In this single-center, single-arm,prospective, open-label, phase 1/2 study, the safety and efficacy of autologous CD70 targeted chimeric antigen receptor modified T (CAR-T) cell therapy will be evaluated in patients with CD70 antigen positive advanced/metastatic solid tumors . In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD70-CAR cell therapy according to the "3+3" principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).
Currently, CAR-T cell therapy has already achieved tremendous success in the treatment of hematological malignancies,however, it remains a severe challenge to treat solid tumors due to multiple obstacles,such as absence of tumor specific antigens, complex immunosuppressive tumor microenvironment, and tumor heterogeneity. CD70 is a member of the tumor factor superfamily and has been found to be highly expressed on the surface of several solid and hematological tumors, correlating with inferior prognosis.Targeting CD70 has emerged as potential novel immunotherapeutic strategy. Investigators have developed CD70-CAR-T cells that could effectively expand and survive,producing strong anti-tumor effects in animal models. Based on the preclinical data, we conduct this clinical trial in order to test the the safety profiles and anti-tumor activities of CD70-CAR-T cells in vivo. In dose escalation period, at least 12 eligible patients will be enrolled and receive 3 doses of CD70-CAR-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 at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell infusion at dose of 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 CD70-CAR-T cell therapy.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Dose escalation: Dose1 (1×10\^6 cells/kg) , Dose 2(3×10\^6 cells/kg) ,Dose 3 (1×10\^7cells/kg); Dose expansion: RP2D Drug: Albumin-bound paclitaxel Administered intravenously at dose of 100-200mg/m2 on day -5; Drug: Cyclophosphamide Administered intravenously at dose of 15-30mg/kg on day -3 and day -2; Drug: Fludarabine Administered intravenously at dose of 30mg/m2 on day -3 and day -2;
China
Beijing, Iotherapeutic Department of Chinsese PLA Gereral Hospital, China
RECRUITINGIncidence of treatment related adverse events
AE is defined as any adverse medical event from the date of randomization to 12 months after CD70-CAR-T cell infusion. Among them, CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0.
Time frame: Up to 12 months since the initiation of CD70-CAR-T cell therapy.
Incidence of dose limiting toxicities (DLTs)
DLT was defined as CD70-CAR-T cells-related events with onset within first 28 days following infusion: The development of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; All G4 non-hematologic toxicities.
Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy
Maximum tolerated dose (MTD)
MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined.
Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy
Number and copy number of CD70-CAR-T cells
Number and copy number of CD70-CAR-T cells are evaluated by number in peripheral blood and tumor tissue.
Time frame: Up to 3 years
Objective response rate (ORR)
Objective response rate includes complete response and partial response defined by investigators according to RECIST 1.1or iRECIST criteria.
Time frame: Up to 3 years
Progression Free Survival (PFS)
Progression Free Survival is defined as the time from the initiation of CD70-CAR-T cell therapy to documented disease progression or death.
Time frame: Up to 3 years
Time to response (TTR)
Time to response is defined as the time from the initiation of CD70-CAR-T cell therapy to first assessed CR or PR by investigators according to RECIST 1.1or iRECIST criteria.
Time frame: Up to 3 years
Duration of response (DOR)
Duration of response is defined as the time from objective response until documented tumor progression among responders.
Time frame: Up to 3 years
Overall Survival (OS)
Overall Survival is defined as the time from the initiation of CD70-CAR-T cell therapy to documented disease progression or death.
Time frame: Up to 3 years
Pharmacodynamics: Peak level of cytokines in serum
The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine.
Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy
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