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

Chronic Lymphocytic Leukemia Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03960840
• Other study ID #: CYTB323A12101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 26, 2019
• Est. completion date: June 30, 2027

Study information

• Verified date: May 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 225
• Est. completion date: June 30, 2027
• Est. primary completion date: June 30, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Chronic Lymphocytic Leukemia
• Diffuse Large B-cell Lymphoma
• Large B-cell Lymphoma
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Large B-Cell, Diffuse
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Small Lymphocytic Lymphoma

Intervention

Biological:
• Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel

Drug:
• Ibrutinib
Tablets or capsules for oral daily use

Locations

Country	Name	City	State
Australia	Novartis Investigative Site	Melbourne	Victoria
Australia	Novartis Investigative Site	Melbourne	Victoria
Austria	Novartis Investigative Site	Wien
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Paris 10
France	Novartis Investigative Site	Pierre Benite
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Frankfurt
Germany	Novartis Investigative Site	Koeln
Italy	Novartis Investigative Site	Bergamo	BG
Italy	Novartis Investigative Site	Bologna	BO
Italy	Novartis Investigative Site	Milano	MI
Italy	Novartis Investigative Site	Rozzano	MI
Japan	Novartis Investigative Site	Bunkyo ku	Tokyo
Japan	Novartis Investigative Site	Fukuoka city	Fukuoka
Japan	Novartis Investigative Site	Sapporo city	Hokkaido
Spain	Novartis Investigative Site	Badalona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Cordoba	Andalucia
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Salamanca	Castilla Y Leon
Spain	Novartis Investigative Site	Sevilla	Andalucia
Spain	Novartis Investigative Site	Valencia	Comunidad Valenciana
United States	Northside Hospital .	Atlanta	Georgia
United States	St Davids South Austin Medical Ctr	Austin	Texas
United States	Mass Gen Hosp Cancer Center .	Boston	Massachusetts
United States	Montefiore Medical Center .	Bronx	New York
United States	Northwestern University Northwestern Memorial Hospital Trans	Chicago	Illinois
United States	Uni of Chi Medi Ctr Hema and Onco	Chicago	Illinois
United States	Uni of TX MD Anderson Cancer Cntr	Houston	Texas
United States	University Of California LA UCLA Hematology Oncology	Los Angeles	California
United States	Medical College of Wisconsin Main Centre	Milwaukee	Wisconsin
United States	Sarah Cannon Research Institute Drug Ship - 4	Nashville	Tennessee
United States	Sarah Cannon Research Institute Methodist Hospital	Nashville	Tennessee
United States	University of Pennsylvania Clinical Perelman Center for Adv Med	Philadelphia	Pennsylvania
United States	Stanford University Medical Center	Stanford	California
United States	H Lee Moffitt Cancer Center and Research Institute .	Tampa	Florida
United States	University of Kansas Cancer Center SC - CTL019C2201	Westwood	Kansas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Austria,  France,  Germany,  Italy,  Japan,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Phase 1: Dose recommendation: Incidence and nature of Dose Limiting Toxicities (Dose Escalation part only)		28 days
Primary	Phase 1: Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs		24 months
Primary	Phase 1: Tolerability: Ibrutinib dose modifications in the CLL/SLL arm		24 months
Primary	Phase 1: Manufacture success: Number of patients infused with planned target dose		24 months
Primary	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	Phase 1: Complete Response (CR)/Partial Response (CR) in CLL/SLL	per international workshop on Chronic Lymphocytic Leukemia (iwCLL) response criteria	24 months
Secondary	Phase 1: BOR of CR/PR per Lugano criteria in 3L+ DLBCL		24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 1: BOR in ALL as assessed by local Investigator	BOR of CR/CRi	24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 1: MRD negative status by flow cytometry in adult ALL		24 months
Secondary	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		24 months
Secondary	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		24 months
Secondary	Phase 1/2: Cellular kinetics	CAR transgene levels by quantitative polymerase chain reaction (qPCR) in peripheral blood, bone marrow and lymph nodes	24 months
Secondary	Phase 1/2: Immunogenicity	Cellular and humoral responses to the CAR transgene	24 months
Secondary	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
Secondary	Phase 2: Complete Response Rate (CRR)	CRR at months 3, 6 in 3L+ DLBCL	months 3, 6
Secondary	Phase 2: Complete Response Rate (CRR)	CRR at months 6, 12 in 1L HR LBCL	months 6, 12
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Phase 2: Manufacturing vein to door time	Time from apheresis completion until return of rapcabtagene autoleucel product to the clinic or hospital	24 months