Phase I/II Study of Rapcabtagene Autoleucel in CLL, 3L+ DLBCL, ALL and 1L HR LBCL
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| ClinicalTrials.gov Identifier: NCT03960840 |
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Recruitment Status :
Recruiting
First Posted : May 23, 2019
Last Update Posted : May 3, 2024
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Sponsor:
Novartis Pharmaceuticals
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
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Brief Summary:
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).
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma Diffuse Large B-cell Lymphoma Acute Lymphoblastic Leukemia Large B-cell Lymphoma | Biological: Rapcabtagene autoleucel single agent Drug: Ibrutinib | Phase 1 Phase 2 |
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.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 225 participants |
| Allocation: | Non-Randomized |
| Intervention Model: | Sequential Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I/II, Open Label, Multicenter Study of Rapcabtagene Autoleucel in Adult Patients With CLL/SLL, 3L+ DLBCL, ALL and 1L HR LBCL |
| Actual Study Start Date : | June 26, 2019 |
| Estimated Primary Completion Date : | June 30, 2027 |
| Estimated Study Completion Date : | June 30, 2027 |
Resource links provided by the National Library of Medicine
Drug Information
available for:
Ibrutinib
| Arm | Intervention/treatment |
|---|---|
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Experimental: CLL/SLL
Dose escalation and expansion of rapcabtagene autoleucel in combination with ibrutinib
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Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel Drug: Ibrutinib Tablets or capsules for oral daily use |
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Experimental: 3L+ DLBCL
Dose escalation and expansion of rapcabtagene autoleucel single agent in 3L+ DLBCL
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Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel |
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Experimental: Adult ALL
Dose escalation and expansion of rapcabtagene autoleucel single agent in adult ALL
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Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel |
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Experimental: 1L HR LBCL
Rapcabtagene autoleucel single agent in 1L HR LBCL
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Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel |
Primary Outcome Measures :
- Phase 1: Dose recommendation: Incidence and nature of Dose Limiting Toxicities (Dose Escalation part only) [ Time Frame: 28 days ]
- Phase 1: Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs [ Time Frame: 24 months ]
- Phase 1: Tolerability: Ibrutinib dose modifications in the CLL/SLL arm [ Time Frame: 24 months ]
- Phase 1: Manufacture success: Number of patients infused with planned target dose [ Time Frame: 24 months ]
- 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 Measures :
- 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
- Phase 1: BOR of CR/PR per Lugano criteria in 3L+ DLBCL [ Time Frame: 24 months ]
- 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
- 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.
- 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
- 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
- Phase 1: BOR in ALL as assessed by local Investigator [ Time Frame: 24 months ]BOR of CR/CRi
- 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.
- 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
- 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
- Phase 1: MRD negative status by flow cytometry in adult ALL [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 24 months ]
- 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
- Phase 1/2: Immunogenicity [ Time Frame: 24 months ]Cellular and humoral responses to the CAR transgene
- 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
- Phase 2: Complete Response Rate (CRR) [ Time Frame: months 3, 6 ]CRR at months 3, 6 in 3L+ DLBCL
- Phase 2: Complete Response Rate (CRR) [ Time Frame: months 6, 12 ]CRR at months 6, 12 in 1L HR LBCL
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
Information from the National Library of Medicine
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
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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
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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.
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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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03960840
Contacts
| Contact: Novartis Pharmaceuticals | 1-888-669-6682 | novartis.email@novartis.com | |
| Contact: Novartis Pharmaceuticals | +41613241111 |
Locations
Show 40 study locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
| Study Director: | Novartis Pharmaceuticals | Novartis Pharmaceuticals |
| Responsible Party: | Novartis Pharmaceuticals |
| ClinicalTrials.gov Identifier: | NCT03960840 |
| Other Study ID Numbers: |
CYTB323A12101 |
| First Posted: | May 23, 2019 Key Record Dates |
| Last Update Posted: | May 3, 2024 |
| Last Verified: | May 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Keywords provided by Novartis ( Novartis Pharmaceuticals ):
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CAR-T Ibrutinib CLL DLBCL |
ALL BLRM YTB323 Rapcabtagene autoleucel |
Additional relevant MeSH terms:
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Lymphoma Leukemia Precursor Cell Lymphoblastic Leukemia-Lymphoma Lymphoma, B-Cell Leukemia, Lymphocytic, Chronic, B-Cell Lymphoma, Large B-Cell, Diffuse Neoplasms by Histologic Type Neoplasms Lymphoproliferative Disorders Lymphatic Diseases Immunoproliferative Disorders Immune System Diseases |
Hematologic Diseases Leukemia, Lymphoid Lymphoma, Non-Hodgkin Leukemia, B-Cell Chronic Disease Disease Attributes Pathologic Processes Ibrutinib Tyrosine Kinase Inhibitors Protein Kinase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |