A Study of CNA3103 (LGR5-targeted, Autologous CAR-T Cells) Administered to Subjects With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This study aims to determine the safety and best response of treatment with CNA3103 (Leucine-rich repeat-containing G protein-coupled receptor 5 [LGR5]-targeted, Autologous Chimeric Antigen Receptor (CAR) -T Cells), for participants with Metastatic Colorectal Cancer. Participants may undergo a pre-screening biopsy procedure to determine expression of LGR5. Participants will undergo screening procedures, including leukapheresis (collection of T cells) and lymphodepletion (chemotherapy), up to 40 days prior to CNA3103 dosing. Participants will receive a single Intravenous dose of CNA3103. Expansion cohorts will open after determination of the maximum tolerated dose and recommended phase 2 dose in the dose escalation stage. Participants will be followed up, monitored and will attend study visits for safety and research related tests and procedures for 2 years until disease progression, unacceptable toxicity or intolerable adverse event/s, death or withdrawal of consent.

Detailed Description
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This is a Phase 1/2a, multicenter, open-label study in adult subjects with metastatic colorectal cancer. (CRC). The study will consist of 2 segments: Phase 1 Segment (Dose Escalation): a Bayesian Optimal Interval (BOIN) study design will be used to minimize any risks of exposure to the novel CNA3103 CAR-T cells during dose escalation while determining the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D). A minimum of 3 subjects per cohort will be enrolled at each dose level, with appropriate staggering of subjects within and between dose levels. Phase 2a Segment (Dose Expansion): After determination of the MTD/RP2D, additional subjects will be enrolled and treated with CNA3103 at that dose to further assess the safety, PK, pharmacodynamic, and anti-tumor properties of CNA3103. Based upon safety data of these additional subjects, the Sponsor, in consult with the Investigators, may choose to enroll additional subjects at the same or a different dose.

Official Title
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A Phase 1/2a, Multicenter, Open-Label, Dose Escalation and Expansion Study of CNA3103 (LGR5-targeted, Autologous CAR-T Cells) Administered to Adult Subjects With Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Biological: CNA3103: 5 x 10^7 cells
* Biological: CNA3103: 1.5 x 10^8 cells
* Biological: CNA3103: 4.5 x 10^8 cells
* Biological: CNA3103: 1.5 x 10^9 cells
* Biological: CNA3103: 2.5 x 10^7 cells


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written Informed Consent. Male and female subjects aged greater than or equal to18 years. Eastern Cooperative Oncology Group (ECOG) Performance Score 0 to 1. Histologically or cytologically confirmed metastatic colorectal cancer previously treated with 5-FU, oxaliplatin and irinotecan-based regimens for metastatic disease and least 4 weeks from last chemotherapy, biologic, radiotherapy, or investigational therapy, with resolution of all lingering toxicities to Grade <1, with the exception of neuropathy and alopecia. Positive for any level of LGR5 expression in tumor biopsies. Measurable or evaluable disease per RECIST version 1.1 . Life expectancy of at least >12 weeks. Normal organ and marrow function. No clinically significant abnormalities in urinalysis results at Screening. No known clinically significant gastrointestinal disease within 28 days prior to beginning study treatment. No ongoing requirement for anti-diarrheal therapy. For female subjects of childbearing potential and male subjects with partners of childbearing potential, agreement (by subject and/or partner) to use a highly effective form of contraception and to continue its use for 6 months after the last dose of IP. Women of childbearing potential must have a negative serum pregnancy test within 72 hours prior to CNA3103 administration. Exclusion Criteria: Inability to comply with study and follow-up procedures. Women who are pregnant or lactating. Has BRAF-mutated colorectal cancer. Has received any third line treatment regimen or received trifluridine/tipiracil (TAS-102) and regorafenib for metastatic disease. Treatment with chemotherapy, hormonal therapy, immunotherapy, biologic therapy, or radiation therapy as cancer therapy within 4 weeks before initiation of study treatment. Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent in the previous 28 days. Have received antibody-based therapies within the previous 28 days or 5 half-lives of the agent, whichever is shorter. Major surgery, other than diagnostic surgery, in the previous 4 weeks. Clinically detectable third-space fluid collections that cannot be controlled by drainage or other procedures prior to study entry. Any uncontrolled medical or psychiatric risk factors which would contraindicate the use or impair the ability of the subject to provide informed consent, receive protocol therapy or may impose excessive risk to the subject. Known central nervous system (CNS) disease. Current use of medications that may have the potential of QTc prolongation. Uncontrolled bacterial, viral, or fungal infection, requiring systemic therapy. Has a known infection with human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C, alcoholic or other hepatitis, or cirrhosis. Inability to be venipunctured and/or tolerate venous access. Second malignancies within 5 years prior to enrollment, except for those with a negligible risk of metastasis or death, such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent. Active autoimmune disease that is not controlled by non-steroidal anti-inflammatory drugs (NSAIDs), inhaled corticosteroids, or the equivalent of ≤10 mg/day prednisone. History of inflammatory bowel disease (active or past) or active peptic ulcer disease. History of connective tissue disorders. History of chronic leukemias. History of previous, whole abdomen radiation therapy (or total pelvic radiation therapy) or more than Grade 1 residual toxicity from previous radiation therapy. High cardiovascular risk, including, but not limited to, recent coronary stenting or myocardial infarction in the past year Left ventricular ejection fraction <50%. Have had a venous thromboembolic event requiring anticoagulation. Congenital or acquired long QT syndrome. QTc prolongation. History of interstitial lung disease, history of slowly progressive dyspnea and unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary hypersensitivity pneumonitis or multiple allergies.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CNA3103 Monotherapy<br>Single intravenous dose of CNA3103 at Day 0 | Biological: CNA3103: 5 x 10^7 cells<br>* CNA3103: 5 x 10^7 cells - intravenous infusion<br>Biological: CNA3103: 1.5 x 10^8 cells<br>* CNA3103: 1.5 x 10^8 cells - intravenous infusion<br>Biological: CNA3103: 4.5 x 10^8 cells<br>* CNA3103: 4.5 x 10^8 cells - intravenous infusion<br>Biological: CNA3103: 1.5 x 10^9 cells<br>* CNA3103: 1.5 x 10^9 cells - intravenous infusion<br>Biological: CNA3103: 2.5 x 10^7 cells<br>* CNA3103: 2.5 x 10^7 cells - intravenous infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of treatment with CNA3103. | Incidence of Treatment-Emergent Adverse Events | 24 Months | 
| To determine the overall best response to CNA3103. | Best response per Response Evaluation Criteria in Solid Tumors (RECIST). | 24 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the recommended Phase 2a dose (RP2D) of CNA3103 | Determined by dose limiting toxicities (DLTs) | 28 days | 
| To monitor for replication competent viral construct in blood specimens | Viral construct presence will be monitored | 24 Months | 
| To determine the Pharmacokinetics of CNA3103 | Levels of CNA3103 cells measured | 24 Months | 
| To determine overall survival | Survival will be calculated from the onset of CNA3103 therapy. | 24 Months | 
| Failure to treat | Caused by manufacturing issues or patient related issues. | 8 Weeks | 
| To determine progression-free survival | Calculated from the onset of therapy to disease progression. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CAR-T, LGR5