A phase II/III clinical study of Serplulimab of patients with metastatic colorectal cancer

JRCT ID: jRCT2061240047

Registered date:20/08/2024

Basic Information

• Recruitment status: Recruiting
• Health condition(s) or Problem(s) studied: Metastatic Colorectal Cancer
• Date of first enrollment: 24/10/2024
• Target sample size: 57
• Countries of recruitment: China,Japan,Indonesia,Japan
• Study type: Interventional

Intervention(s)

Experimental: Serplulima +Bevacizumab+XELOX
Serplulimab (HLX10) in combination with Bevacizumab and chemotherapy (XELOX)
-Serplulimab (HLX10): a single fixed dose of 300 mg, intravenous infusion (IV), every 3 weeks (Day 1 of each cycle [D1]), non-reducible.
-Bevacizumab:7.5mg/kg, IV, every 3 weeks (D1 of each cycle), non-reducible.

Placebo Comparator: placebo + Bevacizumab+XELOX
Placebo in combination with Bevacizumab and chemotherapy (XELOX)
-Bevacizumab:7.5mg/kg, IV, every 3 weeks (D1 of each cycle), non-reducible.

Outcome(s)

• Primary Outcome: Progression-free survival (PFS) assessed by the Independent Radiology Review Committee(IRRC) per RECIST v1.1
• Secondary Outcome: Overall survival(OS),Progression-free survival(PFS) (assessed by the investigator per RECIST v1.1), Progression-free survival in the next line of treatment(PFS2) (assessed by the investigator per RECIST v1.1), Objective response rate(ORR), Duration of response(DOR),Disease control rate(DCR), and quality of life assessment, as well as safety assessment (including immunogenicity) and measurement of serum concentrations of study drugs.

Key inclusion & exclusion criteria

• Age minimum: >= 18age old
• Age maximum: <= 75age old
• Gender: Both

Include criteria

Subjects 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 x 103 copies/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):
Hematologic system:Absolute neutrophil count (ANC) >= 1.5x10 9 /L; Platelet (PLT) >= 100x10 9 /L;Hemoglobin (Hb) >=90g/L Liver function:Total bilirubin (TBIL) =< 1.5x upper limit of normal(ULN); Alanine transaminase(ALT) =< 2.5xULN; =< 5.0xULN for patients with liver metastases; Aspartate aminotransferase (AST) =< 2.5xULN; =< 5.0xULN for patients with liver metastases; Alkaline phosphatase(ALP) =< 2.5xULN; =< 5.0xULN for patients with liver and/or bone metastases; Albumin >= 30 g/L Renal function: Creatinine (Cr) =< 1.5xULN; Creatinine clearance >= 50mL/min if Cr > 1.5xULN; (Calculated by Cockcroft-Gault formula) Coagulation function:Activated partial thromboplastin time(APTT) =< 1.5xULN; Prothrombin time (PT) =< 1.5xULN; International normalized ratio (INR) =< 1.5xULN Urinalysis/24-h urine protein: Urine protein: Urine protein(qualitative) =< 1+; if >= 2+, a 24-hour protein urine test is required, and subjects with 24-hour urine protein of <1g are eligible to be enrolled.
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 either medically acceptable contraceptive measure (e.g. intra-uterine device, contraceptives in combination with ovulation inhibitors or male condoms in combination with other contraceptive methods) during the study period, and until at least 6 months after the last administration of serplulimab/placebo and bevacizumab, and the last chemotherapy session.
15.Provide a signed ICF and be willing to adhere to all study procedures and rules as specified in the protocol

Exclude 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 CTLA-4 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 x 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:
a)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)
b)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
c)Severe, uncontrollable intra-abdominal inflammation requiring clinical intervention as judged by the investigator
d)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 this study
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 Information

• Primary Sponsor: Peng Danyang
• Secondary ID(s): NCT04547166,CTR20200692