A Phase 2 Study of CRG-022 in Participants With Relapsed/Refractory Large B-cell Lymphoma

Sponsor

CARGO Therapeutics (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT05972720

Collaborator

(none)

123

Enrollment

Arms

40.4

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This is a prospective, open-label, multi-center clinical study designed to evaluate the safety, tolerability, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of CRG-022, a CD22-directed Autologous Chimeric Antigen Receptor (CAR) T-cell Therapy for the treatment of relapsed or refractory large B-cell lymphoma.

Condition or Disease	Intervention/Treatment	Phase
Cancer Relapsed/Refractory Large B-cell Lymphoma (LBCL)	Drug: Fludarabine (30 mg/m^2) Drug: Cyclophosphamide (500 mg/m^2) Biological: CRG-022 cells	Phase 2

Detailed Description

Primary Objective:

To evaluate the efficacy of CRG-022 in participants with LBCL

Secondary Objectives:

Efficacy-related:

To evaluate the efficacy of CRG-022 in participants with LBCL

Safety-related:

To evaluate the safety and tolerability of CRG-022 when administered following conditioning chemotherapy

Study Design

Study Type:

Interventional

Anticipated Enrollment :

123 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

The study will enroll ~ 123 participants in 3 cohorts: Cohort 1: ~ 81 Participants will be treated with a target dose of 1 x 10^6 CRG-022 cells/kg. Participants in this cohort will have received prior CD19-directed CAR T therapy. Cohort 2: ~ 5-10 Participants will be treated with nonconforming CRG-022 therapy deemed safe to administer. Cohort 3:~20 Participants will be treated with a target dose of 1 x 10^6 CRG-022 cells/kg. Participants in this cohort will have received prior bispecific T-cell engaging antibody therapy. Study Procedures: PBMC will be obtained by leukapheresis for the manufacturing of CRG-022 at designated Cell Processing Facility. Cryopreserved CRG-022 will then be shipped back to the treating facility On Day -5, patients will begin conditioning chemotherapy comprising fludarabine and cyclophosphamide on Days -5, -4, and -3 On Day 0, CRG-022 cells will be administered Patients will be monitored for toxicity, response, and other biologic correlatesThe study will enroll ~ 123 participants in 3 cohorts:Cohort 1: ~ 81 Participants will be treated with a target dose of 1 x 106 CRG-022 cells/kg. Participants in this cohort will have received prior CD19-directed CAR T therapy. Cohort 2: ~ 5-10 Participants will be treated with nonconforming CRG-022 therapy deemed safe to administer. Cohort 3:~20 Participants will be treated with a target dose of 1 x 106 CRG-022 cells/kg. Participants in this cohort will have received prior bispecific T-cell engaging antibody therapy.Study Procedures:PBMC will be obtained by leukapheresis for the manufacturing of CRG-022 at designated Cell Processing Facility. Cryopreserved CRG-022 will then be shipped back to the treating facility On Day -5, patients will begin conditioning chemotherapy comprising fludarabine and cyclophosphamide on Days -5, -4, and -3 On Day 0, CRG-022 cells will be administered Patients will be monitored for toxicity, response, and other biologic correlates

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

An Open-label, Multicenter Phase 2 Study Evaluating the Efficacy and Safety of CRG-022, a CD22-directed Autologous Chimeric Antigen Receptor (CAR) T-cell Therapy in Participants With Relapsed/Refractory Large B-Cell Lymphoma After CD19-directed CAR T-cell Therapy

Anticipated Study Start Date :

Aug 1, 2023

Anticipated Primary Completion Date :

Sep 13, 2025

Anticipated Study Completion Date :

Dec 13, 2026

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 Relapsed/refractory Large B-cell Lymphoma (Participants in this cohort will have received prior CD19-directed CAR T therapy) Approximately 81 participants will be treated with a target dose of 1 x 10^6 CRG-022 cells/kg. Participants in this cohort will have received prior CD19-directed CAR T therapy. Lymphodepletion prior to CRG-022 cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Autologous CRG-022 cells will be administered intravenously at dose 1 x 10^6 cells/kg on Day 0 after induction chemotherapy regimen.	Drug: Fludarabine (30 mg/m^2) Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Drug: Cyclophosphamide (500 mg/m^2) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Biological: CRG-022 cells Autologous CRG-022 cells will be administered intravenously on Day 0 after induction chemotherapy regimen.
Experimental: Cohort 2 Relapsed/refractory Large B-cell Lymphoma (Patients in this cohort will receive nonconforming CRG-022 cell product that is deemed safe to administer) Lymphodepletion prior to CRG-022 cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Autologous CRG-022 cells will be administered intravenously at dose 0.1 x 10^6 cells/kg on Day 0 after induction chemotherapy regimen (minimum dose).	Drug: Fludarabine (30 mg/m^2) Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Drug: Cyclophosphamide (500 mg/m^2) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Biological: CRG-022 cells Autologous CRG-022 cells will be administered intravenously on Day 0 after induction chemotherapy regimen.
Experimental: Cohort 3 Relapsed/refractory Large B-cell Lymphoma (Participants in this cohort will have received prior bispecific T-cell engaging antibody therapy) Lymphodepletion prior to CRG-022 cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Autologous CRG-022 cells will be administered intravenously at dose 1 x 10^6 cells/kg on Day 0 after induction chemotherapy regimen.	Drug: Fludarabine (30 mg/m^2) Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Drug: Cyclophosphamide (500 mg/m^2) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Biological: CRG-022 cells Autologous CRG-022 cells will be administered intravenously on Day 0 after induction chemotherapy regimen.

Arm

Intervention/Treatment

Experimental: Cohort 1

Relapsed/refractory Large B-cell Lymphoma (Participants in this cohort will have received prior CD19-directed CAR T therapy) Approximately 81 participants will be treated with a target dose of 1 x 10^6 CRG-022 cells/kg. Participants in this cohort will have received prior CD19-directed CAR T therapy. Lymphodepletion prior to CRG-022 cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Autologous CRG-022 cells will be administered intravenously at dose 1 x 10^6 cells/kg on Day 0 after induction chemotherapy regimen.

Drug: Fludarabine (30 mg/m^2)

Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3)

Drug: Cyclophosphamide (500 mg/m^2)

Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3)

Biological: CRG-022 cells

Autologous CRG-022 cells will be administered intravenously on Day 0 after induction chemotherapy regimen.

Experimental: Cohort 2

Relapsed/refractory Large B-cell Lymphoma (Patients in this cohort will receive nonconforming CRG-022 cell product that is deemed safe to administer) Lymphodepletion prior to CRG-022 cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Autologous CRG-022 cells will be administered intravenously at dose 0.1 x 10^6 cells/kg on Day 0 after induction chemotherapy regimen (minimum dose).

Drug: Fludarabine (30 mg/m^2)

Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3)

Drug: Cyclophosphamide (500 mg/m^2)

Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3)

Biological: CRG-022 cells

Autologous CRG-022 cells will be administered intravenously on Day 0 after induction chemotherapy regimen.

Experimental: Cohort 3

Relapsed/refractory Large B-cell Lymphoma (Participants in this cohort will have received prior bispecific T-cell engaging antibody therapy) Lymphodepletion prior to CRG-022 cell infusion (Day 0) will occur as follows: Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3) Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3) Autologous CRG-022 cells will be administered intravenously at dose 1 x 10^6 cells/kg on Day 0 after induction chemotherapy regimen.

Drug: Fludarabine (30 mg/m^2)

Fludarabine 30 mg/m^2 daily by intravenous administration for 3 days (On Days -5, -4, -3)

Drug: Cyclophosphamide (500 mg/m^2)

Cyclophosphamide 500 mg/m^2 daily by intravenous administration for 3 days (on Days -5, -4 and -3)

Biological: CRG-022 cells

Autologous CRG-022 cells will be administered intravenously on Day 0 after induction chemotherapy regimen.

Outcome Measures

Primary Outcome Measures

Objective response rate - Blinded independent review [3 months, 9 months, and 24 month post-treatment follow-up after CRG-022 infusion]
Percentage of participants with complete or partial response determined by a blinded independent review committee according to 2014 Lugano criteria.

Secondary Outcome Measures

Objective response rate - Investigator assessment [3 months, 9 months, and 24-month post-treatment follow-up after CRG-022 infusion]
Percentage of participants with complete or partial response determined by the investigator according to Lugano criteria
Complete response rate [3 months, 9 months, and 24-month post-treatment follow-up after CRG-022 infusion]
Percentage of participants who achieve a Complete Response determined by independent review committee and investigators assessment according to Lugano criteria
Duration of response [3 months, 9 months and 24-month post-treatment follow-up after CRG-022 infusion]
Duration of response (the time from the date of the first occurrence of response to the date of progression, relapse, or death from any cause) determined by independent review committee and investigators according to Lugano criteria.
Progression-free survival [3 months, 9 months, and 24-month post-treatment follow-up after CRG-022 infusion]
Progression-free survival (the time from CRG-022 infusion until the first occurrence of disease progression or relapse) determined by independent review committee and investigator assessment according to Lugano criteria.
Overall Survival [3 months, 9 months, and 24-month post-treatment follow-up after CRG-022 infusion]
Overall Survival (the period from the date of CRG-022 infusion until the date of death from any cause) documented by the investigators.
Incidence rate of adverse events [From Screening up to 15 years at protocol-defined timepoints]
Percentage of participants with treatment-related adverse events is assessed by CTCAEv5.0, CRS, ICANS, and IEC-HS graded by ASTCT criteria.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Must provide signed informed consent
Must be aged ≥18 years
Must have histological confirmation of LBCL
Must have relapsed or refractory disease after the last therapy
For enrollment in cohort 1, patients must have previously received a CD19-directed CAR T-cell therapy
For enrollment in cohort 3, patients must have received at least 2 prior lines of therapy including a bispecific T-cell engaging antibody therapy
Must have at least one radiographically measurable lesion
Must have a washout period of at least 2 weeks or five half-lives, whichever is shorter, since any prior cancer therapy
A tumor tissue sample along with a corresponding local pathology report, must be available for submission to the Sponsor
Must have Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Hematology and organ function:

Absolute neutrophil count ≥ 1000/μL
Platelet count ≥ 75,000/μL or ≥ 50,000/μL with known presence of marrow disease
Absolute lymphocyte count ≥ 100/μL
Estimated creatinine clearance ≥ 45 mL/minute
Serum alanine aminotransferase and aspartate aminotransferase ≤ 2.5 times the upper limit of normal
Total bilirubin ≤ 1.5 mg/dL
Cardiac left ventricular ejection fraction (LVEF) ≥45% and no evidence of pericardial effusion
Blood oxygen saturation > 92%
Serum albumin ≥ 2.5 g/dL

Women of childbearing potential must agree to remain abstinent or use contraceptive methods
Men must agree to be abstinent (refrain from heterosexual intercourse) or use a condom
Able and willing to comply with the study protocol
Willing and able to remain within 1 hour of the treating center for at least 4 weeks after infusion
Must be stable or have recovered from nonhematologic toxicities due to prior therapy to grade ≤ 1

Exclusion Criteria:

Patients who have a history of malignancy other than the lymphoma
Patients with active fungal, bacterial, viral, or other infection that requires intravenous antimicrobials.
Patients who received prior allogeneic stem cell or solid organ transplant
Patients who received prior allogeneic CAR therapy or anti-CD52 antibody therapy
Patients who received prior bispecific T-cell engaging antibody therapy (e.g., glofitamab, epcoritamab) may not be enrolled in cohort 1
Patients with history of central nervous system (CNS) involvement of lymphoma within 1 year prior to enrollment
Patients with ongoing cardiac involvement of lymphoma
History of CD22-directed therapy for lymphoma
History of infection with any of the following: human immunodeficiency virus; hepatitis B virus or hepatitis C virus
Patients with significant, uncontrolled concomitant disease including the following:

History of cardiac disease within 12 months prior to enrollment
Active pulmonary disease
Clinically significant liver disease
Clinically significant neurological disease

History of autoimmune disease or requiring systemic immunosuppression and/or systemic disease modifying agents within the last 2 years
Patients with evidence of moderate to severe forms of primary immunodeficiencies
History of severe, immediate hypersensitivity reaction attributed to aminoglycosides or any of the agents used in this study
Women of child-bearing potential who are pregnant or breastfeeding
Patients who underwent recent major surgery (within 4 weeks prior to leukapheresis), other than for diagnosis
Patients with any in-dwelling line or drain and ommaya reservoirs
History of symptomatic deep vein thrombosis or pulmonary embolism requiring anticoagulation therapy within 6 months prior to enrollment
Patients who received treatment with a live, attenuated vaccine within 6 weeks prior to initiation of study treatment or who are anticipated to need such a vaccine during the course of the study
Patients with Richter's transformation of CLL
Patients with T cell/histiocyte-rich large B-cell lymphoma
Patients who require urgent therapy due to mass effects of tumor of impending oncologic emergency
Patients undergoing concurrent treatment with any other investigational agent