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

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 previouslytreated with no more than 2 prior fluoropyrimidine, oxaliplatin, and/oririnotecan-based regimens for metastatic disease. Antibody-drug conjugates (ADCs)administered in the metastatic setting are also considered cytotoxic treatment andwould count as a prior regimen. Neoadjuvant/adjuvant treatment of resectableoligometastatic disease, does not count as a prior line of therapy in the palliativesetting unless there is development of an unresectable local or distant recurrencewithin 6 months of its last dose.

Subjects who discontinue their prior regimen due to toxicity (in the absence of disease recurrence/progression) will also have their prior therapy count as one prior regimen. Anti-Kirsten rat sarcoma virus (Anti-KRAS) agents are also allowable. The planned lymphodepletion start date must be at least 4 weeks from last chemotherapy, biologic, radiotherapy, or investigational therapy (excluding bridging therapy), with resolution of all lingering toxicities to Grade ≤ 1, with the exception of neuropathy and alopecia.

Subjects previously treated in the adjuvant/neoadjuvant setting with an oxaliplatin/irinotecan regimen, who develop an unresectable local recurrence and/or metastatic disease within 6 months of the date of last oxaliplatin/irinotecan chemotherapy will have their adjuvant/ neoadjuvant therapy count as one prior regimen.

• Positive for any level of LGR5 expression in tumor biopsies.

• Measurable or evaluable disease per RECIST version 1.1. Subjects with lungmetastases involving less than or equal to 20% of both lung fields and with goodrespiratory reserves would be deemed eligible as long as the lesions do notcompromise airways, vascular, pleural, or mediastinal spaces. Both measurable andnon-measurable (evaluable) lesions would count for this assessment.

Subjects whose lung metastases involve more than 20% of both lung fields should be discussed with the Sponsor in more detail, taking into account disease tempo, clinical symptoms, respiratory function and compromise (current or impending) of airways, vascular, pleural, or mediastinal spaces. Both measurable and non-measurable (evaluable) lesions would count for this assessment.

• 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 toenrolment.

• No ongoing requirement for anti-diarrheal therapy.

• For female subjects of childbearing potential and male subjects with partners ofchildbearing potential, agreement (by subject and/or partner) to use a highlyeffective form of contraception and to continue its use for 6 months after the lastdose of IP.

• Women of childbearing potential must have a negative serum pregnancy test within 72hours 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 trifluridine/tipiracil (TAS-102) or regorafenib for metastatic disease.

• Treatment with chemotherapy, hormonal therapy, immunotherapy, biologic therapy, orradiation therapy as cancer therapy (excluding bridging therapy) within 4 weeksprior to the lymphodepletion start date.

• Treatment with any other investigational agent or participation in another clinicaltrial with therapeutic intent in the previous 28 days prior to enrolment.

• Have received antibody-based therapies within the previous 28 days or 5 half-livesof the agent, whichever is shorter.

• Major surgery, in the previous 4 weeks prior to enrolment.

• Clinically detectable pleural effusion requiring drainage in the 4 weeks prior toenrolment.

• Any uncontrolled medical or psychiatric risk factors which would contraindicate theuse or impair the ability of the subject to provide informed consent, receiveprotocol 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 orHepatitis 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 anegligible risk of metastasis or death, such as adequately treated carcinoma in situof the cervix, basal or squamous cell skin cancer, localized prostate cancer treatedsurgically with curative intent, ductal carcinoma in situ treated surgically withcurative intent.

• Active autoimmune disease that is not controlled by non-steroidal anti-inflammatorydrugs (NSAIDs), inhaled corticosteroids, or the equivalent of ≤10 mg/day prednisone.

• History of inflammatory bowel disease (active or past) or active peptic ulcerdisease.

• History of connective tissue disorders.

• History of chronic leukemias.

• History of previous, whole abdomen radiation therapy (or total pelvic radiationtherapy) or more than Grade 1 residual toxicity from previous radiation therapy.

• High cardiovascular risk, including, but not limited to, recent coronary stenting ormyocardial 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 andunproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonaryhypersensitivity pneumonitis or multiple allergies.

• Patients with ascites, previous drainage of ascites, peritoneal caking, and/orsignificant peritoneal deposits at Baseline are excluded from participation in thestudy

• Patients with reduced liver reserves and/or possibility of hepatobiliarycomplications, including, but not limited to; portal hypertension, liver resection (segmentectomy, metastasectomy) in the previous 6 months, patients with existingbiliary stents or the need to receive a biliary stent to relieve bile ductobstruction of any etiology, patients with cholelithiasis, patients who abusealcohol or paracetamol (with or without concomitant alcohol abuse), patients who useherbal medicines, and patients with substance abuse.