A Phase I Interventional Open-label, Non-randomized Dose-escalation Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics, Immunogenicity, and Preliminary Anti-tumor Activity of Autologous p95HER2.CAR-TECH2Me T Cells in Patients With Selected Advanced Cancers.
This is a phase I, open-label, non-randomized, multicenter, dose-escalation trial designed to evaluate the safety, tolerability, and preliminary anti-tumor activity of autologous p95HER2.CAR-TECH2Me T cells in patients with selected advanced HER2-positive (3+) cancers, including locally advanced, recurrent, or metastatic breast, gastric, endometrial, and other selected solid tumors. The study will also assess pharmacokinetics, pharmacodynamics, and immunogenicity of p95HER2.CAR-TECH2Me following intravenous administration. Treatment consists of non-myeloablative lymphodepletion chemotherapy with cyclophosphamide and fludarabine administered on Days -4 to -2, followed by a single infusion of p95HER2.CAR-TECH2Me cells on Day 0. The investigational product is a live cell suspension of autologous CAR-T lymphocytes derived from the patient's peripheral blood. Premedication will be administered before cell infusion according to protocol requirements. The primary objective of the study is to evaluate the safety and tolerability of p95HER2.CAR-TECH2Me and to identify the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D). Primary endpoints include the nature and frequency of adverse events, serious adverse events, clinically relevant changes in laboratory parameters, electrocardiograms, vital signs, physical examination findings, and ECOG performance status, as well as the incidence and nature of dose-limiting toxicities. Adverse events will be graded according to NCI CTCAE v5.0, with cytokine release syndrome and neurotoxicity graded according to established consensus criteria. Secondary objectives include evaluation of preliminary anti-tumor activity and survival outcomes. Secondary endpoints include objective response rate, duration of response, progression-free survival according to RECIST v1.1 as assessed by the investigator, and overall survival. Approximately 15 patients are planned for enrollment over an estimated 36 to 48 months. The total study duration is expected to be approximately 60 months from the time the first subject signs the pre-screening informed consent form until the last subject completes the final study-related follow-up contact.
• Patients must understand and voluntarily sign an informed consent document before any study-related assessments/procedures being conducted.
• Age ≥ 18 and years at the time of signing the ICF
• Patients must be able and willing to comply with the study visit schedule and protocol requirements.
• Patients must have a clinical performance of Eastern Cooperative Oncology Group 0 or 1.
• Life expectancy ≥12 weeks.
• Patients must have histologically or cytologically proven unresectable or metastatic tumors. The disease must be refractory to standard therapy or in the first line if they are unable to receive standard therapy or no standard therapy exists for a particular disease.
• a) Select tumor types: breast, gastric, and endometrial tumors. Other selected solid tumors may be included per investigator discretion if the potential benefit is considered based on the literature updates in HER2/p95HER2 expression.
• Positivity for HER2 expression according to international society guidelines (score in a ISO-certified clinical or equivalent laboratory). To meet study entry eligibility, tumors are required to have at least an intensity score 3+ for HER2 staining following the manufacturer's recommendations
• Measurable disease by the RECIST v. 1.1 criteria (See Section 7.2 for details). Note: Lesions previously irradiated should not be selected as target lesions unless there has been demonstrated progression in those lesions;
• Patients are considered medically fit enough to undergo all study procedures and interventions and adequate hematological, renal, and hepatic functions defined by:
∙ Hemoglobin ≥ 9.0 g/dL.
‣ An absolute neutrophil count ≥ 1x10E9/L without the support of filgrastim
‣ Platelets ≥ 100 x10E9/L.
‣ PT and APTT ≤ 1.5x ULN (unless receiving therapeutic anticoagulation). Note: Subjects receiving therapeutic anticoagulation (such as low-molecular-weight heparin or warfarin) should be on a stable dose.
‣ AST or ALT ≤ 3 x ULN. Patients with liver metastases must have AST and ALT ≤ 5.0 x ULN.
‣ Total bilirubin \< 2 mg/dL. Patients with Gilbert's Syndrome must have a total bilirubin ≤ 3.0 mg/dL.
‣ Serum creatinine \< 1.5 mg/dL or measured creatinine clearance ≥ 50 ml/min calculated using the Cockcroft-Gault glomerular filtration rate estimation: (140 - age) × (weight in kg) × (0.85 if female)/72 × (serum creatinine in mg/dL).
⁃ Patients must be seronegative for HIV antibody.
⁃ Patients must be seronegative for active hepatitis B (defined as having a negative hepatitis B surface antigen \[HBsAg\] test), and seronegative for hepatitis C antibody. Patients with a history of hepatitis B virus (HBV) infection and having a negative HBsAg test and a positive antibody to hepatitis B surface antigen (HBsAg) are eligible. Patients with the hepatitis C antibody test positive are eligible only if tested for the presence of antigen by RT-PCR and be HCV RNA negative.
⁃ Patients must have blood tests results negative for active tuberculosis, syphilis, herpes simplex virus, cytomegalovirus, HTLV or Epstein-Barr virus infection.
⁃ Patients with documented LVEF of ≥ 50%.
⁃ Patients with documented FEV1, FVC, and DLCO ≥ 50% tested by a pulmonary function test.
⁃ Patients who are of childbearing potential (postmenarcheal who has not reached a postmenopausal state and has not undergone surgical sterilization) or have partners of childbearing potential must agree to use a highly effective method of contraception during the study and for at least 12 months after the infusion of the p95HER2.CAR-TECH2Me product .
⁃ Female participants: a female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:
• Women of non-childbearing potential (WONCBP).
∙ Women of childbearing potential (WOCBP), who:
⁃ i) Agree to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of \<1% per year from screening until 12 months after the infusion of the p95HER2.CAR-TECH2Me product. Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal occlusion, male sterilization, and copper intrauterine devices.
⁃ ii) Have a negative pregnancy test (blood) within one week before the first study treatment administration (applicable to premenopausal women and women 2 years after the start of menopause (menopause is defined as amenorrhea for \< 2 years).
⁃ Male Participants: during the treatment period and for at least 6 months after the last dose of study treatment, agreement to:
• Remain abstinent (refrain from heterosexual intercourse) or use contraceptive measures such as a condom or a contraceptive method that result in a failure rate of \<1% per year, with partners who are WOCBP.
∙ Refrain from donating sperm during the study.
∙ Inform if his partner gets pregnant during this time.
⁃ Adequate expanding p95HER2.CAR-TECH2Me cells as defined by the T cell production manual before preparative lymphodepleting chemotherapy infusion (available autologous transduced T lymphocytes with 15% or more expression of p95HER2.CAR-TECH2Me as determined by flow-cytometry and killing of p95HER2-positive targets 20 % or greater in cytotoxicity assay.)
⁃ Any toxicity related to prior systemic therapy must have recovered to grade 1 or less according to NCI-CTCAE v5.0 at least 4 weeks before treatment enrollment, except for alopecia, vitiligo, or endocrinopathy managed with replacement therapy, and Grade 2 peripheral neuropathy.
⁃ Note: Other Grade 2 AEs that are deemed clinically insignificant by treating physician and in consultation with Medical Monitor are permitted.
⁃ Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.