Safety and Efficacy of Fruquintinib+FOLFIRI in RAS-mutated Metastatic Colorectal Cancer

• ClinicalTrials.gov Identifier: NCT05522738
• Recruitment Status: Recruiting
• First Posted: August 31, 2022
• Last Update Posted: January 8, 2024
• Sponsor: Chinese PLA General Hospital
• Collaborator: Hutchison Medipharma Limited
• Information provided by (Responsible Party): Dai, Guanghai, Chinese PLA General Hospital

Study Description

Brief Summary:

Molecular subtypes make difference on clinicopathologic features and response to chemotherapy and targeted agents as well as prognosis. RAS mutation status, which accounting for approximately 35% to 40% of colorectal cancer patients, is an important factor considered in the standard of care for colorectal cancer. For RAS-mutated patients, no targeted driver gene drugs have been approved, and their treatment is based on the anti-VEGF/VEGFR pathway, and corresponding targeted drugs such as bevacizumab, aflibercept, and ramucirumab have also been successfully marketed for the treatment of CRC.

For RAS mutant metastatic colorectal cancer, the commonly used first-line treatment regimen is bevacizumab combined with chemotherapy, which is shown in previous studiesthat the PFS of 1st-line is about 10 months; the standard regimen of second-line treatment is FOLFIRI ± bevacizumab, which is shown in previous study that the 2nd-line PFS is about 5 months with ORR 4%. There are a lot of unmet medical needs to improve the clinical efficacy in secondline-treatment of RAS-mutant patients.

Condition or disease	Intervention/treatment	Phase
Metastatic Colorectal Cancer	Drug: Combination: Fruquintinib + FOLFIRI	Phase 1; Phase 2

Detailed Description:

This is a prospective, single-armed, single-center phase Ib/II study to investigate the safety and efficacy of Fruquintinib combined with FOLFIRI in RAS-mutant patients who failed first-line standard therapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 46 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Prospective, Single-arm, Single-center Phase Ib/II Trial on the Safety and Efficacy of Fruquintinib in Combination With FOLFIRI in RAS-mutated Metastatic Colorectal Cancer
• Actual Study Start Date: August 10, 2022
• Estimated Primary Completion Date: December 2024
• Estimated Study Completion Date: December 2025

Arms and Interventions

Arm

Intervention/treatment

Experimental: study group; Fruquintinib combined with FOLFIRI

Drug: Combination: Fruquintinib + FOLFIRI; Phase 1b Fruquintinib was administered in a 3 + 3 dose escalation regimen at the following doses: L1:3 mg/d, L2:4 mg/d, L3:5 mg/d. Fruquintinib: QD po q2w FOLFIRI regimen: Irinotecan：180 mg/m2, i.v. , d1, q2w LV：200 mg/m2, i.v., d1, q2w 5-FU：2400 mg/m2, i.v.for over 46 hours, q2w Phase II Fruquintinib: RP2D, QD po q2w FOLFIRI regimen: Irinotecan： 180 mg/m2, i.v. , d1, q2w LV： 200 mg/m2, i.v., d1, q2w 5-FU：2400 mg/m2, i.v.for over 46 hours, q2w; Other Names: Elunate; HMPL-013

Outcome Measures

Primary Outcome Measures :

1. Objective Response Rate [ Time Frame: From treatment initiation to progressive disease or EOT due to any cause, assessed up to 1 year ]
   Tumor assessment will be performed using radiography method every 8 weeks until the occurrence of progressive disease (PD), using RECIST v 1.1
2. RP2D [ Time Frame: from first dose up to progressive disease or EOT due to any cause, assessed up to 1 year ]
   RECIST v1.1

Secondary Outcome Measures :

1. Overall Survival [ Time Frame: from treatment initiation until death due to any cause, assessed up to 3 year ]
   every two months follow up after EOT observation period at 30 days after the last medication
2. Progress-Free Survival [ Time Frame: from treatment initiation until death due to any cause, assessed up to 2 year ]
   every two months follow up after EOT observation period at 30 days after the last medication
3. Duration of Response [ Time Frame: from treatment initiation until death due to any cause, assessed up to 2 year ]
   every two months follow up after EOT observation period at 30 days after the last medication
4. Safety and tolerance evaluated by incidence of AE [ Time Frame: from first dose to 30 days post the last dose ]
   Incidence and severity of AE
5. Safety and tolerance evaluated by incidence of SAE [ Time Frame: from first dose to 30 days post the last dose ]
   Incidence and severity of SAE

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Fully understand the study and voluntarily sign the informed consent form;
2. Age ≥ 18 years;
3. Pathologically confirmed unresectable metastatic colorectal cancer;
4. Known RAS gene mutations;
5. failed standard first-line FOLFOX/XELOX combined with bevacizumab;
6. ECOG performance status 0-1;
7. BMI ≥ 18;
8. Expected survival ≥ 3 months;

9. Vital organ function meets the following requirements (any blood components and cell growth factors are not allowed within 14 days before enrollment):

   • Absolute neutrophil count ≥ 1.5 × 109/L and white blood cells ≥ 4.0 × 109/L;
   • Platelets ≥ 100 x 109/L;
   • Hemoglobin ≥ 90 g/L;
   • Total bilirubin TBIL ≤ 1.5 × ULN;
   • ALT and AST ≤ 5 x ULN;
   • Urea nitrogen/urea nitrogen (BUN) and creatinine (Cr) ≤ 1.5 x ULN (and creatinine clearance (CCr) ≥ 50 mL/min);
   • Left ventricular ejection fraction (LVEF) > = 50%;
   • Fridericia corrected QT interval (QTcF) < 470 milliseconds.
   • INR ≤ 1.5 x ULN, APTT ≤ 1.5 x ULN.
10. Women of childbearing age should take effective contraceptive measures;
11. Good compliance and cooperation with follow-up.

Exclusion Criteria:

1. Unable to comply with the study protocol or study procedures;
2. Known BRAF gene mutations;
3. evidence of central nervous system metastasis, or associated with severe malignant pleural effusion and ascites;
4. Previous treatment with irinotecan;
5. previous treatment with VEGFR inhibitor
6. Concurrent use of any other investigational drug, or enrollment in a clinical trial of other investigational drug therapy within 4 weeks before enrollment;
7. Inactivated vaccines within 4 weeks before enrollment or possibly during the study;
8. patients in the study group underwent major surgery or severe traumatic injury, fracture or ulcer within 4 weeks;
9. Receiving blood transfusion therapy, blood products and hematopoietic factors, such as albumin and granulocyte colony-stimulating factor (G-CSF), within 28 days before enrollment;
10. Alcohol or drug abuse within 4 weeks prior to enrollment;
11. Any factor affecting oral administration;
12. Concurrent any of the following: uncontrolled hypertension, coronary artery disease, arrhythmia, and heart failure;
13. Uncontrollable serious concurrent infections resulting in disability;
14. Proteinuria ≥ 2 + (1.0 g/24 h)
15. Evidence or history of bleeding tendency within 2 months before enrollment, regardless of seriousness;
16. Arterial/venous thromboembolic events, such as cerebrovascular accidents (including transient ischemic attack), within 12 months before the first treatment;
17. Acute myocardial infarction, acute coronary syndrome or CABG within 6 months prior to the first treatment;
18. Fractures or wounds that have not been healed for a long time;
19. Coagulopathy, bleeding tendency, or ongoing anticoagulant therapy;
20. Patients with other malignant tumors within 5 years before enrollment, except for skin basal cell carcinoma or squamous cell carcinoma after radical resection, or cervical carcinoma in situ;
21. Active autoimmune disease or history of autoimmune disease within 4 weeks before enrollment;
22. Previous allogeneic bone marrow transplantation or organ transplantation;
23. Subjects who are allergic to the study drug or any of its excipients;
24. clinically significant electrolyte abnormalities judged by the investigator;
25. Known human immunodeficiency virus (HIV) infection. Known history of clinically significant liver disease, including viral hepatitis [known hepatitis B virus (HBV) carriers must have excluded active HBV infection, ie, positive HBV DNA (> 1 × 104 copies/mL or > 2000 IU/mL); known hepatitis C virus (HCV) infection and positive HCV RNA (> 1 × 103 copies/mL);
26. Unresolved toxicities above CTCAE v5.0 grade 1 due to any prior anticancer therapy, excluding alopecia, lymphopenia, and oxaliplatin-induced neurotoxicity ≤ grade 2;
27. Any other diseases, clinically significant metabolic abnormalities, physical examination abnormalities or laboratory abnormalities, according to the investigator 's judgment, there is reason to suspect that the patient has a disease or condition that is not suitable for the use of the study drug (such as having seizures and requiring treatment), or will affect the interpretation of the study results, or put the patient at high risk;
28. Pregnant or lactating females;
29. Patients who the investigator considers inappropriate for inclusion in this study.

Contacts and Locations

Locations

China

Chinese PLA General Hospital; Recruiting

Beijing, China

Contact: Guanghai Dai +8666947252 daigh301@vip.sina.com

Principal Investigator: Guanghai Dai

Principal Investigator: Quanli Han

Sub-Investigator: Ru Jia

Sub-Investigator: Zhikuan Wang

Sponsors and Collaborators

Chinese PLA General Hospital

Hutchison Medipharma Limited

Investigators

• Principal Investigator: Guanghai Dai, Doctor; Chinese PLA General Hospital
• Principal Investigator: Quanli Han, Doctor; Chinese PLA General Hospital

More Information

• Responsible Party: Dai, Guanghai, Director, Medical Oncology Department, Chinese PLA General Hospital
• ClinicalTrials.gov Identifier: NCT05522738
• Other Study ID Numbers: HMPL-013-N1-CRC104
• First Posted: August 31, 2022
• Last Update Posted: January 8, 2024
• Last Verified: January 2024

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Dai, Guanghai, Chinese PLA General Hospital:

RAS-mutant; second-line

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases