A Safety and Efficacy Study of Allogeneic CAR Gamma-Delta T Cells in Subjects with Relapsed/Refractory Solid Tumors

Official title

A Single Arm, Open Label, Dose-escalation Phase I and Dose-expansion Phase IIa Clinical Study to Evaluate the Feasibility, Safety, and Efficacy of Allogeneic Chimeric Antigen Receptor (CAR) Gamma-Delta T Cells CAR001 in Subjects with Relapsed/refractory Solid Tumors

Overview

This study is composed of phase I and IIa parts. The dose-escalation phase I part aims to find the maximum tolerated dose (MTD) and to identify the safety of CAR001 in subjects with relapsed/refractory solid tumor; the dose-expansion phase IIa part aims to evaluate the potential efficacy of CAR001 in subjects with relapsed/refractory non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), colorectal cancer (CRC) or Glioblastoma multiforme (GBM).

Detailed description

Primary Objective:

Phase I:

To evaluate the safety of CAR001 in subjects.

Phase IIa:

To provide potential evidence for the clinical efficacy of CAR001 in improving tumor response rate in subjects.

Secondary Objectives:

To evaluate the safety and potential efficacy of CAR001 in subjects.

Exploratory:

Level of CAR-positive γδT cells in peripheral blood from baseline to subsequent visits. (Time Frame: 12 months after the last infusion)

Interventions

• Biological HLA-G-CAR.BiTE allogeneic γδ T cells
  Phase I is a multiple escalating dose, single arm, open-label and 3+3 design that implemented with five cohorts: low dose for single administration, low dose for twice administrations for 2 weeks, low, middle and high dose for 4 repeated administrations for 4 weeks. Phase IIa is a single-arm, open-label and dose-expansion study and the effective dose of CAR-positive cells will be administered to 27 evaluable subjects with TNBC, NSCLC, CRC or GBM via intravenous infusion weekly for 4 weeks.

Primary outcome measures

• Maximum Tolerated Dose (MTD) of CAR001 for Phase I part [Time frame: 4 weeks after last dosing of CAR001]
• Objective Response Rate (ORR) of CAR001 for Phase IIa part [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]

Secondary outcome measures (9)

• Safety - AEs and SAEs incidences over the study period [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Safety - Vital signs assessments at each post-treatment [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Safety - Laboratory examinations at each post-treatment [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Safety - 12-lead electrocardiogram (ECG) assessments at each post-treatment [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Safety - Physical Examination at each post-treatment [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Efficacy - Progression Free Survival (PFS) rate [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Efficacy - Overall Survival (OS) rate [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Efficacy - Change of QoL from baseline [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]
• Efficacy - Change of ECOG Performance Status Scale [Time frame: from visit 1 to 24-months of safety and efficacy follow-up period]

Eligibility criteria

Inclusion criteria

• Male or female subjects aged ≥ 18 years
• For phase I part, subjects with histologically confirmed diagnosis of solid tumor with expression of PD-L1 ≥ 1% and are relapsed/refractory to at least two lines of standard-of-care therapy. For phase IIa part, subjects with histologically confirmed diagnosis of TNBC, NSCLC, CRC or GBM with expression of PD-L1 ≥ 1%, and are relapsed/refractory to at least two lines of standard-of-care therapy.
• With at least one measurable lesion as defined by RECIST1.1 (for TNBC, NSCLC or CRC) or RANO (for GBM)
• Able to understand and sign the ICF
• Have a life expectancy of > 12 weeks
• ECOG performance status ≤ 1
• Recovered from any previous therapy related toxicity to ≤ grade 2 at screening
• With adequate renal function: serum creatinine ≤ 1.5 X ULN; eGFR > 50 ml/min
• With adequate liver function: ALT, AST, and ALP ≤ 3X ULN or ≤ 5 X ULN if liver metastases; and total bilirubin ≤ 1.5X ULN or ≤ 3 X ULN if due to Gilbert's disease
• With PT and PTT ≤ 1.5X ULN
• With adequate hematopoietic function:

• ANC ≥ 1,000 cells/μl
• Platelets ≥ 75,000 counts/μl
• Total WBC ≥ 2,000 cells/μl
• Hemoglobin ≥ 8 g/dL

Exclusion criteria

• Has received any allogeneic cell therapy before screening
• With known or suspected to be hypersensitivity to CAR001 or its excipients, such as DMSO or human serum albumin
• With more than one kind of active diagnosed primary cancer
• With active infection requiring systemic medication
• With medical conditions who are receiving systemic steroid therapy >10 mg prednisone/day or equivalent dose, or other immune-suppressants in the past 2 weeks
• Has been diagnosed as HIV positive (confirmed by anti-HIV and nucleic acid test)
• With acute cardiovascular disease; NYHA classification ≥ 3; or history of myocardial infarction during the past 6 months; or has active uncontrolled arterial hypertension by medical history. Per investigator's judgment, would not make participation appropriate
• With historical or current auto-immune diseases, such as rheumatoid arthritis, type I diabetes, psoriasis or systemic lupus erythematosus
• Has uncontrolled psychiatric disorder by medical history
• Has CNS diseases except GBM or stroke
• Has received any investigational therapy from another clinical study within 4 weeks
• Inability to undergo radiological assessment, such as MRI or CT for any reason
• Has received radiotherapy or chemotherapy within 2 weeks (but palliative radiation therapy (R/T) for pain control are allowed)
• Not suitable to participate the trial as judged by the investigator
• Female subject of childbearing potential who:

• Is lactating; or
• Has a positive pregnancy test result at eligibility checking; or
• Refuses to adopt at least two form of birth control from signing informed consent to 1 year after the last administration of CAR001.
• Male subject with a female spouse/partner who is of childbearing potential refuses to adopt at least two forms of birth control from signing informed consent to 1 year after the last administration of CAR001.

For exclusion criteria #15 and #16, acceptable forms of birth control include:

• Established use of oral, injected, or implanted hormonal methods of contraception that have comparable efficacy (failure rate < 1 %), for example hormone vaginal ring or transdermal hormone contraception
• Placement of an intrauterine device or intrauterine system
• Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps)

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

Taiwan · 1 center

• China Medical University Hospital — Taichung

Publications

• Huang SW, Pan CM, Lin YC, Chen MC, Chen Y, Jan CI, Wu CC, Lin FY, Wang ST, Lin CY, Lin PY, Huang WH, Chiang YT, Tsai WC, Chiu YH, Lin TH, Chiu SC, Cho DY. BiTE-Secreting CAR-gammadeltaT as a Dual Targeting Strategy for the Treatment of Solid Tumors. Adv Sci (Weinh). 2023 Jun;10(17):e2206856. doi: 10.1002/advs.202206856. Epub 2023 Apr 20. PMID 37078788

Identifiers

NCT: NCT06150885 · ES-CCAR01-A3301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗