtagene autoleucel single agent in r/r adult ALL as assessed by central laboratory.
6. Phase II: 3L+ DLBCL: • Assess antitumor activity of rapcabtagene autoleucel on additional efficacy outcomes (ORR, CRR at months 3 and 6, DOR, PFS, OS).
7. Phase II: 3L+ DLBCL: • Characterize safety of rapcabtagene autoleucel.
8. Phase II: 3L+ DLBCL: • Characterize the in vivo cellular kinetics of rapcabtagene autoleucel in peripheral blood and relevant tissues by quantitative polymerase chain reaction (qPCR).
9. Phase II: 3L+ DLBCL: • Characterize the incidence and prevalence of pre-existing and treatment induced immunogenicity (cellular and humoral) of rapcabtagene autoleucel.
10. Phase II: 3L+ DLBCL: • Evaluate the product vein to door time for rapcabtagene autoleucel.
11. Phase II: 1L HR LBCL: • Assess antitumor activity of rapcabtagene autoleucel on additional efficacy outcomes (ORR, CRR at months 6 and 12, DOR, PFS, EFS, OS).
12. Phase II: 1L HR LBCL: • Assess antitumor activity of rapcabtagene autoleucel within the following subgroups: (1) IPI 4-5 or DH/TH, (2) IPI 3 and not DH/TH (CRR, ORR, CRR at months 6 and 12, DOR, PFS, EFS, OS).
13. Phase II: 1L HR LBCL: • Characterize safety of rapcabtagene autoleucel overall, and separately in the following subgroups: (1) IPI 4-5 or DH/TH, (2) IPI 3 and not DH/TH.
14. Phase II: 1L HR LBCL: • Characterize the in vivo cellular kinetics of rapcabtagene autoleucel in peripheral blood and relevant tissues by quantitative polymerase chain reaction (qPCR).
15. Phase II: 1L HR LBCL: • Characterize the incidence and prevalence of pre-existing and treatment induced immunogenicity (cellular and humoral) of rapcabtagene autoleucel.
16. Phase II: 1L HR LBCL: • Evaluate the product vein to door time for rapcabtagene autoleucel.

Conditions and MedDRA coding

High-Risk large B-Cell lymphoma

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 3L+ DLBCL: Relapsed or refractory disease having received 2 or more lines of therapy, including anti-CD20 and anthracycline-based chemotherapy, and either having progressed (or relapsed) after autologous HSCT or being ineligible/not consenting to the procedure. Measurable disease at time of enrollment.
2. ALL: r/r CD19-positive ALL with morphologic disease in the bone marrow (≥ 5% blasts) and including at least 1 of the following: • After allogeneic HSCT • After 2 or more lines of treatment • Primary refractory disease • First relapse occurring within 12 months from first remission • Patients with Philadelphia chromosome-positive ALL must have failed at least 2 different tyrosine kinase inhibitors.
3. 1L HR LBCL: - Considered to be high-risk based on at least 1 of the following at diagnosis: • IPI score of 3, 4 or 5 • MYC and BCL2 and/or BCL6 rearrangement (DH/TH).
4. 1L HR LBCL: - Participants must have received 2 cycles of frontline therapy for LBCL with R-CHOP or Pola-R-CHP or DA-EPOCH-R. Participants with DH/TH lymphoma must have received DA-EPOCH-R.
5. 1L HR LBCL: - Participants must have a positive PET per Lugano classification (Deauville PET score of 4 or 5 and an overall response of PR/SD) after 2 cycles of frontline CIT. Note: Patient’s with Deauville PET score of 5 and overall response of PD, or with Deauville PET score of 1, 2, or 3 and overall response of CR, are not eligible for this trial.

Exclusion criteria 5

1. ALL: allogeneic HSCT within 12 weeks prior to screening
2. Prior CD19-directed therapy with the exception of blinatumomab for patients with ALL
3. Prior administration of a genetically modified cellular product
4. 3L+ DLBCL with primary CNS lymphoma
5. 3L+ DLBCL: prior allogeneic HSCT

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Phase I part - CLL/SLL, 3L+ DLBCL, ALL: - Incidence and nature of Dose Limiting Toxicities during the first 28 days after rapcabtagene autoleucel infusion (Dose Escalation part only) Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs after rapcabtagene autoleucel infusion.
2. Phase I part - CLL/SLL, 3L+ DLBCL, ALL: - Ibrutinib dose modifications following rapcabtagene autoleucel infusion.
3. Phase I part - CLL/SLL, 3L+ DLBCL, ALL: - Manufacture success rate (defined as number of participants with product that meets release specifications and at or above the planned target dose divided by total number of patients enrolled).
4. Phase II part – 3L+ DLBCL: - CRR defined as BOR of CR after rapcabtagene autoleucel infusion as per Lugano criteria.
5. Phase II part – 1L HR LBCL: - CRR defined as BOR of CR after rapcabtagene autoleucel infusion as per Lugano criteria.

Secondary endpoints 26

1. Phase I part - CLL/SLL, 3L+ DLBCL and ALL: - qPCR-detected rapcabtagene autoleucel transgene concentrations over time in peripheral blood and relevant tissues.
2. Phase I part - CLL/SLL, 3L+ DLBCL, ALL: - Pre-existing and treatment induced immunogenicity (cellular and humoral) of rapcabtagene autoleucel.
3. Phase I part - CLL/SLL: - BOR of CR/PR per iwCLL response criteria Duration of response (DOR), i.e., time from first achievement of CR/PR after rapcabtagene autoleucel infusion until first documented disease progression or death due to any cause.
4. Phase I part - 3L+ DLBCL: - BOR of CR/PR as per Lugano criteria. Complete response rate (CRR) at months 3 and 6 DOR.
5. Phase I part - ALL: - BOR of CR/Cri. Disease response (CR/Cri) at month 3 and 6. DOR, defined as the time from achievement of CR or Cri to relapse or death due to any cause. EFS, defined as the date from rapcabtagene autoleucel infusion to the earliest date of relapse after CR/Cri, treatment failure (defined as failure to achieve CR/Cri within 12 weeks of infusion), or death due to any cause.
6. Phase I part – ALL: - MRD negative status by flow cytometry.
7. Phase II part – 3L+ DLBCL: - Overall response rate (ORR) defined as BOR of CR/PR as per Lugano criteria.
8. Phase II part – 3L+ DLBCL: - CRR at months 3 and 6.
9. Phase II part – 3L+ DLBCL: - Duration of response (DOR), defined as time from first CR/PR to first documented progression or death due to any cause.
10. Phase II part – 3L+ DLBCL: - Progression-free survival (PFS) defined as time from rapcabtagene autoleucel infusion to first documented progression or death due to any cause.
11. Phase II part – 3L+ DLBCL: - Overall survival (OS), defined as time from date of rapcabtagene autoleucel infusion to date of death due to any cause.
12. Phase II part – 3L+ DLBCL: - Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs after rapcabtagene autoleucel infusion.
13. Phase II part – 3L+ DLBCL: - qPCR-detected rapcabtagene autoleucel transgene concentrations over time in peripheral blood and relevant tissues.
14. Phase II part – 3L+ DLBCL: - Pre-existing and treatment induced immunogenicity (cellular and humoral) of rapcabtagene autoleucel.
15. Phase II part – 3L+ DLBCL: - Time from apheresis completion until return of rapcabtagene autoleucel product to the clinic or hospital.
16. Phase II part – 1L HR LBCL: - Overall response rate (ORR) defined as BOR of CR/PR as per Lugano criteria.
17. Phase II part – 1L HR LBCL: - CRR at months 6 and 12.
18. Phase II part – 1L HR LBCL: - Duration of response (DOR). Defined as time from first CR/PR to first documented progression or death due to any cause.
19. Phase II part – 1L HR LBCL: - Progression-free survival (PFS) defined as time from rapcabtagene autoleucel infusion to first documented progression or death due to any cause.
20. Phase II part – 1L HR LBCL: - Event-free survival (EFS) defined as time from rapcabtagene autoleucel infusion to first documented progression, start of new anti-lymphoma therapy, biopsy-proven residual disease on or after month 6, or death due to any cause.
21. Phase II part – 1L HR LBCL: - Overall survival (OS), defined as time from date of rapcabtagene autoleucel infusion to date of death due to any cause.
22. Phase II part – 1L HR LBCL: - Within each subgroup: CRR, ORR CRR at months 6 and 12 DOR, PFS, EFS, OS
23. Phase II part – 1L HR LBCL: - Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs after rapcabtagene autoleucel infusion.
24. Phase II part – 1L HR LBCL: - qPCR-detected rapcabtagene autoleucel transgene concentrations over time in peripheral blood and relevant tissues.
25. Phase II part – 1L HR LBCL: - Pre-existing and treatment induced immunogenicity (cellular and humoral) of rapcabtagene autoleucel.
26. Phase II part – 1L HR LBCL: - Time from apheresis completion until return of rapcabtagene autoleucel product to the clinic or hospital.

Investigational products

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

Test 2

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Novartis Pharma AG

Sponsor organisation

Novartis Pharma AG

Address

Lichtstrasse 35

City

Basel Town

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 18

Locations

5 EU/EEA countries · 22 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 71 files

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

Application history

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