CD70 Targeted CAR-T Cells in CD70 Positive Advanced/Metastatic Solid Tumors

Official title

Phase I/II Study of CD70 Targeted CAR-T Cell Treatment in CD70 Positive Advanced/Metastatic Solid Tumors

Overview

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).

Detailed description

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.

Interventions

• Biological CD70-targeting CAR-T cells
  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;

Primary outcome measures

• Incidence of treatment related adverse events [Time frame: Up to 12 months since the initiation of CD70-CAR-T cell therapy.]
• Incidence of dose limiting toxicities (DLTs) [Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy]
• Maximum tolerated dose (MTD) [Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy]

Secondary outcome measures (7)

• Number and copy number of CD70-CAR-T cells [Time frame: Up to 3 years]
• Objective response rate (ORR) [Time frame: Up to 3 years]
• Progression Free Survival (PFS) [Time frame: Up to 3 years]
• Time to response (TTR) [Time frame: Up to 3 years]
• Duration of response (DOR) [Time frame: Up to 3 years]
• Overall Survival (OS) [Time frame: Up to 3 years]
• Pharmacodynamics: Peak level of cytokines in serum [Time frame: Up to 28 days since the initiation of CD70-CAR-T cell therapy]

Eligibility criteria

Inclusion criteria

• Age 18-75 (inclusive).
• ECOG performance status ≤2 and Estimated life expectancy of more than 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. CD70 antigen expression level ≥ 30%.
• At least one measurable lesion at baseline per RECIST version 1.1.
• 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.
• Adequate organ function as defined by the following criteria: ANC≥1.5x10\^9/L; Platelet count ≥75x10\^9/L; Hemoglobin ≥90 g/L;Serum AST and serum ALT, ≤3.0 x ULN (≤5 x ULN for patients with liver cancer or metastases); Total serum bilirubin ≤1.5 x ULN(≤3 x ULN for patients with liver cancer or metastases); Serum creatinine ≤1.5 xULN or creatinine clearance of ≥60 mL/min.
• Pregnancy tests for women of childbearing age shall be negative; Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year.
• Ability to understand and sign a written informed consent documen.

Exclusion criteria

• Subjects are being treated with either corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of enrollment.
• Received cytotoxic chemicals, monoclonal antibodies, or immunotherapy within 4 weeks or 5 half-lives before enrollment;
• Pregnant, lactating, or breastfeeding females;
• Known positive test result for human immunodeficiency virus (HIV) oracquired immune deficiency syndrome (AIDS);Active infection of hepatitis B virus (HBV), or hepatitis C virus (HCV);
• History of allergy or intolerance to study drug components;
• Prior organ allograft transplantations or allogeneic hematopoietic stem cell transplantation;
• Major surgery or trauma occurred within 28 days prior to enrollment, or major side effects have not been recovered.
• 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.
• Previous or concurrent cancer within 5 years prior to treatment start except for curatively treated cervical cancer in situ, non-melanoma skin cancer, superficial bladder tumors;
• Any serious underlying medical (eg, pulmonary, renal, hepatic,gastrointestinal, or neurological) or psychiatric condition or any issue that would limit compliance with study requirements;
• Vaccination within 30 days of study enrollment;
• Previously received CD70-CAR T cell therapy;
• Being participating any other trials or withdraw within 4 weeks;
• Researchers believe that other reasons are not suitable for clinical trials.

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

China · 1 center

• China — Beijing

Identifiers

NCT: NCT05947487 · CHN-PLAGH-BT-080

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗