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

January 1, 2024 updated by: Novartis Pharmaceuticals

Phase I/II, Open Label, Multicenter Study of Rapcabtagene Autoleucel in Adult Patients With CLL/SLL, 3L+ DLBCL, 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 Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

225

Phase

  • Phase 2
  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Novartis Pharmaceuticals
  • Phone Number: +41613241111

Study Locations

  • Australia
    • Victoria
      • Melbourne, Victoria, Australia, 3000
        • Recruiting
        • Novartis Investigative Site
      • Melbourne, Victoria, Australia, 3004
        • Recruiting
        • Novartis Investigative Site
  • Austria
      • Wien, Austria, A-1090
        • Recruiting
        • Novartis Investigative Site
  • France
      • Marseille, France, 13273
        • Recruiting
        • Novartis Investigative Site
      • Paris 10, France, 75475
        • Recruiting
        • Novartis Investigative Site
      • Pierre Benite, France, 69495
        • Recruiting
        • Novartis Investigative Site
  • Germany
      • Frankfurt, Germany, 60590
        • Recruiting
        • Novartis Investigative Site
      • Koeln, Germany, 50937
        • Recruiting
        • Novartis Investigative Site
  • Italy
    • BG
      • Bergamo, BG, Italy, 24128
        • Recruiting
        • Novartis Investigative Site
    • BO
      • Bologna, BO, Italy, 40138
        • Recruiting
        • Novartis Investigative Site
    • MI
      • Milano, MI, Italy, 20132
        • Recruiting
        • Novartis Investigative Site
  • Japan
    • Fukuoka
      • Fukuoka city, Fukuoka, Japan, 812-8582
        • Recruiting
        • Novartis Investigative Site
    • Hokkaido
      • Sapporo city, Hokkaido, Japan, 060 8648
        • Recruiting
        • Novartis Investigative Site
    • Tokyo
      • Bunkyo ku, Tokyo, Japan, 113-8677
        • Recruiting
        • Novartis Investigative Site
  • Spain
      • Barcelona, Spain, 08041
        • Recruiting
        • Novartis Investigative Site
      • Madrid, Spain, 28041
        • Recruiting
        • Novartis Investigative Site
      • Madrid, Spain, 28009
        • Recruiting
        • Novartis Investigative Site
    • Andalucia
      • Cordoba, Andalucia, Spain, 14004
        • Recruiting
        • Novartis Investigative Site
      • Sevilla, Andalucia, Spain, 41013
        • Recruiting
        • Novartis Investigative Site
    • Catalunya
      • Badalona, Catalunya, Spain, 08916
        • Recruiting
        • Novartis Investigative Site
      • Barcelona, Catalunya, Spain, 08035
        • Recruiting
        • Novartis Investigative Site
    • Comunidad Valenciana
      • Valencia, Comunidad Valenciana, Spain, 46010
        • Recruiting
        • Novartis Investigative Site
  • United States
    • California
      • Los Angeles, California, United States, 90095
        • Recruiting
        • University Of California Los Angeles UCLA Hematology Oncology
        • Principal Investigator:
          • Patricia Young
        • Contact:
      • Stanford, California, United States, 94305-5826
        • Recruiting
        • Stanford University Medical Center
        • Principal Investigator:
          • Lori Muffly
        • Contact:
    • Florida
      • Tampa, Florida, United States, 33612
        • Recruiting
        • H Lee Moffitt Cancer Center and Research Institute .
        • Principal Investigator:
          • Julio Chavez
        • Contact:
    • Georgia
      • Atlanta, Georgia, United States, 30342
        • Recruiting
        • Northside Hospital .
        • Principal Investigator:
          • Scott D. Solomon
        • Contact:
    • Illinois
      • Chicago, Illinois, United States, 60637
        • Recruiting
        • University of Chicago Medical Center Hematology and Oncology
        • Contact:
        • Principal Investigator:
          • Peter Riedell
      • Chicago, Illinois, United States, 60611
        • Recruiting
        • Northwestern University Northwestern Memorial Hospital Trans
        • Principal Investigator:
          • Shira Dinner
        • Contact:
    • Kansas
      • Westwood, Kansas, United States, 66205
        • Recruiting
        • University of Kansas Cancer Center SC - CTL019C2201
        • Principal Investigator:
          • Leyla Shune
        • Contact:
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Recruiting
        • Mass Gen Hosp Cancer Center .
        • Principal Investigator:
          • Matthew Frigault
        • Contact:
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Recruiting
        • University of Pennsylvania Clinical Perelman Center for Adv Med
        • Contact:
        • Principal Investigator:
          • Noelle Frey
    • Tennessee
      • Nashville, Tennessee, United States, 37203
        • Recruiting
        • Sarah Cannon Research Institute Drug Ship - 4
        • Principal Investigator:
          • Ian W. Flinn
        • Contact:
      • Nashville, Tennessee, United States, 37221
        • Recruiting
        • Sarah Cannon Research Institute Methodist Hospital
        • Principal Investigator:
          • Paul Shaughnessy
        • Contact:
    • Texas
      • Austin, Texas, United States, 78704
        • Recruiting
        • St Davids South Austin Medical Ctr
        • Principal Investigator:
          • Aravind Ramakrishnan
        • Contact:
      • Houston, Texas, United States, 77030
        • Recruiting
        • Uni of TX MD Anderson Cancer Cntr
        • Principal Investigator:
          • Jason Westin
        • Contact:
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Recruiting
        • Medical College of Wisconsin Main Centre
        • Principal Investigator:
          • Nirav Shah
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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.

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?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Sequential Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: CLL/SLL
Dose escalation and expansion of rapcabtagene autoleucel in combination with ibrutinib
Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel
Drug: Ibrutinib
Tablets or capsules for oral daily use
Experimental: 3L+ DLBCL
Dose escalation and expansion of rapcabtagene autoleucel single agent in 3L+ DLBCL
Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel
Experimental: Adult ALL
Dose escalation and expansion of rapcabtagene autoleucel single agent in adult ALL
Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel
Experimental: 1L HR LBCL
Rapcabtagene autoleucel single agent in 1L HR LBCL
Biological: Rapcabtagene autoleucel single agent
Single infusion of rapcabtagene autoleucel

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Phase 1: Dose recommendation: Incidence and nature of Dose Limiting Toxicities (Dose Escalation part only)
Time Frame: 28 days
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
24 months
Phase 1: Tolerability: Ibrutinib dose modifications in the CLL/SLL arm
Time Frame: 24 months
24 months
Phase 1: Manufacture success: Number of patients infused with planned target dose
Time Frame: 24 months
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)
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
24 months
Phase 1: BOR of CR/PR per Lugano criteria in 3L+ DLBCL
Time Frame: 24 months
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
24 months
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.
month 3
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
24 months
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
24 months
Phase 1: BOR in ALL as assessed by local Investigator
Time Frame: 24 months
BOR of CR/CRi
24 months
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.
24 months
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
24 months
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
24 months
Phase 1: MRD negative status by flow cytometry in adult ALL
Time Frame: 24 months
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
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
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
24 months
Phase 1/2: Immunogenicity
Time Frame: 24 months
Cellular and humoral responses to the CAR transgene
24 months
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
24 months
Phase 2: Complete Response Rate (CRR)
Time Frame: months 3, 6
CRR at months 3, 6 in 3L+ DLBCL
months 3, 6
Phase 2: Complete Response Rate (CRR)
Time Frame: months 6, 12
CRR at months 6, 12 in 1L HR LBCL
months 6, 12
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
24 months
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
24 months
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
24 months
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
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
Time Frame: months 6, 12
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
Time Frame: 24 months
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
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
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
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
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
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
24 months
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
24 months
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
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

June 26, 2019

Primary Completion (Estimated)

June 30, 2027

Study Completion (Estimated)

June 30, 2027

Study Registration Dates

First Submitted

May 21, 2019

First Submitted That Met QC Criteria

May 21, 2019

First Posted (Actual)

May 23, 2019

Study Record Updates

Last Update Posted (Actual)

January 3, 2024

Last Update Submitted That Met QC Criteria

January 1, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CYTB323A12101

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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