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Phase I/II Study of Rapcabtagene Autoleucel in CLL, 3L+ DLBCL, r/r ALL and 1L HR LBCL
This is a phase I/II study to evaluate the feasibility, safety and preliminary antitumor efficacy of rapcabtagene autoleucel (also known as YTB323). Rapcabtagene autoleucel will be investigated in combination with ibrutinib in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and as single agent in diffuse large B-cell lymphoma (3L+ DLBCL), adult acute lymphoblastic leukemia (ALL) and 1st Line High Risk Large B-Cell Lymphoma (1L HR LBCL).
Study details:
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 50-60 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.
Eligibility criteria
Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.
Inclusion criteria
Exclusion criteria
Eligibility
Age eligible for study : 18 and older
Healthy volunteers accepted : No
Gender eligible for study: All
Things to know
Study dates
Study start: 2019-06-26
Primary completion: 2027-06-30
Study completion finish: 2028-05-31
Study type
TREATMENT
Phase
PHASE1
PHASE2
Trial ID
NCT03960840
Intervention or treatment
BIOLOGICAL: Rapcabtagene autoleucel single agent
DRUG: Ibrutinib
Conditions
- • Chronic Lymphocytic Leukemia
- • Acute Lymphoblastic Leukemia
- • Small Lymphocytic Lymphoma
- • Diffuse Large B-cell Lymphoma
- • Large B-cell Lymphoma
Find a site
Closest Location:
Novartis Investigative Site
Research sites nearby
Select from list below to view details:
Novartis Investigative Site
Melbourne, Victoria, Australia
Novartis Investigative Site
Melbourne, Victoria, Australia
Study Plan
This section provides details of the study plan, including how the study is designed and what the study is measuring.
How is the study designed?
| Participant Group/Arm | Intervention/Treatment |
|---|---|
EXPERIMENTAL: CLL/SLL
| BIOLOGICAL: Rapcabtagene autoleucel single agent
|
EXPERIMENTAL: 3L+ DLBCL
| BIOLOGICAL: Rapcabtagene autoleucel single agent
|
EXPERIMENTAL: Adult ALL
| BIOLOGICAL: Rapcabtagene autoleucel single agent
|
EXPERIMENTAL: 1L HR LBCL
| BIOLOGICAL: Rapcabtagene autoleucel single agent
|
What is the study measuring?
Primary outcome
| Primary Outcome Measure | Primary Outcome Description | Primary Outcome Time Frame |
|---|---|---|
| Phase 1: Dose recommendation: Incidence and nature of Dose Limiting Toxicities (Dose Escalation part only) | Not Specified | 28 days |
| Phase 1: Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs | Not Specified | 24 months |
| Phase 1: Tolerability: Ibrutinib dose modifications in the CLL/SLL arm | Not Specified | 24 months |
| Phase 1: Manufacture success: Number of patients infused with planned target dose | Not Specified | 24 months |
| Phase 2: Complete Response Rate (CRR) as assessed by local Investigator | 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) | 24 months |
Secondary outcome
| Secondary Outcome Measure | Secondary Outcome Description | Secondary Outcome Time Frame |
|---|---|---|
| Phase 1: Complete Response (CR)/Partial Response (CR) in CLL/SLL | per international workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria | 24 months |
| Phase 1: BOR of CR/PR per Lugano criteria in 3L+ DLBCL | Not Specified | 24 months |
| Phase 1: Duration of response (DOR) in CLL/SLL and 3L+ DLBCL | 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 | 24 months |
| Phase 1: BOR in ALL as assessed by an Independent Review Committee (IRC) | BOR of CR/CRi by 3 months after rapcabtagene autoleucel infusion as per IRC assessment. | month 3 |
| Phase 1: DOR in ALL as assessed by an Independent Review Committee | DOR, defined as the time from achievement of CR or CRi to relapse or death due to any cause | 24 months |
| Phase 1: EFS in ALL as assessed by an Independent Review Committee | 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 | 24 months |
| Phase 1: BOR in ALL as assessed by local Investigator | BOR of CR/CRi | 24 months |
| Phase 1: DOR in ALL as assessed by local Investigator | DOR, defined as the time from achievement of CR or CRi to relapse or death due to any cause. | 24 months |
| Phase 1: EFS in ALL as assessed by local Investigator | 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 | 24 months |
| Phase 1: Overall survival in adult ALL | OS defined as time from the date of infusion to the date of death due to any reason | 24 months |
| Phase 1: MRD negative status by flow cytometry in adult ALL | Not Specified | 24 months |
| 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 | Not Specified | 24 months |
| 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 | Not Specified | 24 months |
| Phase 1/2: Cellular kinetics | CAR transgene levels by quantitative polymerase chain reaction (qPCR) in peripheral blood, bone marrow and lymph nodes | 24 months |
| Phase 1/2: Immunogenicity | Cellular and humoral responses to the CAR transgene | 24 months |
| Phase 2: Overall response rate (ORR) | ORR defined as BOR of CR/PR as per Lugano criteria in 3L+ DLBCL and 1L HR LBCL | 24 months |
| Phase 2: Complete Response Rate (CRR) | CRR at months 3, 6 in 3L+ DLBCL | months 3, 6 |
| Phase 2: Complete Response Rate (CRR) | CRR at months 6, 12 in 1L HR LBCL | months 6, 12 |
| Phase 2: Duration of response (DOR) | 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 | 24 months |
| Phase 2: Progression-free survival (PFS) | 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 | 24 months |
| Phase 2: Event-free survival (EFS) | 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 | 24 months |
| Phase 2: Overall survival (OS) | 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 | 24 months |
| Phase 2: Complete Response Rate (CRR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH | CRR at months 6, 12 in 1L HR LBCL | months 6, 12 |
| Phase 2: Overall response rate (ORR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH | ORR defined as BOR of CR/PR as per Lugano criteria 1L HR LBCL | 24 months |
| Phase 2: Duration of response (DOR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH | DOR defined as time from first CR/PR to first documented progression or death due to any cause in 1L HR LBCL | 24 months |
| Phase 2: Progression-free survival (PFS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH | PFS defined as time from rapcabtagene autoleucel infusion to first documented progression or death due to any cause in 1L HR LBCL | 24 months |
| Phase 2: Event-free survival (EFS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH | 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 | 24 months |
| Phase 2: Overall survival (OS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH | OS defined as time from date of rapcabtagene autoleucel infusion to date of death due to any cause in 1L HR LBCL | 24 months |
| Phase 2: Manufacturing vein to door time | Time from apheresis completion until return of rapcabtagene autoleucel product to the clinic or hospital | 24 months |
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