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JOURNAL ONKOLOGIE – STUDIE

Phase I/II Study of Rapcabtagene Autoleucel in CLL, 3L+ DLBCL, ALL and 1L HR LBCL

Rekrutierend

NCT-Nummer:
NCT03960840

Studienbeginn:
Juni 2019

Letztes Update:
03.01.2024

Wirkstoff:
Rapcabtagene autoleucel single agent, Ibrutinib

Indikation (Clinical Trials):
Lymphoma, Leukemia, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Lymphoma, B-Cell, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphoma, Large B-Cell, Diffuse

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
-

Sponsor:
Novartis Pharmaceuticals

Collaborator:
-

Studienleiter

Novartis Pharmaceuticals
Study Director
Novartis Pharmaceuticals

Kontakt

Studienlocations
(3 von 36)

Novartis Investigative Site
60590 Frankfurt
(Hessen)
GermanyRekrutierend» Google-Maps
Novartis Investigative Site
50937 Koeln
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
University Of California Los Angeles UCLA Hematology Oncology
90095 Los Angeles
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Elizabeth Benkert
Phone: 310-794-6500
E-Mail: EBenkert@mednet.ucla.edu
» Ansprechpartner anzeigen
Northwestern University Northwestern Memorial Hospital Trans
60611 Chicago
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Holly Roberta Krieg
E-Mail: hollyroberta.krieg@northwestern.edu
» Ansprechpartner anzeigen
University of Chicago Medical Center Hematology and Oncology
60637 Chicago
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Elaine Hoekstra
Phone: 773-834-8980
E-Mail: ehoekstra1@medicine.bsd.uchicago.edu
» Ansprechpartner anzeigen
University of Pennsylvania Clinical Perelman Center for Adv Med
19104 Philadelphia
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Rachael Purri
Phone: 215-615-6721
E-Mail: rachael.purri@pennmedicine.upenn.edu
» Ansprechpartner anzeigen
Novartis Investigative Site
3000 Melbourne
AustraliaRekrutierend» Google-Maps
Novartis Investigative Site
3004 Melbourne
AustraliaRekrutierend» Google-Maps
Novartis Investigative Site
13273 Marseille
FranceRekrutierend» Google-Maps
Novartis Investigative Site
69495 Pierre Benite
FranceRekrutierend» Google-Maps
Novartis Investigative Site
812-8582 Fukuoka city
JapanRekrutierend» Google-Maps
Novartis Investigative Site
060 8648 Sapporo city
JapanRekrutierend» Google-Maps
Novartis Investigative Site
113-8677 Bunkyo ku
JapanRekrutierend» Google-Maps
Alle anzeigen

Studien-Informationen

Detailed Description:

This clinical trial is phase I/II open label, multi-center study of rapcabtagene autoleucel.

The Phase I part of the study comprises three independent treatment arms:

- Rapcabtagene autoleucel in combination with ibrutinib in adult CLL/SLL participants with

SD or PR after at least 6 months of second or subsequent line ibrutinib therapy. As of

05-May-2021, this arm had completed enrollment.

- Rapcabtagene autoleucel single agent in adult DLBCL participants having failed two or

more lines of chemotherapy and either having progressed (or relapsed) after autologous

HSCT or being ineligible for or not consenting to the procedure.

- Rapcabtagene autoleucel single agent in adult relapsed/refractory ALL participants

The Phase II part of the study comprises two independent cohorts:

- Rapcabtagene autoleucel single agent in adult 3L + DLBCL participants having failed two

or more lines of chemoimmunotherapy and either having progressed (or relapsed) after

autologous HSCT or being ineligible for or not consenting to the procedure. This is an

extension of the Phase I r/r DLBCL treatment arm to support Phase II objectives

- Rapcabtagene autoleucel single agent in newly diagnosed, adult 1L HR LBCL participants

defined as IPI 3-5 and/or DH/TH disease who have completed 2 cycles of CIT and have a

response of PR/SD (with a Deauville score of 4-5).

In the Phase I part of the trial, the 3L+ DLBCL and ALL arms consist of two parts: a dose

escalation part to evaluate feasibility, characterize safety and identify the recommended

dose (RD) of rapcabtagene autoleucel, and a dose expansion part to further characterize

safety, study rapcabtagene autoleucel cellular kinetics and assess preliminary antitumor

activity. Once the RD of rapcabtagene autoleucel is determined for each arm, the

corresponding expansion part will commence.

In the Phase II part of the trial, approximately 70 additional participants will be enrolled

in a 3L+ DLBCL cohort treated at the recommended dose (RD). Including the 3L+ DLBCL

participants who were treated at the RD from the Phase I part, it is planned to have in total

a cohort of approximately 100 participants included in the primary efficacy analysis based on

the efficacy analysis set. In addition, a separate cohort in 1LHR LBCL will be included, with

approximately 40 participants planned for the primary efficacy analysis based on the efficacy

analysis set.

Participants will be followed under the current treatment protocol for safety and efficacy

within this trial for a minimum of 2 years before being transferred to the long-term

follow-up trial. Once the study is complete, participants will be enrolled in a post-study

long term follow-up for lentiviral vector safety for up to 15 years. This post-study long

term follow-up for lentiviral vector safety will continue under a separate destination

protocol.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- ECOG performance status 0-1

- CLL or SLL diagnosis according to iwCLL criteria

- CLL/SLL in SD or PR after at least 6 months of ibrutinib, either as second or

subsequent line of therapy

- DLBCL diagnosis by local histopathology

- DLBCL relapsed or refractory after 2 or more lines of therapy, including autologous

hematopoietic stem cell transplantation (HSCT)

- Refractory or relapsed CD19-positive ALL

- ALL with morphologic disease in the bone marrow

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/THL)

- 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.

- 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:

- Prior CD19-directed therapy

- Prior administration of a genetically engineered cellular product

- Prior allogeneic HSCT

- Richter's transformation

- For 1L HR LBCL: Richter's transformation, Burkitt lymphoma, primary DLBCL of CNS,

DLBCL associated with chronic inflammation, intravascular large B-cell lymphoma,

ALK- positive large B-cell lymphoma, HHV8 positive LBCL, DLBCL leg type or EBV

positive DLBCL, NOS.

- Active CNS lymphoma

- For 1L HR LBCL: Active CNS involvement by malignancy

- Targeted small molecule or kinase inhibitor within 2 weeks from leukapheresis

Other protocol-defined inclusion/exclusion may apply.

Studien-Rationale

Primary outcome:

1. Phase 1: Dose recommendation: Incidence and nature of Dose Limiting Toxicities (Dose Escalation part only) (Time Frame - 28 days)

2. Phase 1: Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs (Time Frame - 24 months)

3. Phase 1: Tolerability: Ibrutinib dose modifications in the CLL/SLL arm (Time Frame - 24 months)

4. Phase 1: Manufacture success: Number of patients infused with planned target dose (Time Frame - 24 months)

5. Phase 2: Complete Response Rate (CRR) as assessed by local Investigator (Time Frame - 24 months):
CRR defined as best overall response (BOR) of CR after rapcabtagene autoleucel infusion as per Lugano criteria for 3L+ Diffuse Large B-Cell Lymphoma (DLBCL) and 1L High Risk Large B-Cell (HR LBCL)

Secondary outcome:

1. Phase 1: Complete Response (CR)/Partial Response (CR) in CLL/SLL (Time Frame - 24 months):
per international workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria

2. Phase 1: BOR of CR/PR per Lugano criteria in 3L+ DLBCL (Time Frame - 24 months)

3. Phase 1: Duration of response (DOR) in CLL/SLL and 3L+ DLBCL (Time Frame - 24 months):
DOR as assessed by time from first achievement of CR/PR after rapcabtagene autoleucel infusion until first documented disease progression or death due to any cause

4. Phase 1: BOR in ALL as assessed by an Independent Review Committee (IRC) (Time Frame - month 3):
BOR of CR/CRi by 3 months after rapcabtagene autoleucel infusion as per IRC assessment.

5. Phase 1: DOR in ALL as assessed by an Independent Review Committee (Time Frame - 24 months):
DOR, defined as the time from achievement of CR or CRi to relapse or death due to any cause

6. Phase 1: EFS in ALL as assessed by an Independent Review Committee (Time Frame - 24 months):
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

7. Phase 1: BOR in ALL as assessed by local Investigator (Time Frame - 24 months):
BOR of CR/CRi

8. Phase 1: DOR in ALL as assessed by local Investigator (Time Frame - 24 months):
DOR, defined as the time from achievement of CR or CRi to relapse or death due to any cause.

9. Phase 1: EFS in ALL as assessed by local Investigator (Time Frame - 24 months):
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

10. Phase 1: Overall survival in adult ALL (Time Frame - 24 months):
OS defined as time from the date of infusion to the date of death due to any reason

11. Phase 1: MRD negative status by flow cytometry in adult ALL (Time Frame - 24 months)

12. Phase 1: Quality of life in adult ALL patients enrolled in the expansion part by use of Electronic Patient Reported Outcomes (ePRO) as per EORTC QLQ-C30 questionnaire (Time Frame - 24 months)

13. Phase 1: Quality of life in adult ALL patients enrolled in the expansion part by use of Electronic Patient Reported Outcomes (ePRO) as per EQ-5D-3 questionnaire (Time Frame - 24 months)

14. Phase 1/2: Cellular kinetics (Time Frame - 24 months):
CAR transgene levels by quantitative polymerase chain reaction (qPCR) in peripheral blood, bone marrow and lymph nodes

15. Phase 1/2: Immunogenicity (Time Frame - 24 months):
Cellular and humoral responses to the CAR transgene

16. Phase 2: Overall response rate (ORR) (Time Frame - 24 months):
ORR defined as BOR of CR/PR as per Lugano criteria in 3L+ DLBCL and 1L HR LBCL

17. Phase 2: Complete Response Rate (CRR) (Time Frame - months 3, 6):
CRR at months 3, 6 in 3L+ DLBCL

18. Phase 2: Complete Response Rate (CRR) (Time Frame - months 6, 12):
CRR at months 6, 12 in 1L HR LBCL

19. Phase 2: Duration of response (DOR) (Time Frame - 24 months):
DOR defined as time from first CR/PR to first documented progression or death due to any cause in 3L+ DLBCL and 1L HR LBCL

20. Phase 2: Progression-free survival (PFS) (Time Frame - 24 months):
PFS defined as time from rapcabtagene autoleucel infusion to first documented progression or death due to any cause in 3L+ DLBCL and 1L HR LBCL

21. Phase 2: Event-free survival (EFS) (Time Frame - 24 months):
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 in 1L HR LBCL

22. Phase 2: Overall survival (OS) (Time Frame - 24 months):
OS defined as time from date of rapcabtagene autoleucel infusion to date of death due to any cause in 3L+ DLBCL and 1L HR LBCL

23. Phase 2: Complete Response Rate (CRR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH (Time Frame - months 6, 12):
CRR at months 6, 12 in 1L HR LBCL

24. Phase 2: Overall response rate (ORR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH (Time Frame - 24 months):
ORR defined as BOR of CR/PR as per Lugano criteria 1L HR LBCL

25. Phase 2: Duration of response (DOR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH (Time Frame - 24 months):
DOR defined as time from first CR/PR to first documented progression or death due to any cause in 1L HR LBCL

26. Phase 2: Progression-free survival (PFS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH (Time Frame - 24 months):
PFS defined as time from rapcabtagene autoleucel infusion to first documented progression or death due to any cause in 1L HR LBCL

27. Phase 2: Event-free survival (EFS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH (Time Frame - 24 months):
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 in 1L HR LBCL

28. Phase 2: Overall survival (OS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH (Time Frame - 24 months):
OS defined as time from date of rapcabtagene autoleucel infusion to date of death due to any cause in 1L HR LBCL

29. Phase 2: Manufacturing vein to door time (Time Frame - 24 months):
Time from apheresis completion until return of rapcabtagene autoleucel product to the clinic or hospital

Studien-Arme

  • Experimental: CLL/SLL
    Dose escalation and expansion of rapcabtagene autoleucel in combination with ibrutinib
  • Experimental: 3L+ DLBCL
    Dose escalation and expansion of rapcabtagene autoleucel single agent in 3L+ DLBCL
  • Experimental: Adult ALL
    Dose escalation and expansion of rapcabtagene autoleucel single agent in adult ALL
  • Experimental: 1L HR LBCL
    Rapcabtagene autoleucel single agent in 1L HR LBCL

Geprüfte Regime

  • Rapcabtagene autoleucel single agent:
    Single infusion of rapcabtagene autoleucel
  • Ibrutinib:
    Tablets or capsules for oral daily use

Quelle: ClinicalTrials.gov


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