A Clinical Study to Evaluate Efficacy and Safety of Serplulimab（HLX10） Combined With Bevacizumab（HLX04) and Chemotherapy (XELOX) in Patients With Metastatic Colorectal Cancer (mCRC)

Metastatic Colorectal Cancer Clinical Trial

Official title:

A Randomized, Double-blind, Multicenter, PhaseⅡ/Ⅲ Clinical Study of Serplulimab in Combination With Bevacizumab and Chemotherapy (XELOX) Versus Placebo in Combination With Bevacizumab and Chemotherapy (XELOX) in First-line Treatment of Patients With Metastatic Colorectal Cancer (mCRC)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04547166
• Other study ID #: HLX10-015-CRC301
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: March 10, 2021
• Est. completion date: December 30, 2026

Study information

• Verified date: June 2024
• Source: Shanghai Henlius Biotech
• Contact: Ruihua Xu
• Phone: 020-87343292
• Email: xurh[@]sysucc.org.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a two-arm, randomized, double-blinded, multicenter phase III clinical study to evaluate the clinical efficacy of Serplulimab (HLX10) in Combination With Bevacizumab and Chemotherapy (XELOX) Versus Placebo in Combination With Bevacizumab and Chemotherapy (XELOX) in First-line Treatment of Patients With Metastatic Colorectal Cancer (mCRC)

Description:

Patients with confirmed unresectable metastatic/recurrent colorectal adenocarcinoma who have not received systemic anti-neoplastic therapy for metastatic/recurrent lesions will be included in this study.Approximately 6-12 patients will be enrolled in the Part I (Safety Run-in Period).Approximately 100 patients will be enrolled in the Part II (Phase II study, 50 in the test group and 50 in the control group).Approximately 568 patients will be enrolled in the Part III (Phase III study, 284 in the test group and 284 in the control group).

Part II (Phase II study): Approximately 40 study sites in China will participate.

Part III (Phase III study): A total of approximately 75 study sites in 3 countries(including China, Japan, Indonesia) will participate.

The study consists of a screening period (up to 28 days), a treatment period (3-week cycle, up to 2 years), and a follow-up period (including a safety follow-up period, and a survival follow-up every 12 weeks).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 568
• Est. completion date: December 30, 2026
• Est. primary completion date: September 24, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Patients are eligible for the study if they meet all of the following criteria:

1. Male or female aged 18-75 years (inclusive) when signing the ICF

2. Histopathologically confirmed unresectable metastatic/recurrent colorectal adenocarcinoma

3. Life expectancy = 12 weeks

4. Have not received any previous systemic anti-tumor drug treatment for metastatic colorectal adenocarcinoma

5. For participants who have previously received neoadjuvant/adjuvant therapy, the time from the last treatment to recurrence or progression must exceed 12 months.

6. The interval between the end of previous traditional Chinese medicine treatment and the first dose in this study should be = 2 weeks

7. Recovering of previous treatment-related AEs to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade = 1 (except for alopecia)

8. With at least one measurable lesion as assessed by the IRRC per RECIST v1.1, and the measurable lesion should not have been treated locally such as with radiotherapy (a lesion located in an area subjected to previous radiotherapy can also be regarded as a measurable lesion if PD is confirmed)

9. Agree to provide sufficient previously preserved tumor tissue specimens or agree to undergo biopsy to collect tumor tissue for PD-L1 and CD8 expression level determination, TMB testing, as well as gene mutation detection of KRAS, BRAF, NRAS, etc.

10. Have an ECOG PS score of 0 or 1 within 7 days prior to receiving the first dose of the study drugs

11. Hepatitis B surface antigen (HBsAg) (-) and hepatitis B core antibody (HBcAb) (-), with no clinically judged active hepatitis. If HBsAg (+) or HBcAb (+), then hepatitis B virus deoxyribonucleic acid (HBV-DNA) must be < 2.5 × 103copies/mL or 500 IU/mL (if the lower limit of detection of the study site is > 500 IU/mL, below the limit of detection is acceptable for inclusion)

12. Hepatitis C Virus (HCV) antibody (-); if HCV antibody is positive (+), HCV-RNA test must be negative for patients to be enrolled. Subjects with co-infection with hepatitis B and C should be excluded (positive for HBsAg or HBcAb test, and positive for HCV antibody test)

13. Adequate major organ functions indicated by the following criteria (no treatment with blood transfusions, albumin, recombinant human thrombopoietin, or colony-stimulating factor [CSF] within 14 days prior to the first dose of study drugs):

Hematological System:Neutrophils (ANC): = 1.5×10 9 /L; Platelets (PLT) = 100×10 9 /L;Hemoglobin (Hb) = 90g/L Hepatic Function:Total bilirubin (TBIL) = 1.5×upper limit of normal(ULN) Glutamate aminotransferase (ALT) : = 2.5×ULN; = 5.0×ULN for patients with liver metastases Aspartate aminotransferase (AST) = 2.5×ULN; = 5.0×ULN for patients with liver metastases Alkaline Phosphatase(ALP): = 2.5×ULN; = 5.0×ULN for patients with liver and/or bone metastases; Albumin = 30 g/L Renal Function: Creatinine (Cr) = 1.5×ULN; Creatinine clearance = 50mL/min if Cr > 1.5 × ULN; (Calculated by Cockcroft-Gault formula) Coagulation Activated partial thromboplastin time(APTT) = 1.5×ULN Prothrombin time (PT) = 1.5×ULN International Normalized Ratio (INR) = 1.5×ULN Urinalysis/24-hour urine protein Urine protein Qualitative examination on urine protein = 1+; in case of = 2+, a 24-hour urine protein test will be required, and if the 24-hour urine protein is <1g, the enrollment will be allowed

14. Female subjects of childbearing potential (including subjects whose pregnancy cannot be ruled out by treatment with antineoplastic agents even if they have had amenorrhea for 12 months or longer) must have a negative serum pregnancy test within 7 days prior to receiving the first dose of study drugs. For female subjects of childbearing potential, and male subjects with partners of childbearing potential, they must agree to use at least one medically acceptable contraceptive measure (e.g. intra-uterine device, contraceptives or condoms) during the study period, and until at least 3 months after the last administration of serplulimab/placebo and bevacizumab, and at least 6 months after the last chemotherapy session (whichever occurs later).

15. Provide signed ICF and is willing to comply with all study procedures and rules as specified in the protocol

Exclusion Criteria:

• Patients will be excluded from the study if they meet any of the following exclusion criteria:

1. Other active malignancies within 5 years prior to the first dose of study drugs. Localized tumors that have been cured, such as basal cell carcinoma of skin, squamous cell carcinoma of skin, superficial bladder cancer, prostate carcinoma in situ, cervix carcinoma in situ, breast carcinoma in situ, etc., may be enrolled in this study

2. Have confirmed MSI-H CRC

3. Subjects with oligometastatic liver disease and presenting the potential for becoming resectable

4. Presence of central nervous system (CNS) or leptomeningeal metastases

5. Have received radiotherapy within 6 months prior to the initiation of study treatment, except for palliative radiotherapy for bone disorders at least 14 days prior to initiation of study treatment; radiotherapy covering more than 30% of the bone marrow area within 28 days prior to the first dose is not allowed

6. Have received postoperative adjuvant therapy with targeted drugs targeting EGFR or VEGF/vascular endothelial growth factor receptor (VEGFR) (including bevacizumab, cetuximab,panitumumab, aflibercept, regorafenib, or biosimilars of the above drugs)

7. Have received treatment with any T-cell co-stimulation or immune checkpoint therapy, including but not limited to CTLA4 inhibitors, PD-1 inhibitors, PD-L1/2 inhibitors, or other drugs targeting T cells

8. With a known history of severe allergy to any monoclonal antibody or excipients of the study drugs.

9. With uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage after appropriate intervention

10. Cerebrovascular accident, myocardial infarction, unstable angina, poorly controlled arrhythmia (including QTc interval = 450 ms in males and = 470 ms in females) within 6 months (QTc interval is calculated by Fridericia's formula)

11. New York Heart Association (NYHA) Class III or IV cardiac insufficiency, or left ventricular ejection fraction (LVEF) < 50% by echocardiography

12. With history of immunodeficiency, including positive human immunodeficiency virus (HIV) antibody test, or other acquired, congenital immunodeficiency disorders, or history of organ transplantation and allogeneic bone marrow transplantation

13. With active pulmonary tuberculosis

14. With a history of or current interstitial pneumonia, pneumoconiosis, radiation pneumonitis, drug-related pneumonitis, severe pulmonary dysfunction, or any condition that may interfere with the detection and management of suspected drug-related pulmonary toxicity

15. With active or a history of autoimmune diseases (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes). The following subjects are allowed: patients with vitiligo or recovered childhood asthma/allergy without need of any intervention in adulthood; patients with autoimmune-mediated hypothyroidism treated with a stable dose of thyroid replacement hormone; patients with type I diabetes mellitus on a stable dose of insulin

16. Have received treatment with live attenuated vaccine within 28 days prior to the first dose of study drugs

17. Requiring continuous use (> 7 days) of corticosteroids (> 10 mg/day of prednisone or an equivalent dose of a similar drug) or other immunosuppressive agents for systemic treatment within 14 days prior to the first dose of study drugs or during the study period. In the absence of active autoimmune diseases, the use of inhaled or topical steroids is permitted, as is adrenal hormone replacement therapy with a therapeutic dose of = 10 mg/day prednisone

18. Severe infection (CTCAE Grade > 2) occurred within 4 weeks prior to the first dose of study drugs, such as severe pneumonia, bacteremia and infection complications requiring hospitalization; baseline chest imaging indicates the presence of active pulmonary inflammation with associated clinical symptoms or signs; symptoms and signs of infection within 2 weeks prior to the first dose of study drugs, or the need for treatment with oral or intravenous antibiotics, except in cases of prophylactic use of antibiotics

19. Have received major surgery within 28 days prior to the first dose of study drugs. A major surgery in this study is defined as a surgery requiring at least 3 weeks of recovery to be able to receive the treatment in this study

20. Previously received intestinal stent implantation, with the stent remaining in place at the screening period

21. Uncontrolled hypertension despite clinical treatment (defined as systolic blood pressure = 150 mmHg and/or diastolic blood pressure = 100 mmHg)

22. With a history of hypertensive crisis or hypertensive encephalopathy

23. CT/MRI images showing tumor encapsulating or invading a large vascular lumen (e.g., pulmonary artery or superior vena cava)

24. With a history of significant/severe hemorrhage within 1 month prior to randomization, or have received blood transfusion within 2 weeks prior to randomization.

25. Currently receiving or have received aspirin (> 325 mg/day) or dipyridamole, ticlopidine, clopidogrel, and cilostazol within 7 days prior to the first dose of study drugs.

26. Currently receiving or have received full-dose of anticoagulants or thrombolytic agents via oral or injection for therapeutic purposes within 7 days prior to the first dose of the study drugs. Prophylactic anticoagulation therapy for an open intravenous infusion system is permitted, provided that the drug activity keeps the international normalized ratio (INR) < 1.5 × ULN and activated partial thromboplastin time (APTT) is within normal range within 14 days prior to the first dose of study drugs. Prophylactic use of low molecular weight heparin (i.e., enoxaparin at 40 mg/day) is allowed

27. . Requiring long-term treatment with daily administration of nonsteroidal anti-inflammatory drugs (NSAIDs). Occasional use of NSAIDs to relieve medical symptoms such as headache or pyrexia is allowed

28. With evidence showing the presence of meteorism that cannot be attributed to puncture or recent surgery

29. Presence of severe, unhealed or split wounds and active ulcers or untreated fractures

30. Presence of any of the following medical conditions within 6 months prior to the first dose of study drugs:

1. Abdominal or tracheoesophageal fistula, gastrointestinal perforation or intra-abdominal abscess, massive ascites as judged by the investigator (defined as patients requiring drainage or treatment within two weeks)

2. Intestinal obstruction and/or previous clinical signs or symptoms of gastrointestinal obstruction, including incomplete obstruction associated with a preexisting disease or requiring routine parenteral hydration, parenteral nutrition, or tube feeding. Patients with previous symptoms of incomplete obstruction/obstructive syndrome/signs/symptoms of intestinal obstruction that have improved after treatment may be enrolled in the study as assessed by the investigator

3. Severe, uncontrollable intra-abdominal inflammation requiring clinical intervention as judged by the investigator

4. Major vascular disease (e.g., aortic aneurysm requiring surgical repair or associated with recent peripheral artery thrombosis)

31. With a known history of psychotropic substance abuse or drug use

32. Participating in another clinical study, or have completed the treatment of another clinical study within 14 days before the planned study treatment in thisstudy

33. Pregnant or lactating women (including subjects with negative pregnancy test results who are found to be potentially pregnant through medical interview)

34. Any other factors that may lead to study discontinuation as assessed by the investigator, such as other severe diseases (including mental diseases) that require concomitant therapy, significant laboratory abnormalities, family or social factors, and other conditions possibly affecting the safety or study data collection of the subject

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• HLX10
a single fixed dose of 300 mg, intravenous infusion (IV), every 3 weeks (Day 1 of each cycle [D1]), non-reducible.
• HLX04?
7.5mg/kg, IV, every 3 weeks (D1 of each cycle), non-reducible.

Locations

Country	Name	City	State
China	Center for Cancer Prevention and Treatment of Sun Yat-sen University	Guangzhou	Guangdong
China	Zhejiang Cancer Hospital	Hangzhou	Zhejiang
China	Linyi Cancer Hospital	Linyi
China	Fudan University Affiliated Oncology Hospital	Shanghai
Japan	National Cancer Center	Kashiwa

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Henlius Biotech

Countries where clinical trial is conducted

China,  Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	PFS	Progression-free survival (assessed by independent radiological review committee (IRRC) based on RECIST v1.1)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Secondary	OS	Overall survival (OS)	From date of randomization until the date of first date of death from any cause, assessed up to 100 months
Secondary	PFS	Progression-free survival (assessed by the investigators based on RECIST v1.1)	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Secondary	ORR	Objective response rate (assessed by independent radiological review and the investigators based on RECIST v1.1))	through study completion, an average of 1 year
Secondary	Duration of response	Duration of response	from the date when CR or PR (whichever recorded earlier) is firstly achieved until the date when disease progression or death is firstly recorded (whichever occurs earlier),assessed up to 2 years
Secondary	DCR	Disease control rate	the proportion of patients with the best overall response of CR, PR, or stable disease (SD) persisting for 12 weeks
Secondary	PFS2	Progression-free survival in the next line of treatment(assessed by the investigators based on RECIST v1.1)	From date of randomization until the date of the second documented PD as assessed by the investigator or date of death from any cause, whichever came first, assessed up to 100 months