| 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) at the time of signing the informed
consent form (ICF)
2. Histopathologically confirmedunresectable metastatic/recurrent colorectal
adenocarcinoma
3. Expected survival = 12 weeks
4. Have not received any previous systemic antineoplastic drug therapy for
metastatic/recurrent colorectal adenocarcinoma
5. Time from last treatment to recurrence or progression = 12 monthsforpatients who
have previously received neoadjuvant/adjuvant therapy
6. Time from the end of previous traditional Chinese medicine to the first dose of
the study drugs = 2 weeks
7. Recovering to = Grade 1 of any AE related with the previous treatment according
to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI-CTCAE) (except for alopecia)
8. At least one measurable lesion assessed by central imaging according to RECIST
v1.1, the measurable lesion should not have received local treatment such as
radiotherapy (lesions located in the previous irradiated area may also be
considered as acceptable measurable lesions if progression is confirmed)
9. Paitent agrees to provide sufficient archival tumor tissue specimen or perform
biopsy for determination of PD-L1 expression and second generation genome
sequencing
10. ECOG PS score of 0-1 within 7 days prior to the first dose of the studydrugs
11. Negative (-) hepatitis B surface antigen (HBsAg), negative (-) hepatitis B core
antibody (HBcAb), and the absence of active hepatitis as clinically determined.
In case of positive (+) HBsAg or HBcAb, hepatitis B virus deoxyribonucleic acid
(HBV-DNA) should be < 1000 copies/mL or 200 IU/mL before enrollment (if the lower
limit of detection of the study site is > 200 IU/mL, patient with HBV-DNA below
the lower limit of detection is allowed to be enrolled)
12. Negative (-) hepatitis C virus (HCV) antibody; in case of positive (+) HCV
antibody, a negative HCV-RNA test is required for enrollment. Patients with
co-infection with hepatitis B and C should be excluded (positive for HBsAg or
HBcAb and positive for HCV antibody)
13. Adequate major organs function as indicated by the following laboratory 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 patients of childbearing potential should have a negative serum pregnancy
test within 7 days prior to the first dose of study drugs. For female patients of
childbearing potential, and male patients with partners of childbearing
potential, at least one medically acceptable contraceptive measure (e.g.,
intrauterine device, contraceptives or condom) is required and will continue for
the duration of the study treatment, and for at least 3 months after the last
dose of HLX10/placebo, HLX04/Avastin ® , and for at least 6 months after the last
dose of chemotherapy, 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.
Patients with localized tumors that have been cured, such as basal cell carcinoma
of skin, squamous cell carcinoma of skin, superficial bladder cancer, carcinoma
in situ of prostate, carcinoma in situ of cervix, carcinoma in situ of breast,
etc., may be enrolled in the study
2. Presence of central nervous system (CNS) or leptomeningeal metastases
3. Radiation therapy within 6 months prior to initiation of study treatment with the
exception of palliative radiation therapy for bone disorders at least 14 days
prior to initiation of study treatment; radiation therapy covering more than 30%
of the bone marrow area within 28 days prior to the first dose is not allowed
4. Prior postoperative adjuvant therapy with targeted agents targeting EGFR or
VEGF/vascular endothelial growth factor receptor (VEGFR) (including bevacizumab,
cetuximab, panitumumab, aflibercept, regorafenib, or biosimilars of these agents,
etc.)
5. Prior treatment with any T-cell costimulation or immune checkpoint inhibitors,
including but not limited to CTLA-4 inhibitors, PD-1 inhibitors, PD-L1/2
inhibitors, or other drugs targeting T cells
6. Known history of severe allergy to any monoclonal antibody or study drug
excipients
7. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring
frequent drainage after appropriate intervention
8. 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)
9. A cardiac insufficiency of Grade III or IV according to the New York Heart
Association (NYHA) criteria, or a left ventricular ejection fraction (LVEF) < 50%
based on echocardiography
10. Known 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
11. History of active tuberculosis
12. Patients with previous and current interstitial pneumonia, pneumoconiosis,
radiation pneumonitis, drug-related pneumonia, severely impaired lung function,
etc. that may interfere with the detection and management of suspected
drug-related pulmonary toxicity
13. Patients with currently 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 patients 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 with a stable
dose of insulin
14. Treatment with live attenuated vaccine within 28 days before the first dose of
study drug
15. Patients who require continuous (for > 7 days) systemic treatment with
corticosteroids (> 10mg/day prednisone or equivalents) or other immunosuppressive
agents within 14 days before the first dose of study drug or during the study
period. Inhaled or topical steroids or adrenal replacement at doses = 10mg/day
prednisone or equivalent dose are permitted in the absence of active autoimmune
disease
16. 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; active pulmonary inflammation accompanied with
relevant clinical symptoms or signs based on chest X-ray at baseline; symptoms
and signs of infection requiring oral or intravenous antibiotic therapy within 2
weeks prior to the first dose of study drugs, except prophylactic use of
antibiotics
17. Major surgery within 28 days prior to the first dose of study drugs. A major
surgery is defined as a surgery that takes at least 3 weeks of postoperative
recovery before receiving treatment in this study
18. Have previously received intestinal stent implantation and the intestinal stent
has not been explanted until screening
19. Inadequately controlled hypertension (defined as systolic blood pressure = 150
mmHg and/or diastolic blood pressure = 100 mmHg) after more than 2 years of
antihypertensive therapy
20. Prior history of hypertensive crisis or hypertensive encephalopathy
21. CT/MRI images showing tumor encircling or invading a large vascular lumen (e.g.,
pulmonary artery or superior vena cava)
22. Bleeding outside the gastrointestinal tract (including hemoptysis, abnormal
vaginal bleeding, etc.) at screening, or Grade 2 bleeding outside the
gastrointestinal tract within 3 months, or Grade 3 or higher bleeding outside the
gastrointestinal tract within 6 months prior to signing the ICF
23. Currently receiving or have received aspirin (> 325mg/day) or dipyridamole,
ticlopidine, clopidogrel, and cilostazol within 7 days before the first dose of
study drugs
24. Currently receving 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 study drugs. Prophylactic anticoagulation therapyis allowed for
open intravenous infusion systems as long as the international normalized ratio
(INR) < 1.5×ULN) and partial thromboplastin time (APTT) is within normal range
thereafter within 14 days prior to the first dose of study drug. Prophylactic use
of low molecular weight heparin (i.e. enoxaparin at 40mg/day) is allowed
25. Long-term treatment with daily administration of nonsteroidal anti-inflammatory
drugs (NSAIDs). Occasional use of NSAIDs to relieve medical symptoms such as
headache or fever is allowed
26. Evidence showing the presence of meteorismthat cannot be explained by puncture or
recent surgery
27. Presence of severe, unhealed or split wounds and active ulcers or untreated
fractures
28. Presence of any of the following medical conditions within 6 months prior to the
first dose of study drugs:
1. Gastrointestinal bleeding (macroscopic melena, bloody stool, etc., except
for hemorrhoidal bleeding)
2. Abdominal or tracheoesophageal fistula, gastrointestinal perforation or
intra-abdominalabscess, massive ascites identified by investigator (defined
as patients requiring drainage or management within 2 weeks), or significant
peritoneal metastases
3. 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 incomplete
obstruction/obstruction syndrome/signs or symptoms of intestinal obstruction
at the time of initial diagnosis may be eligible for study enrollment if
they receive definitive (surgical) treatment to resolve symptoms
4. Intra-abdominal inflammation, including but not limited to peptic ulcer,
diverticulitis or colitis
5. Major vascular disease (e.g., aortic aneurysm requiring surgical repair or
associated with recent peripheral artery thrombosis)
29. Known history of psychotropic substance abuse or drug use
30. 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
31. Pregnant or lactating women
32. Any other factors that may lead to study discontinuation assessed by the
investigator, such as other severe diseases (including mental disease) that
require concomitant therapy, seriousabnormalities in laboratory findings, family
or social factors, and other conditions possibly affecting the safety or study
data collection of the patient
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