XS-03 in Combination With FOLFOX or FOLFIRI and Bevacizumab for Treatment of Metastatic Colorectal Cancer Patients With RAS Mutation (XS-03-II201)

NovaOnco Therapeutics Co., Ltd.

Status and phase: Invitation-only; Phase 2; Phase 1

Conditions: Metastatic Colorectal Cancer With RAS Mutation; Colorectal Cancer

Treatments: Biological: Drug: XS-03, Biological: Bevacizumab, Drug: FOLFOX, Drug: FOLFIRI; Biological: Biological: Bevacizumab, Drug: FOLFOX, Drug: FOLFIRI; Biological: Drug: XS-03

Study type: Interventional

Funder types: Industry

Identifiers

NCT06936527

XS-03-II201

Details and patient eligibility

About

XS-03 in combination with FOLFOX or FOLFIRI and Bevacizumab for treatment of metastatic colorectal cancer patients with RAS mutation

Enrollment: 102 estimated patients

Sex: All

Ages: 18 to 70 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

1. Voluntarily participate in the clinical trial and sign the informed consent form.
2. Age ≥18 and ≤ 70 years. No gender restrictions.
3. Patients with histologically and/or cytologically confirmed metastatic colorectal cancer who are not suitable for surgical treatment.
4. Advanced or metastatic colorectal cancer: Stage Ib patients must have received at least one prior systemic therapy; Stage II patients have no prior systemic therapy. For patients with previously neoadjuvant/adjuvant therapy, disease progression must occur no less than 6 months after the end of therapy to be eligible for inclusion.
5. Documentation of RAS mutation. The previously gene test report issued by qualified testing institution is acceptable. BRAF status is not restricted.
6. Consent to provide tumor tissue samples and peripheral blood for biomarker analysis.
7. Has measurable extracranial lesion according to RECIST v1.1 criteria, defined as at least one lesion that has not received radiotherapy. For previously radiotherapy lesion, there must be imaging evidence of progression after radiotherapy.
8. Eastern Cooperative Oncology Group (ECOG) performance status score 0-1.
9. Expected life expectancy ≥ 6 months.
10. The patient has adequate hepatic, renal and bone marrow function.
11. For a woman of child-bearing potential must have a negative serum pregnancy test within 7 days prior to enrollment. Woman of child-bearing potential and fertile men must agree to use adequate contraception for the duration of study participation and for 6 months after the last dose.

Exclusion Criteria

1. Patients with known high microsatellite instability (MSI-H) or mismatch repair deficiency (dMMR) primary or metastatic colorectal cancer and suitable for immune checkpoint inhibitor treatment assessed by investigators.

2. Previously received bevacizumab and its biosimilar therapy. (Only for phase II)

3. Central nervous system metastases which are symptomatic or require therapy.

4. Imaging shows major blood vessel invasion (such as the aorta, pulmonary artery, pulmonary vein, vena cava, etc.).

5. Adverse events and/or complications that caused by previous antitumor therapy have not recovered to baseline level or ≤ CTCAE grade 1.

   Baseline level or ≤ Grade 1. However, any grade of alopecia, pigmentation, or ≤ Grade 2 peripheral sensory neuropathy, or other conditions assessed by the investigator as having become chronic and not affecting the safety of the study medication are allowed for inclusion.

6. With a history of other malignancies within 5 years or with other malignancies currently prior to screening, except colorectal cancer. Exception: curatively treated early-stage malignancies (in situ carcinoma or stage I tumors), such as adequately treated basal cell or squamous cell skin cancer or in situ cancer of the cervix.

7. Patients have a significant risk of bleeding.

8. Patients have a significant risk of thrombus.

9. Patients have severe cardiovascular disease, including but not limited to: Ischemic heart disease within the past 6 months prior to screening; coronary artery disease post-surgery or stent implantation within 6 months; New York Heart Association (NYHA) functional classification ≥ Class II within 6 months prior to screening; or known left ventricular insufficiency (LVEF <50%)；severe arrhythmia requiring clinical intervention; any other cardiovascular disease that researchers regard the patient unsuitable for participation in the study.

10. Patients with a significantly increased risk of QTc prolongation.

11. Patients unable to swallow drugs or have severe diseases that significantly affect drug absorption.

12. Patients have one of the following viral active infections: active hepatitis B or C; human immunodeficiency virus (HIV) infection; active syphilis

13. During screening, the presence of interstitial lung disease, interstitial pneumonia, pulmonary interstitial fibrosis requiring therapy, or a history of pneumonia caused by tyrosine kinase inhibitors.

14. Patients received radiotherapy within the past 4 weeks prior to the first first dose of study drug.

15. Patients received therapeutic surgeries (excluding diagnosis, biopsy, or drainage procedures) within the past 4 weeks prior to the first dose of study drug, including local treatments such as radiofrequency ablation for liver metastases, or are expected to have major surgeries during the study period.

16. Severity infection need intravenous infusion of antibiotics, antiviral drugs, or hospitalisation within the past 2 weeks prior to the first dose of study drug.

17. Patients must use strong CYP3A4 inducers or inhibitors within the past 2 weeks prior to the first administration, or during the anticipated study period,

18. History of severe allergy, or known allergy to any active or inactive components of the study drug product.

19. Pregnancy or lactation.

20. Patients with severe diseases of any organs or systems, any clinical or laboratory test abnormalities, or other reasons that investigator assess them unsuitable to participate in this clinical study.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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102 participants in 3 patient groups

Experimental arm 1: XS-03 + FOLFOX/FOLFIRI + Bevacizumab

Experimental group

Description:

Phase 1b: XS-03 escalating orally Day 1 through Day 5 and Day 15 through Day 19 of each 28-day cycle in combination with FOLFOX or FOLFIRI and bevacizumab. FOLFOX (85 mg/m\^2 oxaliplatin, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU) , 5 mg/kg bevacizumab FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU), 5 mg/kg bevacizumab

Treatment:

Biological: Drug: XS-03, Biological: Bevacizumab, Drug: FOLFOX, Drug: FOLFIRI

Experimental arm 2: XS-03 + FOLFOX/FOLFIRI + Bevacizumab

Experimental group

Description:

Phase 2: XS-03 Recommended Phase 2 Dose (RP2D) and selected one more dosage orally Day 1 through Day 5 and Day 15 through Day 19 of each 28-day cycle in combinationwith FOLFOX or FOLFIRI and bevacizumab. FOLFOX (85 mg/m\^2 oxaliplatin, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU) , 5 mg/kg bevacizumab FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU), 5 mg/kg bevacizumab

Treatment:

Biological: Drug: XS-03

Comparator: FOLFOX/FOLFIRI + Bevacizumab

Active Comparator group

Description:

Phase 2: Comparator arm treat with FOLFOX or FOLFIRI + bevacizumab intravenously. FOLFOX (85 mg/m\^2 oxaliplatin, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU) , 5 mg/kg bevacizumab FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU), 5 mg/kg bevacizumab

Treatment:

Biological: Biological: Bevacizumab, Drug: FOLFOX, Drug: FOLFIRI