Clinical trial NCT03960840: Phase I/II Study of Rapcabtagene Autoleucel in CLL, 3L+ DLBCL, r/r ALL and 1L HR LBCL
Official title: Phase I/II, Open Label, Multicenter Study of Rapcabtagene Autoleucel in Adult Patients With CLL/SLL, 3L+ DLBCL, r/r ALL and 1L HR LBCL
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukemia
Small Lymphocytic Lymphoma
Diffuse Large B-cell Lymphoma
Acute Lymphoblastic Leukemia
Large B-cell Lymphoma
Keywords: CAR-T
Ibrutinib
CLL
DLBCL
ALL
BLRM
YTB323
Rapcabtagene autoleucel
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2019-05-23
Enrollment: 206
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).

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 may be followed by 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 may 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: Inclusion Criteria:

* ECOG performance status 0-1 for ALL and DLBCL
* ECOG performance status 0-2 for 1L HR LBCL at screening
* 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/TH lymphoma)
* 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 at least one cycle (the most recent) 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 or prior history CNS involvement by malignancy
* Targeted small molecule or kinase inhibitor within 2 weeks from leukapheresis

Other protocol-defined inclusion/exclusion may apply.

Primary outcomes:
measure: Phase 1: Dose recommendation: Incidence and nature of Dose Limiting Toxicities (Dose Escalation part only)
timeFrame: 28 days
measure: Phase 1: Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, ECG and vital signs
timeFrame: 24 months
measure: Phase 1: Tolerability: Ibrutinib dose modifications in the CLL/SLL arm
timeFrame: 24 months
measure: Phase 1: Manufacture success: Number of patients infused with planned target dose
timeFrame: 24 months
measure: Phase 2: Complete Response Rate (CRR) as assessed by local Investigator
timeFrame: 24 months
Secondary outcomes:
measure: Phase 1: Complete Response (CR)/Partial Response (CR) in CLL/SLL
timeFrame: 24 months
measure: Phase 1: BOR of CR/PR per Lugano criteria in 3L+ DLBCL
timeFrame: 24 months
measure: Phase 1: Duration of response (DOR) in CLL/SLL and 3L+ DLBCL
timeFrame: 24 months
measure: Phase 1: BOR in ALL as assessed by an Independent Review Committee (IRC)
timeFrame: month 3
measure: Phase 1: DOR in ALL as assessed by an Independent Review Committee
timeFrame: 24 months
measure: Phase 1: EFS in ALL as assessed by an Independent Review Committee
timeFrame: 24 months
measure: Phase 1: BOR in ALL as assessed by local Investigator
timeFrame: 24 months
measure: Phase 1: DOR in ALL as assessed by local Investigator
timeFrame: 24 months
measure: Phase 1: EFS in ALL as assessed by local Investigator
timeFrame: 24 months
measure: Phase 1: Overall survival in adult ALL
timeFrame: 24 months
measure: Phase 1: MRD negative status by flow cytometry in adult ALL
timeFrame: 24 months
measure: 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
timeFrame: 24 months
measure: 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
timeFrame: 24 months
measure: Phase 1/2: Cellular kinetics
timeFrame: 24 months
measure: Phase 1/2: Immunogenicity
timeFrame: 24 months
measure: Phase 2: Overall response rate (ORR)
timeFrame: 24 months
measure: Phase 2: Complete Response Rate (CRR)
timeFrame: months 3, 6
measure: Phase 2: Complete Response Rate (CRR)
timeFrame: months 6, 12
measure: Phase 2: Duration of response (DOR)
timeFrame: 24 months
measure: Phase 2: Progression-free survival (PFS)
timeFrame: 24 months
measure: Phase 2: Event-free survival (EFS)
timeFrame: 24 months
measure: Phase 2: Overall survival (OS)
timeFrame: 24 months
measure: Phase 2: Complete Response Rate (CRR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH
timeFrame: months 6, 12
measure: Phase 2: Overall response rate (ORR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH
timeFrame: 24 months
measure: Phase 2: Duration of response (DOR) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH
timeFrame: 24 months
measure: Phase 2: Progression-free survival (PFS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH
timeFrame: 24 months
measure: Phase 2: Event-free survival (EFS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH
timeFrame: 24 months
measure: Phase 2: Overall survival (OS) in subgroups 1) IPI 4-5 or DH/TH and 2) IPI 3 and not DH/TH
timeFrame: 24 months
measure: Phase 2: Manufacturing vein to door time
timeFrame: 24 months
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California LA
state: California
city: Stanford
country: United States
facility: Stanford University Medical Center
state: California
city: Tampa
country: United States
facility: H Lee Moffitt Cancer Center and Research Institute
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Chicago
country: United States
facility: Northwestern University Northwestern Memorial Hospital Trans
state: Illinois
city: Chicago
country: United States
facility: Uni of Chi Medi Ctr Hema and Onco
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Cancer Center
state: Kansas
city: Boston
country: United States
facility: Mass Gen Hosp Cancer Center
state: Massachusetts
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Portland
country: United States
facility: Oregon Health Sciences University
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania Clinical
state: Pennsylvania
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Nashville
country: United States
facility: Sarah Cannon Research Institute
state: Tennessee
city: Austin
country: United States
facility: St Davids South Austin Medical Ctr
state: Texas
city: Houston
country: United States
facility: Uni Of TX MD Anderson Cancer Cntr
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Wien
country: Austria
facility: Novartis Investigative Site
city: Marseille
country: France
facility: Novartis Investigative Site
city: Paris 10
country: France
facility: Novartis Investigative Site
city: Pierre Benite
country: France
facility: Novartis Investigative Site
city: Rennes
country: France
facility: Novartis Investigative Site
city: Frankfurt am Main
country: Germany
facility: Novartis Investigative Site
state: Hessen
city: Leipzig
country: Germany
facility: Novartis Investigative Site
state: Sachsen
city: Essen
country: Germany
facility: Novartis Investigative Site
city: Bergamo
country: Italy
facility: Novartis Investigative Site
state: BG
city: Bologna
country: Italy
facility: Novartis Investigative Site
state: BO
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Rozzano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Fukuoka city
country: Japan
facility: Novartis Investigative Site
state: Fukuoka
city: Sapporo city
country: Japan
facility: Novartis Investigative Site
state: Hokkaido
city: Bunkyo ku
country: Japan
facility: Novartis Investigative Site
state: Tokyo
city: Cordoba
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Sevilla
country: Spain
facility: Novartis Investigative Site
state: Andalucia
city: Salamanca
country: Spain
facility: Novartis Investigative Site
state: Castilla Y Leon
city: Badalona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Hospitalet de LLobregat
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Valencia
country: Spain
facility: Novartis Investigative Site
state: Comunidad Valenciana
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: