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

NCT ID: NCT05681650

Last Updated: 2023-12-12

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 30 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-11
• Study Completion Date: 2026-12-31

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.

Detailed Description

Currently, chimeric antigen receptor modified T (CAR-T) cell therapy has achieved a series of achievements in hematological malignancies, however, it still has to face plenty of obstacles in more bulky solid tumors, such as absence of tumor specific antigens, complex immunosuppressive tumor microenvironment, and tumor heterogeneity, which may taken together to restrict the efficacy of CAR-T cells in eliminating solid tumors. Previous studies found that intratumoral hypoxic microenvironment facilitated the development and metastasis of tumor cells. Meanwhile, it was difficult for cytotoxic T cells including CAR-T cells to survive and expand in such a hypoxic microenvironment.

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,which has been demonstrated in animal models. Based on the preclinical data, investigators will further conduct this clinical trial in order to test the potential of this novel system targeting HER2 antigen in vivo. In dose escalation period, at least 9 eligible patients will be enrolled and receive 5 doses of HypoSti.CAR-HER2 T cell therapy (1 × 10^6 cells/kg, 3 × 10^6 cells/kg, 6 × 10^6 cells/kg,1 × 10^7 cells/kg, 1.5 × 10^7 cells/kg) according to the "3+3" principle. In dose expansion period, additional 10 to 21 patients will be enrolled to receive HypoSti.CAR-HER2 T cell therapy at dose of recommended phase 2 dose (RP2D), which is determined by data from dose escalation period, including occurrence of dose limiting toxicities (DLT), pharmacokinetics/pharmacodynamics, efficacy and other parameters, to furtherly evaluate the safety and efficacy profiles of HypoSti.CAR-HER2 T cell therapy.

Conditions

HER2 Positive Advanced Solid Tumors

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

HypoSti.CAR-HER2 T cells

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.

Group Type: EXPERIMENTAL

HypoSti.CAR-HER2 T cells

Intervention Type: 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

Albumin-bound paclitaxel

Intervention Type: DRUG

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

Cyclophosphamide

Intervention Type: DRUG

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

Fludarabine

Intervention Type: 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

Interventions

HypoSti.CAR-HER2 T cells

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

Intervention Type: BIOLOGICAL

Albumin-bound paclitaxel

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

Intervention Type: DRUG

Cyclophosphamide

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

Intervention Type: DRUG

Fludarabine

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

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 1. Age from 18 to 75 years with estimated life expectancy >3 months.
• 2. 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%.
• 3. Have at least one measurable target lesion.
• 4. 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.
• 5. 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.
• 6. Have an Eastern Cooperative Oncology Group performance status (ECOG) of 0 or 2 at the time of enrollment.
• 7. Have adequate organ function, which should be confirmed within 2 weeks prior to the first dose of study drugs.
• 8. Previous treatment with anti-PD-1/PD-L1 antibodies are allowed.
• 9. Ability to understand and sign a written informed consent document.
• 10. 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.

Exclusion Criteria

• 1. Active, known or suspected autoimmune diseases.
• 2. 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.
• 3. Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
• 4. History of severe hypersensitive reactions to other monoclonal antibodies.
• 5. History of allergy or intolerance to study drug components.
• 6. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results.
• 7. History or concurrent condition of interstitial lung disease of any grade or severely impaired pulmonary function.
• 8. 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.
• 9. History of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS).
• 10. 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.
• 11. 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)].
• 12. Vaccination within 30 days of study enrollment.
• 13. Active bleeding or known hemorrhagic tendency.
• 14. Subjects with unhealed surgical wounds for more than 30 days.
• 15. Being participating any other trials or withdraw within 4 weeks.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Fudan University

OTHER

Sponsor Role: collaborator

Chinese PLA General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Han weidong

Director of Biotherapeutic Department

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Jianqing Xu, PhD

Role: STUDY_DIRECTOR

Fudan University

Locations

Kaichao Feng

Beijing, Beijing Municipality, China

Site Status: RECRUITING

Countries

China

Central Contacts

Kaichao Feng, MD

Role: CONTACT

Phone: +861066947300

Email: timothyfkc@126.com

Weidong Han, PhD

Role: CONTACT

Phone: +861066937463

Email: hanwdrsw69@yahoo.com

Facility Contacts

Kaichao Feng, MD

Role: primary

Other Identifiers

CHN-PLAGH-BT-076

Identifier Type: -

Identifier Source: org_study_id