Dose Escalation and Expansion Clinical Trial of Irinotecan Liposome Combined With Oxaliplatin and 5-FU/LV Plus Bevacizumab as First-line Treatment of Metastatic Colorectal Cancer

Metastatic Colorectal Cancer Clinical Trial

Official title:

Dose Escalation and Expansion Clinical Trial of Irinotecan Liposome Combined With Oxaliplatin and 5-FU/LV Plus Bevacizumab as First-line Treatment of Metastatic Colorectal Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06225622
• Other study ID #: CSPC-DEY-CRC-K01
• Status: Recruiting
• Phase: Phase 1
• Start date: March 11, 2024
• Est. completion date: May 1, 2026

Study information

• Verified date: March 2024
• Source: Shanghai Zhongshan Hospital
• Contact: Tianshu Liu, Doctor
• Phone: +861368 1973 996
• Email: liu.tianshu[@]zs-hospital.sh.cn
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Dose escalation clinical trial: To explore the dose limiting toxicity (DLT) of irinotecan liposome injection combined with oxaliplatin +5-FU/LV+ bevacizumab in first-line treatment of patients with advanced metastatic colorectal cancer, and to estimate the maximum tolerated dose (MTD) of combined administration. Expansion clinical trial: To evaluate the safety and efficacy of irinotecan liposome injection combined with oxaliplatin +5-FU/LV+ bevacizumab or cetuximab in first-line treatment of patients with advanced metastatic colorectal cancer. Exploratory analysis of ctDNA changes and genetic mutations in patients at baseline.

Description:

This is a dose escalation and expansion study to evaluate the safety and efficacy of irinotecan liposome injection in patients with first-line treatment for metastatic colorectal cancer. In the dose escalation phase, patients will be treated with a combination regimen of irinotecan liposome injection at doses of 60mg/m2, 70mg/m2, and 80mg/m2, and 9 to 18 eligible patients are expected to be enrolled. In the expansion phase, approximately 60 patients will receive combination therapy with irinotecan liposome RP2D dose and exploratory analysis of genetic mutations at baseline and ctDNA changes during treatment.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 78
• Est. completion date: May 1, 2026
• Est. primary completion date: January 1, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• 18-75 years old.
• Histopathologically confirmed patient with an inoperable metastatic colorectal adenocarcinoma.
• The unresectable stage of metastatic disease has not received any systemic antitumor therapy.
• For subjects previously receiving neoadjuvant or adjuvant therapy, the date of first discovery of disease progression must be at least 12 months removed from the date of last administration of neoadjuvant or adjuvant therapy.
• The presence of at least 1 measurable lesion that can be evaluated according to the RECIST v1.1 criteria.
• ECOG 0
• Normal bone marrow and organ function: ? Neutrophils (ANC) =1.5×10^9/L, platelets (PLT) =100×10^9/L, hemoglobin (Hb) =90g/L, white blood cells (WBC) =3.0×10^9/L, albumin (ALB) =35 g/L, and no bleeding tendency; ? AST, ALT and alkaline phosphatase (ALP) were all =2.5× upper limit of normal range (ULN), and =5×ULN when liver metastases occurred; The total bilirubin level doesn't exceed the upper limit of the agency's normal range; Serum creatinine (Cr) =1.5×ULN or creatinine clearance =60 ml/min (calculated according to Cockroft-Gault)
• Understand the situation of this study, patients and/or legal representatives voluntarily agree to participate in this study and sign informed consent form.

Exclusion Criteria:

• Patients with known MSI-H or dMMR who were evaluated by investigators as suitable for treatment with immune checkpoint inhibitors.
• Patients allergic to the investigational drug and its excipients.
• Underweight (body mass index [BMI]<18.5 kg/m^2).
• Known or suspected central nervous system metastasis.
• Received irinotecan before enrollment.
• Had undergone surgery and other oncologic treatments within the first 4 weeks of enrollment.
• Previous treatment-related toxicity didn't return to NCI-CTCAE v5.0 class I or below.
• The use of CYP3A, CYP2C8, and UGT1A1 inhibitors or inducers couldn't be discontinued or were not discontinued within 2 weeks prior to enrollment.
• Serious gastrointestinal disorders.
• Interstitial lung disease.
• Tendency of arterial embolism and massive bleeding within 6 months before enrollment (except surgical bleeding).
• Patients with fluid accumulation that couldn't reach a stable state and small amount of pleural effusion or ascites on imaging without clinical symptoms could be enrolled.
• Intestinal obstruction, signs and symptoms of intestinal obstruction, or the stent has been previously implanted and the stent has not been removed before the screening period.
• Gastrointestinal perforation, intraperitoneal abscess, and fistula.
• Any serious or uncontrolled systemic disease, including uncontrolled high blood pressure, heart disease, active bleeding, active viral infection, etc.
• Have had other malignancies within the past 5 years or currently, except cured cervical carcinoma in situ, uterine carcinoma in situ, and non-melanoma skin cancer.
• Patients of childbearing age who refuse to take contraceptives, women who are pregnant or breastfeeding.
• The researchers didn't consider it appropriate to participate in this study.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Irinotecan Liposome
In dose escalation study, irinotecan liposome injection will be administered by an intravenous infusion at three doses of 60 mg/m2, 70 mg/m2 and 80 mg/m2, d1, 14 days per cycle. In expansion study, irinotecan liposome injection will be administered by an intravenous infusion at the dose of RP2D, d1, 14 days per cycle. Until the disease progresses or surgery is possible.
• Oxaliplatin
85 mg/m2, intravenously infusion, d1, 14 days per cycle, up to 12 cycles.
• 5-FU
2400mg/m2, intravenous infusion, d1-2, 14 days per cycle. Until the disease progresses or surgery is possible.
• LV
400mg/m2, intravenous infusion, d1, 14 days per cycle. Until the disease progresses or surgery is possible.
• Bevacizumab
5mg/kg, intravenous infusion, d1, 14 days per cycle. Until the disease progresses or surgery is possible.It is used to patients in dose escalation phase and with gene mutation in extension phase.
• Cetuximab
500mg/m2, intravenous infusion, d1, 14 days per cycle. Until the disease progresses or surgery is possible.For wild-type patients in extended phase studies.

Locations

Country	Name	City	State
China	Zhongshan Hospital Affiliated to Fudan University	Shanghai	Shanghai

Sponsors (2)

Lead Sponsor	Collaborator
Shanghai Zhongshan Hospital	CSPC Ouyi Pharmaceutical Co., Ltd.

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes of tumor ctDNA	To investigate the preliminary antitumor effect of this study and the relationship between ctDNA changes and disease prognosis.	From initial medication to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 20 months.
Other	Gene polymorphism	To investigate the polymorphism of UGT1A1 and colorectal cancer genes at baseline.	Within a month of enrollment.
Primary	Maximum-tolerated dose	To investigate the safety.	Up to 14 days
Primary	Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	To evaluate the incidence and severity of hematological adverse events in patients.	Start by signing the informed consent form until 4 weeks after the last dose.
Secondary	Objective response rate	To investigate the preliminary antitumor efficacy of study.	From initial medication to the date of first documented progression or end of medication, assessed up to 20 months.
Secondary	Disease control rate	To investigate the preliminary antitumor efficacy of study.	From initial medication to the date of first documented progression or end of medication , assessed up to 20 months.
Secondary	Progression free survival	To investigate the preliminary antitumor efficacy of study.	From initial medication to the date of first documented progression or date of death from any cause, whichever came first , assessed up to 22 months.
Secondary	R0 resection	To assess surgical conversion rates in patients who could be surgically resected.	From the first dose to the surgery, assessed up to 22 months.