HER2 Targeted HypoSti.CAR-T Cells in HER2 Positive Advanced Solid Tumors

NCT05681650 | Recruiting Phase 1 DMC

• 1 other identifier: CHN-PLAGH-BT-076
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

Brief Summary

Chimeric antigen receptor modified T (CAR-T) cell therapy still has multiple difficulties in solid tumors, such as absence of tumor specific antigens, complex immunosuppressive tumor microenvironment, and tumor heterogeneity. In this study, investigators developed a novel hypoxia-stimulated CAR expression system (HypoSti.CAR) that could enable CAR-T cell effectively expand and survive in hypoxic tumor microenvironment. After accomplishment of animal model verification, investigators conduct this clinical trial in order to assess the in vivo safety, feasibility and efficacy of HypoSti.CAR-HER2 T cells in HER2 antigen positive advanced solid tumors.

Conditions

HER2 Positive Advanced Solid Tumors

Outcome Measures

Primary Outcomes (3)

• Incidence of treatment related adverse events

  Treatment related adverse events are defined as any medical events since the initiation of preconditioning chemotherapy. Adverse events will be graded by CTCAE V5.0

  Up to 12 months following the infusion of HypoSti.CAR-HER2 T cells

• Incidence of dose limiting toxicities (DLTs)

  Dose limiting toxicities are defined as HypoSti.CAR-HER2 T cell related adverse events within the first 28 days that meet the following criteria: grade 3 or higher CRS or CRES, grade 3 or higher cutaneous/ mucosal toxicity, and any other grade 4 toxicities.

  Up to 28 days following the infusion of HypoSti.CAR-HER2 T cells

• Determination of the maximum tolerated dose (MTD)

  Maximum tolerated dose is defined as the highest dose that is less than or equal to 2 DLT among 6 subjects.

  Up to 28 days following the infusion of HypoSti.CAR-HER2 T cells

Secondary Outcomes (6)

• Objective response rate (ORR)

  Up to 3 years

• Time to response (TTR)

  Up to 3 years

• Duration of response (DOR)

  Up to 3 years

• Progression Free Survival (PFS)

  Up to 3 years

• Overall Survival (OS)

  Up to 3 years

Study Arms (1)

HypoSti.CAR-HER2 T cells

EXPERIMENTAL

Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel, cyclophosphamide and/or fludarabine before the infusion of HypoSti.CAR-HER2 T cells. Fludarabine will be administered only before the first dose infusion, and will not be administered before the secondary or multiple doses of HypoSti.CAR-HER2 T cell infusion.

Biological: HypoSti.CAR-HER2 T cells; Drug: Albumin-bound paclitaxel; Drug: Cyclophosphamide; Drug: Fludarabine

Interventions

HypoSti.CAR-HER2 T cells BIOLOGICAL

Dose escalation: dose -1 (1×10\^6 cells/kg) ,dose 1 (3×10\^6 cells/kg) , dose 2 (6×10\^6 cells/kg), dose 3 (1×10\^7 cells/kg), dose 4 (1.5×10\^7 cells/kg). Dose expansion: RP2D

HypoSti.CAR-HER2 T cells

Albumin-bound paclitaxel DRUG

Administered intravenously at dose of 100-200mg/m2 on day -5

HypoSti.CAR-HER2 T cells

Cyclophosphamide DRUG

Administered intravenously at a total dose of 15-30mg/kg on day -3 and day-2

HypoSti.CAR-HER2 T cells

Fludarabine DRUG

Administered intravenously at dose of 30mg/m2/d on day -3 and day -2 only in the first infusion of HypoSti.CAR-HER2 T cells

HypoSti.CAR-HER2 T cells

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• \. Age from 18 to 75 years with estimated life expectancy \>3 months.
• \. Histopathological confirmed advanced or metastatic solid tumors failed to at least first-line treatment or initially diagnosed advanced/metastatic solid tumors that have no NCCN guideline recommended standard first-line therapy. HER2 antigen expression percentage ≥ 30%.
• \. Have at least one measurable target lesion.
• \. Fresh solid tumor samples or formalin-fixed paraffin embedded tumor archival samples within 6 months are necessary; Fresh tumor samples are preferred. Subjects are willing to accept tumor rebiopsy in the process of this study.
• \. Previous treatment must be completed for more than 4 weeks prior to the enrollment of this study, and subjects have recovered to \<= grade 1 toxicity.
• \. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment.
• \. Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
• \. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
• \. Ability to understand and sign a written informed consent document.
• \. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, and up to 90 days after the last dose of the drug.

You may not qualify if:

• \. Active, known or suspected autoimmune diseases.
• \. Known brain metastases or active central nervous system (CNS). Subjects with CNS metastases who were treated with radiotherapy for at least 3 months prior to enrollment, have no central nervous symptoms and are off corticosteroids, are eligible for enrollment, but require a brain MRI screening.
• \. Subjects are being treated with either corticosteroids (\>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
• \. History of severe hypersensitive reactions to other monoclonal antibodies.
• \. History of allergy or intolerance to study drug components.
• \. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• \. History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
• \. Uncontrolled intercurrent illness, including ongoing or active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia (excluding insignificant sinus bradycardia and sinus tachycardia) or psychiatric illness/social situations and any other illness that would limit compliance with study requirements and jeopardize the safety of the patient.
• \. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• \. Pregnant or breast-feeding. Women of childbearing potential must have a pregnancy test performed within 7 days before the enrollment, and a negative result must be documented.
• \. Previous or concurrent cancer within 3 years prior to treatment start EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors \[Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)\].
• \. Vaccination within 30 days of study enrollment.
• \. Active bleeding or known hemorrhagic tendency.
• \. Subjects with unhealed surgical wounds for more than 30 days.
• \. Being participating any other trials or withdraw within 4 weeks.

Sponsors & Collaborators

• Chinese PLA General Hospital: lead
• Fudan University: collaborator

Study Sites (1)

Kaichao Feng

Beijing, Beijing Municipality, +86100853, China

RECRUITING

MeSH Terms

Interventions

Albumin-Bound Paclitaxel; Cyclophosphamide; fludarabine

Intervention Hierarchy (Ancestors)

Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Phosphoramides; Organophosphorus Compounds

Study Officials

• Jianqing Xu, PhD

  Fudan University

  STUDY DIRECTOR

Central Study Contacts

Kaichao Feng, MD

CONTACT

+861066947300; timothyfkc@126.com

Weidong Han, PhD

CONTACT

+861066937463; hanwdrsw69@yahoo.com

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Director of Biotherapeutic Department

Study Record Dates

• First Submitted: December 27, 2022
• First Posted: January 12, 2023
• Study Start: October 11, 2023
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: December 12, 2023

Record last verified: 2023-12

Locations

CN (1)