A Phase II/III Study of HR070803 in Combination With Oxaliplatin, 5-fluorouracil, Calcium Folinate and Bevacizumab Versus FOLFOX in Combination With Bevacizumab for First-line Treatment of Advanced Colorectal Cancer

Study Overview
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Brief Summary
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This is a double-blind, randomized, multi-center, II/III study in at least 606 patients with advanced colorectal cancer. The study is being conducted to evaluate the safety of HR070803 combined with oxaliplatin, 5-FU/LV and bevacizumab in phase II and to evaluate the efficacy of HR070803 in combination with oxaliplatin, 5-FU/LV, and bevacizumab versus HR070803 simulator in combination with FOLFOX and bevacizumab for first-line treatment of patients with unresectable metastatic colorectal cancer.

Official Title
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A Phase II/III, Double-blind, Randomized, Multi-center Study of HR070803 in Combination With Oxaliplatin, 5-fluorouracil, Calcium Folinate and Bevacizumab Versus FOLFOX in Combination With Bevacizumab for First-line Treatment of Advanced Colorectal Cancer

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: HR070803 plus oxaliplatin, 5-FU/LV, bevacizumab
* Drug: HR070803 simulator plus oxaliplatin, 5-FU/LV, bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female who is 18-75 years of age; Histologically-confirmed metastatic and unresectable (Stage IV as defined by American Joint Committee on Cancer [AJCC eighth edition]) colorectal adenocarcinoma No previous systemic antitumor therapy (including but not limited to systemic chemotherapy, molecularly targeted therapy, immunotherapy, biotherapy, and other investigational therapeutic agents) for colorectal cancer (patients with confirmed relapse ≥6 months after the last administration of neoadjuvant or adjuvant therapy can be enrolled); Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 ; Life expectancy of ≥ 6 months; Vital organ functions meet the criteria. Exclusion Criteria: With confirmed MMR deficient (dMMR) or microsatellite instability high (MSI-H). With central nervous system metastases. Previous oxaliplatin-containing chemotherapy within 12 months prior to enrolment. Previous treatment with irinotecan, immune checkpoint inhibitor, anti-epidermal growth factor receptor or any anti-angiogenic drug. Patients with large amount of pleural effusion, ascites or pericardial effusion that could not reach a stable state within 2 weeks prior to enrolment. Severe gastrointestinal dysfunction (inflammation or diarrhea > grade 1). With diagnosed interstitial lung disease. Severe cardiovascular and cerebrovascular diseases. Peripheral neuropathy > grade 1. Intestinal obstruction within the 6 months prior to enrolment. Gastrointestinal perforation, gastrointestinal fistula, intraperitoneal abscess, and non-gastrointestinal fistula (e.g. tracheoesophageal fistula) within 6 months prior to enrolment. Patients with CTCAE≥ grade 3 gastrointestinal bleeding within 6 months prior to enrolment, or any grade gastrointestinal bleeding within 1 month prior to enrolment. Patients with CTCAE≥ grade 3 extra-gastrointestinal bleeding within 6 months prior to enrolment, or CTCAE≥ grade 2 extra-gastrointestinal bleeding within 3 months prior to enrolment. Uncontrolled hypertension (systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg under regular antihypertensive therapy), and a history of hypertensive crisis or hypertensive encephalopathy. History of hypersensitivity or contraindications to any of irinotecan liposomes/simulator, irinotecan, other liposomal products, 5-FU, calcium folinate, oxaliplatin, bevacizumab.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HR070803<br>HR070803 plus oxaliplatin, 5-FU/LV, bevacizumab | Drug: HR070803 plus oxaliplatin, 5-FU/LV, bevacizumab<br>* HR070803 plus oxaliplatin, 5-FU/LV, bevacizumab Patients will receive the study drug after randomization, and those with effective efficacy evaluation (CR, PR or SD) will receive intravenous chemotherapy for up to 8-12 cycles, and then enter the maintenance treatment stage until PD, death, intolerable toxicity or withdrawal of informed consent (whichever occurs first)<br>|
| Placebo Comparator: HR070803 simulator<br>HR070803 simulator plus oxaliplatin, 5-FU/LV, bevacizumab | Drug: HR070803 simulator plus oxaliplatin, 5-FU/LV, bevacizumab<br>* HR070803 simulator plus oxaliplatin, 5-FU/LV, bevacizumab Patients will receive the study drug after randomization, and those with effective efficacy evaluation (CR, PR or SD) will receive intravenous chemotherapy for up to 8-12 cycles, and then enter the maintenance treatment stage until PD, death, intolerable toxicity or withdrawal of informed consent (whichever occurs first)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Events (AE) According to NCI-CTCAE v5.0（Phase II） | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant after signing the informed consent form and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that is temporally associated with the use of study treatment, is also an AE. | From Baseline to primary completion date, about 48 months | 
| Serious Adverse Events (SAE)（Phase II） | An SAE is defined as any of the following adverse events in a participant or clinical investigation participant after signing the informed consent form and which does not necessarily have to have a causal relationship with this treatment: events that result in death, life-threatening events; events requiring hospitalization or prolonged hospitalization; events leading to permanent or severe disability/loss of function (significant impairment of the ability to carry out normal life functions); congenital abnormalities or birth defects; a medically important event or intervention may be required to prevent any of these outcomes. | From Baseline to primary completion date, about 48 months | 
| Progression-Free Survival (PFS) Assessed by IRC（Phase III） | from randomization to PD or death from any cause | From Baseline to primary completion date, about 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) Assessed by investigator（Phase II） | The proportion of patients who acquired complete response and partial response during treatment. | From Baseline to primary completion date, about 48 months | 
| Disease Control Rate (DCR) by investigator（Phase II） | The proportion of patients who acquired complete response and partial response and stable disease during treatment. | From Baseline to primary completion date, about 48 months | 
| Duration of Overall Response (DoR) by investigator（Phase II） | For subjects who demonstrated CR or PR, response duration is defined as the time from the date of first response (CR or PR) until the date of first documented disease progression or death. | From Baseline to primary completion date, about 48 months | 
| Progression-Free Survival (PFS) Assessed by investigator（Phase II） | from randomization to PD or death from any cause. | From Baseline to primary completion date, about 48 months | 
| Overall Survival (OS)（Phase II） | from randomization to death from any cause. | From Baseline to primary completion date, about 48 months | 
| Characterize the PK（Phase II） | Serum concentrations of SN-38 and CPT-11 will be monitored. PK modeling will be performed and an appropriate model will be selected to describe the data. | From Baseline to primary completion date, about 48 months | 
| Overall Survival (OS)（Phase III） | from randomization to death from any cause. | From Baseline to primary completion date, about 48 months | 
| Progression-Free Survival (PFS) Assessed by investigator（Phase III） | from randomization to PD or death from any cause. | From Baseline to primary completion date, about 48 months | 
| Overall Response Rate (ORR) Assessed by IRC and investigator（Phase III） | The proportion of patients who acquired complete response and partial response during treatment. | From Baseline to primary completion date, about 48 months | 
| Duration of Overall Response (DoR) by IRC and investigator（Phase III） | For subjects who demonstrated CR or PR, response duration is defined as the time from the date of first response (CR or PR) until the date of first documented disease progression or death. | From Baseline to primary completion date, about 48 months | 
| Disease Control Rate（DCR） by IRC and investigator（Phase III） | The proportion of patients who acquired complete response and partial response and stable disease during treatment. | From Baseline to primary completion date, about 48 months | 
| Adverse Events (AE) According to NCI-CTCAE v5.0（Phase III） | An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant after signing the informed consent form and which does not necessarily have to have a causal relationship with this treatment. An AE could be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a study treatment, whether or not considered related to the study treatment. Any worsening (i.e., any clinically significant adverse change infrequency and/or intensity) of a preexisting condition that is temporally associated with the use of study treatment, is also an AE. | From Baseline to primary completion date, about 48 months | 
| Serious Adverse Events (SAE)（Phase III） | An SAE is defined as any of the following adverse events in a participant or clinical investigation participant after signing the informed consent form and which does not necessarily have to have a causal relationship with this treatment: events that result in death; life-threatening events; events requiring hospitalization or prolonged hospitalization; events leading to permanent or severe disability/loss of function (significant impairment of the ability to carry out normal life functions); congenital abnormalities or birth defects; a medically important event or intervention may be required to prevent any of these outcomes. | From Baseline to primary completion date, about 48 months |