NKG2D CAR-T Cells to Treat Patients With Previously Treated Liver Metastatic Colorectal Cancer

Hepatic Artery Transfusion of NKG2D CAR-T Cells to Treat Patients With Previously Treated Liver Metastatic Colorectal Cancer: a Prospective, Multicenter Clinical Trial

Evaluate the clinical safety and feasibility of NKG2D CAR-T administrated by hepatic artery transfusion for patients with previously treated liver metastatic colorectal cancer.

Study Overview

• Status: Recruiting
• Conditions: Refractory Metastatic Colorectal Cancer
• Intervention / Treatment: Biological: CAR-T infusion

Detailed Description

Evaluate the clinical safety and feasibility of NKG2D CAR-T administrated by hepatic artery transfusion for patients with previously treated liver metastatic colorectal cancer. Evaluate the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and toxicity spectrum of NKG2D CAR-T treatment administrated by hepatic artery transfusion. Secondary Objectives: Evaluate the efficacy of NKG2D CAR-T administrated by hepatic artery transfusion for patients with previously treated liver metastatic colorectal cancer, including PSF, DCR, SD >= 8 weeks, ORR, OS, and DOR.

• Study Type: Interventional
• Enrollment (Anticipated): 9
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Xuehu Xu, MD; Phone Number: 0086 13609020099; Email: maxtiger@126.com
• Study Contact Backup: Name: Nanqi Huang; Phone Number: 13560316181

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China
      • Recruiting
      • The Third Affiliated Hospital of Guangzhou Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Prior to performing any study protocol-related procedures other than routine care, a voluntarily signed and dated subject informed Consent Form (ICF) must be obtained in accordance with regulatory and institutional guidelines.
2. Aged 18-75 years.
3. There is definite histological evidence of adenocarcinoma of the colon or rectum.
4. The Eastern Cooperative Oncology Group (ECOG) performance Status (PS) score was 0-1 (see Appendix 1).
5. Liver metastasis was confirmed by PET-CT, CT, MR, and/or intraoperative exploration (histological diagnosis is not required).
6. According to the response evaluation criteria in solid Tumors (RECIST) (Version 1.1), patients have at least one target lesion with a measurable diameter line (CT scan of tumor lesion length >= 10 mm, The short diameter of CT scan of lymph node lesions >= 15 mm, and the scanning layer thickness is no more than 5 mm).
7. Failure of treatment after previous standard chemotherapy for metastatic colorectal cancer (including disease progression and unacceptable adverse reactions):

(1)Chemotherapy regimens must include fluorouracil (5-fluorouracil/capecitabine /S-1), oxaliplatin and irinotecan (2)Patients receiving oxaliplatin in adjuvant therapy should develop disease progression during adjuvant therapy or within 6 months after completion of adjuvant therapy; (3)patients may have previously received bevacizumab and/or cetuximab and/or rigfinil and/or furoquitinib.

8. The primary tumor of the colon or rectum has been surgically removed, or the liver metastases are considered to be irretrievable after the evaluation of a multidisciplinary colorectal cancer team consisting of at least two gastrointestinal surgeons, one hepatobiliary surgeon, one oncologist, one interventional surgeon, and one radiologist.

9. The following laboratory test values obtained during the root screening period (reaching the standard and stable before participating in the study) have appropriate organ functions: Neutrophil count >= 1.5 x 109/L, platelet count >= 75 x 10^9/L, serum total bilirubin <= upper normal limits UNL), aspartate aminotransferase <= 2 x UNL, alanine aminotransferase <= 2 x UNL, serum creatinine <= 1.5 x UNL.

10. Negative urine or serum pregnancy tests in women of reproductive age within 7 days prior to treatment.

Exclusion Criteria:

1. The presence or co-existence of other active malignancies (other than those that have been curable for more than 5 years and have received curative treatment or carcinoma in situ that can be cured with adequate treatment).
2. Subjects have central nervous system metastasis or previous brain metastases.
3. Had received hepatic arterial infusion chemotherapy, hepatic arterial embolization chemotherapy or hepatic radiotherapy within 3 months.
4. Received liver surgery (except biopsy for liver metastasis) and liver interventional ablation within the previous 3 months.
5. CT angiography showed severe arterial embolism or hepatic arterial variation.
6. Partial prothrombin time (APTT) or prothrombin time (PT) exceeded 1.5 x ULN (based on the normal value in the clinical trial research center), or patients with evidence or history of bleeding tendency within 2 months prior to enrollment, regardless of severity.
7. Active infection less than 7 days after completion of systemic antibiotic therapy.
8. Major surgery or severe trauma, such as laparotomy, thoracotomy, laparoscopic viscerectomy, etc. within 4 weeks prior to enrollment (surgical incisions should be completely healed before randomization).
9. Active coronary artery disease, severe/unstable angina or newly diagnosed angina or myocardial infarction within 12 months prior to enrollment.
10. Thrombosis or embolism events, such as cerebrovascular accident (including transient ischemic attack), pulmonary embolism, and deep vein thrombosis, occurred within 12 months prior to enrollment.

The New York Heart Association (NYHA) has grade II congestive Heart failure or higher (see Appendix 2).

12. Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS), active hepatitis (hepatitis B, defined as HBV-DNA >= 500 IU/ mL; Hepatitis C, defined as hcV-RNA higher than the lower limit of the assay) or co-infection with hepatitis B and c.

13. Presence of any active, known or suspected autoimmune disease. Subjects who are in a stable state and do not require systemic immunosuppressive therapy, such as type I diabetes, hypothyroidism requiring only hormone replacement therapy, and skin conditions that do not require systemic therapy (e.g., vitiligo, psoriasis, and hair loss) are allowed to be enrolled.

14. Presence of interstitial lung disease, non-infectious pneumonia or uncontrolled systemic disease (e.g., diabetes, hypertension, pulmonary fibrosis and acute pneumonia).

15. Common Terminology Criteria for Adverse Events (CTCAE) (version 5.0) grade 2 or above toxicity (except anaemia, hair loss, skin pigmentation) arising from any prior treatment that has not subsided.

16. Programmed death-1 within 3 months Pd-1) or its ligand (PD-L1) antibody, anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) antibody, or other drugs/antibodies that act on T cell co-stimulation or checkpoint pathways.

17. Positive pregnancy test before first use in women who are pregnant or breast-feeding or who are at risk of pregnancy.

18. The investigator considers that the subject has any clinical or laboratory abnormalities or compliance issues that make it inappropriate to participate in this clinical study.

19. There are serious psychological or mental abnormalities. 20. Participated in clinical trials of other drugs within 4 weeks.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SEQUENTIAL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: NKG2D CAR-NK; CAR-T infusion	Biological: CAR-T infusion; NKG2D CAR-NK Cell Therapy in Patients With Refractory Metastatic Colorectal Cancer; Other Names: Natural killer group 2 member D (NKG2D) ligand-targeting chimeric antigen receptor (CAR) natural killer (NK) cells

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Limiting Toxicity#DLT#	Safety	28 days
Maximal Tolerable Dose#MTD#	tolerability evaluation	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Antitumor efficacy-Objective response rate (ORR)	The number of cases in which tumor size is reduced to partial response (PR) or complete response (CR) / the total number of evaluable cases (%).	52 weeks
Antitumor efficacy-Overall survival (OS)	The period from the first study treatment to any cause of death	52 weeks

Collaborators and Investigators

• Sponsor: The Third Affiliated Hospital of Guangzhou Medical University
• Collaborators: Hangzhou Cheetah Cell Therapeutics Co., Ltd
• Investigators: Principal Investigator: Xuehu Xu, MD, The Third Affiliated Hospital of Guangzhou Medical University

Study record dates

Study Major Dates

• Study Start (ACTUAL): September 13, 2021
• Primary Completion (ANTICIPATED): October 1, 2022
• Study Completion (ANTICIPATED): October 1, 2022

Study Registration Dates

• First Submitted: February 8, 2022
• First Submitted That Met QC Criteria: February 9, 2022
• First Posted (ACTUAL): February 21, 2022

Study Record Updates

• Last Update Posted (ACTUAL): February 21, 2022
• Last Update Submitted That Met QC Criteria: February 9, 2022
• Last Verified: February 1, 2022

More Information

Terms related to this study

• Keywords: NKG2D; CAR-NK; Refractory Metastatic Colorectal Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: CART-002

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No