HER2 Targeted HypoSti.CAR-T Cells in HER2 Positive Advanced Solid Tumors
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|ClinicalTrials.gov Identifier: NCT05681650|
Recruitment Status : Not yet recruiting
First Posted : January 12, 2023
Last Update Posted : January 13, 2023
|Condition or disease||Intervention/treatment||Phase|
|HER2 Positive Advanced Solid Tumors||Biological: HypoSti.CAR-HER2 T cells Drug: Albumin-bound paclitaxel Drug: Cyclophosphamide||Phase 1 Phase 2|
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 3 doses of HypoSti.CAR-HER2 T cell therapy (1 × 10^6 cells/kg, 3 × 10^6 cells/kg, 1 × 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||30 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Phase I/II Clinical Trial of HER2 Targeted HypoSti.CAR-T Cells in Treating Patients With HER2 Positive Local Advanced or Metastatic Solid Tumors|
|Estimated Study Start Date :||February 1, 2023|
|Estimated Primary Completion Date :||December 31, 2025|
|Estimated Study Completion Date :||December 31, 2026|
Experimental: HypoSti.CAR-HER2 T cells
Enrolled participants will be given a preconditioning regimen consisted of albumin-bound paclitaxel and cyclophosphamide before the infusion of HypoSti.CAR-HER2 T cells.
Biological: HypoSti.CAR-HER2 T cells
Dose escalation: dose1 (1×10^6 cells/kg) ,dose 2 (3×10^6 cells/kg) ,dose 3 (1×10^7 cells/kg. Dose expansion: RP2D
Drug: Albumin-bound paclitaxel
Administered intravenously at dose of 100-200mg/m2 on day -5
Administered intravenously at dose of 15-30mg/kg on day -3 and day -2
- Incidence of treatment related adverse events [ Time Frame: Up to 12 months following the infusion of HypoSti.CAR-HER2 T cells ]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
- Incidence of dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days following the infusion of HypoSti.CAR-HER2 T cells ]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.
- Determination of the maximum tolerated dose (MTD) [ Time Frame: Up to 28 days following the infusion of HypoSti.CAR-HER2 T cells ]Maximum tolerated dose is defined as the highest dose that is less than or equal to 2 DLT among 6 subjects.
- Objective response rate (ORR) [ Time Frame: Up to 3 years ]Objective response rate is defined as complete response (CR) or partial response (PR) by RECIST 1.1or iRECIST
- Time to response (TTR) [ Time Frame: Up to 3 years ]Time to response is defined as the time from HypoSti.CAR-HER2 T cell infusion to first assessed CR or PR by investigators according to RECIST 1.1or iRECIST.
- Duration of response (DOR) [ Time Frame: Up to 3 years ]Duration of response is defined as the time from objective response (OR) until documented tumor progression date among responders.
- Progression Free Survival (PFS) [ Time Frame: Up to 3 years ]Progression Free Survival is defined as the time from HypoSti.CAR-HER2 T cell infusion to documented disease progression or death.
- Overall Survival (OS) [ Time Frame: Up to 3 years ]Overall Survival is defined as the time from HypoSti.CAR-HER2 T cell infusion to the date of death.
- Number and copy number of HypoSti.CAR-HER2 T cell [ Time Frame: Up to 3 years ]Number and copy number of HypoSti.CAR-HER2 T cell are assessed by number in peripheral blood and tumor tissue.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05681650
|Contact: Kaichao Feng, MDemail@example.com|
|Contact: Weidong Han, PhDfirstname.lastname@example.org|
|Study Director:||Jianqing Xu, PhD||Fudan University|