Study of Autologous CAR-T Cells Targeting B7-H3 in TNBC iC9-CAR.B7-H3 T Cells

Phase 1

Recruiting

• Conditions: Relapse; Resistant Cancer; Breast Cancer; Triple Negative Breast Cancer
• Interventions: Biological: iC9-CAR.B7-H3 T Cell Therapy; Drug: cyclophosphamide; Drug: fludarabine

• Registration Number: NCT06347068
• Lead Sponsor: UNC Lineberger Comprehensive Cancer Center

Brief Summary

This phase 1, single-center, open-label study explores the safety of escalating doses of chimeric antigen receptor T cells (CAR-T) cells in subjects with relapsed/refractory triple-negative breast cancer (TNBC).

Detailed Description

T lymphocyte chimeric antigen receptor cells against the B7-H3 antigen (iC9-CAR.B7-H3 T cells) treatment is experimental and has not been approved by the Food and Drug Administration. The safety of iC9-CAR.B7-H3 T cells will be investigated using a modified 3+3 design. The data from the dose escalation will be used to determine a recommended phase 2 dose (RP2D), which will be decided based on the maximum tolerated dose (MTD) and additional factors such as the ability to manufacture sufficient cells for infusion.

Subjects with TNBC who meet procurement eligibility criteria will have cells collected to manufacture iC9-CAR.B7-H3 T cells. Eligible subjects will receive lymphodepletion with cyclophosphamide and fludarabine.

Study Timeline

• Study First Submitted: 2024-03-22
• Study First Submitted QC: 2024-03-28
• Study First Posted: 2024-04-04
• Study Start: 2024-06-27
• Status Verified: 2024-10
• Last Update Submitted: 2024-10-23
• Last Update Posted: 2024-10-26
• Primary Completion: 2026-05
• Study Completion: 2028-05

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 42

Inclusion Criteria

Unless otherwise noted, subjects must meet all of the following criteria to participate in in all phases of the study:

1. Written informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information explained to, understood by and signed by the subject or legally authorized representative.

2. Age ≥ 18 years at the time of consent.

3. Karnofsky score of > 60% (see APPENDIX VI- Karnofsky Scale))

4. Histologically confirmed TNBC (ER-, PR-, HER2-negative)

   1. ER- and PR-negative: defined as < 1% staining by immunohistochemistry (IHC)
   2. HER2-negative: defined as IHC 0-1+ or fluorescence in situ hybridization (FISH) ratio < 2.0

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Exclusion Criteria

1. Patients with a history of symptomatic CNS involvement or multiple metastases requiring whole-brain radiation.
2. Subjects with a prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
3. Subject does not have a measurable and or evaluable disease as defined by RECIST 1.1

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
iC9-CAR.B7-H3 T cells	iC9-CAR.B7-H3 T Cell Therapy	Specimen will be collected to prepare the iC9-CAR.B7-H3 T cells. Disease-fighting T cells will be isolated and modified to prepare the iC9-CAR.B7-H3 T cells. In part 2, the iC9-CAR.B7-H3 T cells are given by infusion after completion of lymphodepletion chemotherapy.
iC9-CAR.B7-H3 T cells	fludarabine	Specimen will be collected to prepare the iC9-CAR.B7-H3 T cells. Disease-fighting T cells will be isolated and modified to prepare the iC9-CAR.B7-H3 T cells. In part 2, the iC9-CAR.B7-H3 T cells are given by infusion after completion of lymphodepletion chemotherapy.
iC9-CAR.B7-H3 T cells	cyclophosphamide	Specimen will be collected to prepare the iC9-CAR.B7-H3 T cells. Disease-fighting T cells will be isolated and modified to prepare the iC9-CAR.B7-H3 T cells. In part 2, the iC9-CAR.B7-H3 T cells are given by infusion after completion of lymphodepletion chemotherapy.

Primary Outcome Measures

Name	Time	Method
Toxicity: Cytokine Release Syndrome (CRS)	Up to 8 weeks after infusion of Biological/Vaccine	CRS will be graded according to the American Society for Transplantation and Cellular Therapy (ASTCT) CRS Consensus Grading. Grade 1 - Mild: Fever ≥38\^ o C, No hypotension, No hypoxia, Grade 2 - Moderate: Fever ≥38\^ o C, Hypotension not requiring vasopressors, Hypoxia requiring low-flow nasal cannula (≤6 L/minute) or blow-by, Grade 3 - Severe: Fever ≥ 38\^ o C, Hypotension requiring a vasopressor with or without vasopressin, Hypoxia requiring high-flow nasal cannula (\>6 L/minute), facemask, nonrebreather mask, or Venturi mask, Grade 4 - Life-threatening: Fever ≥38\^oC, Hypotension requiring multiple vasopressors (excluding vasopressin), Hypoxia requiring positive pressure (e.g. Continuous positive airway pressure, BiPAP, intubation, mechanical ventilation), Grade 5 - Death
Toxicity: Immune effector cell-associated neurotoxicity syndrome (ICANS)	Up to 4 weeks	Neurotoxicity will be graded according to the Immune effector cell-associated neurotoxicity syndrome (ICANS) criteria.; Immune effector cell-associated neurotoxicity syndrome (ICANS) symptoms will be graded according to the criteria outlined in the protocol on a scale from 1 (mild) to 4 (critical). Cytokine release syndrome (CRS) will be graded according to criteria outlined in the protocol on a scale from 1 (mild) to grade 5 (death).
Toxicity: NCI-CTCAE	Up to 4 weeks	Toxicity will be graded as the Number of participants with adverse events (AE)s; AEs will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0.

Secondary Outcome Measures

Name	Time	Method
The recommended phase 2 dose (RP2D) CRS Grading	Up to 4 weeks	The RP2D of iC9-CAR.B7-H3 T cells will be determined based on modified 3+3 dose finding rules and the tolerability of iC9-CAR.B7-H3 T cells will be assessed byASTCT Consensus CRS Grading Criteria.
The recommended phase 2 dose (RP2D)	Up to 4 weeks	The RP2D of iC9-CAR.B7-H3 T cells will be determined based on modified 3+3 dose finding rules and the tolerability of iC9-CAR.B7-H3 T cells will be assessed by ASTCT Consensus ICANS Grading Criteria.
Progression Free Survival (PFS)	Up to 2 years	PFS will be measured from the first day of lymphodepletion chemotherapy prior to iC9-CAR.B7-H3 T cell infusion to progression per RECIST 1.1 or death.
The recommended phase 2 dose (RP2D) NCI-CTCAE v5.	Up to 4 weeks	The RP2D of iC9-CAR.B7-H3 T cells will be determined based on modified 3+3 dose finding rules and the tolerability of iC9-CAR.B7-H3 T cells will be assessed by NCI-CTCAE v5 criteria.
Objective response rate	Up to 2 years	Objective response rate is defined as the percentage of subjects achieving a confirmed partial response (PR) or better (≥ PR) based on RECIST 1.1 criteria.; Complete response - Disappearance of all target lesions. Any pathological lymph node (LN) must be \<10mm. Partial response: At least a 30% decrease in the sum of the largest distance (LD) of the target lesions. Progressive Disease (PD): At least a 20% increase in the sum of the LD of the target lesions taking as reference the smallest sum LD recorded since the treatment started including baseline if that is the smallest in the study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm. The appearance of one or more new lesions also constitutes PD. Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD since the treatment started.
Overall Survival (OS)	Up to 2 years	OS will be measured from the first day of lymphodepleting chemotherapy prior to iC9-CAR.B7-H3 T cell infusion to the date of death for any cause.
Duration of Response (DOR)	Up to 2 years	DOR is defined as the time from documentation of PR or better to progressive disease (PD) based on RECIST 1.1 and/or irRECIST.; Per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) for target and/or non-target lesions and assessed by imaging: Complete Response (irCR), Disappearance of all lesions, no new lesions, lymph nodes \< 10 mm in short axis; Partial Response (irPR), ≥30% decrease in the sum of target lesions and non-target lesions are irNN; Stable response (irSD), not meeting criteria for irCR, irPR, or irPD; Progressive Disease (irPD), ≥20% increase in tumor burden and minimum 5 mm absolute increase in compared to nadir; for no new non-target or (irNN) and where irPR or irPD are confirmed by a repeat, consecutive assessment no less than 4 weeks later.

Trial Locations

Locations (1)

University of North Carolina; 🇺🇸 Chapel Hill, North Carolina, United States