Clinical trial NCT06767046: KRAS-Specific Autologous TCR-T Cell Therapy for KRAS Mutation in Advanced Solid Tumors
Official title: An Exploratory Study to Evaluate the Safety and Preliminary Efficacy of KRAS-Specific Autologous TCR-T Cells in Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE1
Conditions: Colorectal
Pancreatic
Non-small Cell Lung Cancer (NSCLC)
Keywords: KRAS G12V
immunotherapy
T cell
Adoptive cell therapy
T cell receptor
TCR
Lead sponsor: Corregene Biotechnology Co., Ltd
Sponsor class: INDUSTRY
First posted: 2025-01-09
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a single-center, open-label, single-arm, dose-escalation study aimed at evaluating the safety and preliminary efficacy of KRAS-specific autologous TCR-T cells in patients with advanced solid tumors harboring KRAS mutations (e.g., G12V).

Detailed description: T cell receptor-gene engineered T cells (TCR-T) therapy is a highly targeted form of cellular immunotherapy. It is safer than Chimeric Antigen Receptor T-Cell Immunotherapy (CAR-T) and is currently a hot topic in immunotherapy. In the case of advanced pancreatic cancer with KRAS mutations, the infusion of TCR-T cells has achieved good efficacy and safety, further suggesting the promising prospects of TCR-T cell immunotherapy for advanced solid tumors with KRAS gene mutations.

It is planned to enroll 9 - 18 patients with advanced solid tumors who have KRAS mutations, HLA-A\*11:01 genotype, and have failed standard treatments. A single-center, open-label, single-arm study design will be adopted. The KRAS-specific autologous TCR-T cell injection will be used to treat these patients. The primary endpoint is safety, and the secondary endpoints include efficacy, cell activity, etc. It is planned to select three dose groups with 5×10⁹, 1×10¹⁰, and 2×10¹⁰ TCR-T cells respectively, and conduct dose escalation using a 3 + 3 study design.

The key steps involved in the study are the preparation and quality control of TCR-T cells, lymphocyte depletion (lymphodepletion), and the infusion of autologous TCR-T cell injection. Record and promptly handle specific adverse reactions of cellular immunotherapy, such as cytokine release syndrome (CRS), various other adverse events, off-target effects of TCR-T, and adverse events related to tumorigenic potential, etc., to obtain safety data. It is hoped that the results of this study will bring a new future for patients with advanced solid tumors with specific KRAS mutations.

Eligibility criteria: Inclusion Criteria:

* Patients aged 18-70 years.
* Histologically or cytologically confirmed advanced solid tumors (e.g., colorectal cancer, pancreatic cancer, NSCLC) with KRAS G12V mutations and HLA-A\*11:01 genotype.
* Failed standard therapies or no effective treatment available.
* ECOG performance status of 0-1.
* Life expectancy of ≥3 months.
* Presence of at least one measurable lesion as defined by RECIST 1.1 criteria.
* Female patients of childbearing potential must agree to use highly effective contraceptive methods during the study and for at least 6 months after the last dose. A negative pregnancy test within 7 days prior to treatment initiation is required.
* Written informed consent provided by the patient, with an expectation of compliance with study procedures.

Exclusion Criteria:

* 1.Prior treatment with gene-modified T-cell therapies.
* Current treatment with T-cell suppressive agents (e.g., cyclophosphamide, FK506, tripterygium glycosides) or T-cell stimulants.
* Chemotherapy, targeted therapy, immunotherapy, or investigational drugs administered within 2 weeks, or radiotherapy within 4 weeks prior to enrollment.
* Significant organ dysfunction, as evidenced by:

  * leukocytes\<3.0 x 109/L
  * absolute neutrophil count \>1.5 x 109/L
  * hemoglobin\<90g/L
  * platelets \<100 x 109/L
  * Creatinine\>1.5×ULN or creatinine clearance \<50mL/min
  * lymphocytes\<0.5 x 109/L
  * total bilirubin\>3×ULN; ALT/AST\>3×ULN (or \>5× ULN in patients with liver metastases)
  * INR/APTT\>1.5×ULN；
  * SpO2≤93%
* Presence of serious diseases and comorbidities, including but not limited to: severe heart disease, cerebrovascular disease, seizures, poorly controlled diabetes (such as Type 1 diabetes or insulin-dependent diabetes), pancreatic dysfunction, severe infections, active gastrointestinal ulcers, gastrointestinal bleeding, mechanical or paralytic bowel obstruction, pulmonary fibrosis, renal failure, respiratory failure, etc.
* History of severe cardiovascular diseases within the past 6 months, including but not limited to: myocardial infarction, severe or unstable angina, coronary artery or peripheral artery bypass surgery, New York Heart Association (NYHA) Class III or IV heart failure, etc.
* Left ventricular ejection fraction (LVEF) \< 50%.
* Symptomatic brain metastases unless stabilized with prior treatment (e.g., surgery or radiotherapy).
* Known history of myelodysplastic syndrome, lymphoma, or other malignancies.
* Known allergy to albumin, investigational drugs, or their excipients.
* Active autoimmune diseases, including but not limited to acquired/congenital immunodeficiency, organ transplantation, autoimmune hepatitis, systemic lupus erythematosus, or inflammatory bowel disease.
* Active hepatitis B, hepatitis C, or HIV infection.
* Pregnancy or breastfeeding.
* Uncontrolled mental or neurological disorders.
* Any condition deemed unsuitable for study participation by the investigator.

Primary outcomes:
measure: Incidence of treatment related AEs, AEs of special interest and serious adverse events (SAEs)
timeFrame: 2 years
Secondary outcomes:
measure: Objective Response Rate (ORR)
timeFrame: 2 years
measure: Disease Control Rate (DCR)
timeFrame: 2 years
measure: Duration of Response (DOR)
timeFrame: 2 years
measure: Progression-Free Survival (PFS)
timeFrame: 2 years
measure: Overall Survival (OS)
timeFrame: 2 years
Other outcomes:
Locations:
Study officials:
References: