Colorectal Cancer (Diagnosis) 、Colorectal Cancer Metastatic、 Colorectal Cancer (CRC)、 Immunotherapy

This trial aims to evaluate potential new therapies for metastatic colorectal cancer (mCRC). Currently, participants who have received chemotherapy and biotherapy may have limited options for further treatment, as existing third-line therapies typically show only moderate efficacy. We urgently need innovative treatments to improve participant outcomes. The trial aims to: • Evaluate the safety and tolerability of ABT-301 and identify any potential side effects. • Determine the appropriate dosage for future trials. • Understand how the body processes and eliminates ABT-301 (pharmacodynamic (PD) or pharmacokinetic (PK) assays). • Evaluate the efficacy of ABT-301 in shrinking tumor size and controlling cancer progression. • Identify biomarkers that may indicate a participant's response to treatment. • Investigate how ABT-301 affects the immune system and tumor-associated angiogenesis.

Capsules
Intravenous infusion
Intravenous infusion

ABT-301
BEVACIZUMAB
Tislelizumab

130
246
246

50mg
100mg/4ml
100mg/10ml

Part 1:
*Evaluate the safety and tolerability of escalating doses of ABT-301 in combination with fixed doses of Tislelizumab (200 mg, IV infusion) and Bevacizumab (7.5 mg/kg, IV infusion every 3 weeks) in patients with pMMR/non-MSI-H colorectal cancer.

*Determine the maximum tolerated dose (MTD) of ABT-301 and select its recommended phase 2 dose (RP2D).

Part 2:
*Evaluate the efficacy of two dose/regimen of ABT-301 in combination with Tislelizumab and Bevacizumab.

Inclusion Criteria:

Participant must be ≥18 years at the time of signing the informed consent.
Participant with pMMR/non-MSI-H advanced/recurrent histologically confirmed CRC with at least one measurable lesion, per RECIST version 1.1.
Participant must have received ≥2 lines of prior systemic therapy (including but not limited to chemotherapeutic agents of 5-fluorouracil, oxaliplatin, irinotecan; participant may or may not have received biologic agents such as cetuximab, panitumumab, aflibercept, ramucirumab, bevacizumab; tyrosine kinase inhibitors of regorafenib, fruquintinib).
NOTE: Participants with BRAF V600E, HER2 amplification/ mutation, KRAS G12C mutation, NTRK gene fusion, RET fusion, may or may not have received relevant targeted therapy and failed.

Participant must submit an archival formalin-fixed, paraffin-embedded tumor specimen collected within 5 years before screening. If archival specimens are unavailable, alternative samples, such as colon endoscopy biopsy, are acceptable.
NOTE: For participants who consent to join the exploratory biomarker study, a fresh biopsy sample is required during the screening and treatment periods. Exceptions may be granted if tumor tissue cannot be obtained due to specific circumstances.

Tumor tissues were identified as pMMR by immunohistochemistry (IHC) method or nonMSI-H by polymerase chain reaction (PCR) (Appendix 13).
ECOG Performance Status of 0 or 1.
Adequate hematologic and end-organ function, defined by laboratory data obtained within 7 days prior to the first dose of study intervention:

Absolute neutrophil count ≥1.5 × 109/L (1500/μL) without granulocyte colony-stimulating factor support.
Lymphocyte count >0.5 × 109/L (500/µL).
Platelet count >100 × 109/L (100,000/μL), without transfusion.
Hemoglobin >90 g/L (9 g/dL), participants may be transfused to meet this criterion.
AST, ALT, and ALP <2.5 × ULN (must be ≤5 × ULN for participants with liver metastases).
Total serum bilirubin <1.5 × ULN (<3 × ULN in the presence of documented Gilbert's syndrome [unconjugated hyperbilirubinemia] or liver metastases at baseline).
Creatinine clearance >60 mL/min.
Serum albumin ≥30 g/L (3 g/dL).
International normalized ratio (INR) or activated partial thromboplastic time (aPTT) <1.5 × ULN.
Urine dipstick for proteinuria ≤2+ (within seven days prior to the first dose of study intervention).
Resolution of any acute, clinically significant treatment-related toxicity from prior therapy to Grade ≤1 prior to study entry, with the exception of Grade ≤2 chemotherapy-related peripheral neuropathy or any Grade alopecia.
Participant must have a negative test for Hepatitis B surface antigen (HBsAg), Hepatitis C antibody, or human immunodeficiency virus (HIV) antibody.
NOTE: Participants with active hepatitis B virus (HBV) infection are eligible for the study if the following applies: HBV deoxyribonucleic acid (DNA) <500 IU/mL within 28 days prior to initiation of study intervention, and anti-HBV treatment (per local standard of care, e.g., entecavir) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study. Participants with positive hepatitis C virus (HCV) test are eligible for the study if they complete their antiviral therapy prior to study entry.

Contraceptive use by participants or participant partners must be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
NOTE: The reliability of sexual abstinence for male and/or female enrollment eligibility needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or post ovulation methods) and withdrawal are not acceptable methods of contraception.

Male Participants:

A male participant must agree to use a highly effective contraception as detailed in Appendix 4 of this protocol during the intervention period and for at least 90 days after the last dose of study intervention and refrain from donating sperm during this period.

Female Participants:

A female participant is eligible to participate if she is not pregnant (see Appendix 4), not breastfeeding, and at least one of the following conditions applies:

o Not a CBP participant as defined in Appendix 4 and below: surgically sterile (documented hysterectomy, bilateral salpingectomy, or bilateral oophorectomy as confirmed by review of the participant's medical records, medical examination, or medical history interview), or postmenopausal (defined as no menses for 12 months) without an alternative medical cause with follicle-stimulating hormone (FSH) level in the postmenopausal range ≥1 year.

OR

o A CBP participant who agrees to follow the contraceptive guidance in Appendix 4 during the intervention period and for at least 180 days after the last dose of study intervention.

- Participant is capable of giving signed informed consent as described in Appendix 1, Section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion Criteria:

History of leptomeningeal disease.
Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, or ankylosing spondylitis.