Pemetrexed and S-1 in Combination With Bevacizumab in Refractory Colorectal Cancer

A Single Arm, Open Label, Exploratory Study of Pemetrexed and S-1 in Combination With Bevacizumab in Patients Who Have Progressed After Standard Second Line Therapy

Limited agents are optional after standard first and second line treatment for mCRC. Only Regorafenib and Fruquintinib are approved in China. PFS of these targeted drugs are not very long. Pemetrexed has shown significant efficacy in advanced lung cancer regarding PFS and OS with controllable toxicity. S-1 has been used in colorectal cancer with promising outcomes. Bevacizumab is also an important monoclonal antibody which could make benefits in treated patients. This study is aimed to explore the efficacy, safety in advanced colorectal cancer failed to standard therapy in Chinese population.

Study Overview

• Status: Withdrawn
• Conditions: Colorectal Neoplasms
• Intervention / Treatment: Drug: Pemetrexed; Drug: S-1; Drug: Bevacizumab

• Study Type: Interventional
• Phase: Phase 2

Contacts and Locations

Study Locations

• China
  • Jiangsu
    • Nanjing, Jiangsu, China, 210029
      • The First Affiliated Hospital of Nanjing Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histological or cytological documentation of adenocarcinoma of the colon or rectum. All other histological types are excluded.
• Subjects with metastatic colorectal cancer(CRC) (Stage IV).
• Subjects must have failed at least two lines of prior treatment, which must include a fluoropyrimidine, oxaliplatin and irinotecan.
• Subjects have failed or refused third-line treatment with regorafenib or fruquintinib.
• Subjects treated with oxaliplatin in an adjuvant setting should have progressed during or within 6 months of completion of adjuvant therapy.
• Subjects who have withdrawn from standard treatment due to unacceptable toxicity and precluding retreatment with the same agent prior to progression of disease will also be allowed.
• Prior treatment with bevacizumab and/or cetuximab will be allowed, but the use of bevacizumab should be no more than one single line treatment.
• Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria, version 1.1.is necessary.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• Life expectancy of at least 3 months.
• Adequate bone marrow, liver, cardiac and renal function as assessed by the laboratory required by protocol.
• Assigned informed consent.

Exclusion Criteria:

• Previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer EXCEPT for curatively treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder tumors [Ta (non-invasive tumor), Tis (carcinoma in situ) and T1 (tumor invades lamina propria)].
• Participants of other clinical trial within 4 weeks.
• Diseases which will impact the absorption of S-1, eg. dysphagia, chronic diarrhea, bowl obstruction
• Hemorrhage events of ≥grade 3 within 4 weeks.
• Known central nervous system metastasis.
• Uncontrolled hypertension. (Systolic blood pressure 140 mmHg or diastolic pressure 90 mmHg despite optimal medical management). Unstable angina,congestive heart failure,Myocardial infarction, Cardiac arrhythmias requiring anti-arrhythmic therapy.
• Urine protein ≥++ and 24h urine protein more than 1.0g.
• Chronically green wound or bone fracture.
• Arterial or venous thrombotic or embolic events.
• Tumor invading important blood vessel with high risk of severe hemorrhage.
• Current active bleeding or any surgery taken within 2 months.
• Abnormal coagulation function.
• Thromboemboli events within 6 months.
• Immune diseases or organ transplantation history.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pemetrexed + S-1 + Bevacizumab; Pemetrexed 500 mg/m2 d1+ S-1 (20mg、25mg), capsule, 40~60mg, Bid,p.o, d1~14 + Bevacizumab 7.5 mg/kg d1; Repeated every 3 weeks	Drug: Pemetrexed; Pemetrexed 500 mg/m2 d1; Drug: S-1; S-1 (20mg、25mg), capsule, 40~60mg, Bid,p.o, d1~14; Drug: Bevacizumab; Bevacizumab 7.5 mg/kg d1; Other Names: Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free Survival(PFS)	PFS was defined as the time from assignment to disease progression radiological/clinical or death due to any cause, whichever occurs first. Subjects without progression or death at the time of analysis were censored at their last date of tumor evaluation.	From assignment of the first subject to 3 months later after the last participant is recruited.The last participant will be recruited before November 1,2021

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	OS is defined as the time from date of assignment to death due to any cause. Subjects still alive at the time of analysis were censored at their last date of last contact.	From assignment of the first subject until 40 death events observed, up to 2 years.
Disease control rate (DCR)	DCR is defined as the percentage of subjects whose best response was not Progressive Disease (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) (= total number of Complete Response (CR) + total number of Partial Response (PR) + total number of Stable Disease (SD)	From assignment of the first subject to 3 months later after the last participant is recruited.The last participant will be recruited before November 1,2021
Objective response rate(ORR)	The percentage of subjects with total number of Complete Response (CR) + total number of Partial Response (PR)	From assignment of the first subject to 3 months later after the last participant is recruited.The last participant will be recruited before November 1,2021
Number of participants with treatment-related adverse events as assessed by CTCAE v4.0	adverse events will be assessed according to CTCAE v4.0, including hematological and non-hematological adverse events. Non-hematological adverse events will be collected by patients reported outcomes questionaire. The adverse events of interest include hypertension,hand-foot syndrome,proteinuria,hoarseness,rash,etc.The dose reduction and drug discontinuance due to adverse events will also be recorded.	From assignment of the first subject to 3 months later after the last participant is recruited.The last participant will be recruited before November 1,2021

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital with Nanjing Medical University
• Collaborators: Jiangsu HanSoh Tharmaceutical Group Co., Ltd

Publications and helpful links

General Publications

• Wu XY, Huang XE, You SX, Lu YY, Cao J, Liu J. Phase II study of pemetrexed as second or third line combined chemotherapy in patients with colorectal cancer. Asian Pac J Cancer Prev. 2013;14(3):2019-22. doi: 10.7314/apjcp.2013.14.3.2019.
• Passardi A, Fanini F, Turci L, Foca F, Rosetti P, Ruscelli S, Casadei Gardini A, Valgiusti M, Dazzi C, Marangolo M. Prolonged Pemetrexed Infusion Plus Gemcitabine in Refractory Metastatic Colorectal Cancer: Preclinical Rationale and Phase II Study Results. Oncologist. 2017 Aug;22(8):886-e79. doi: 10.1634/theoncologist.2017-0206. Epub 2017 Jun 7.
• Lim SW, Lee S, Lee J, Park SH, Park JO, Park YS, Lim HY, Kang WK, Kim ST. Pemetrexed Monotherapy as Salvage Treatment in Patients with Metastatic Colorectal Cancer Refractory to Standard Chemotherapy: A Phase II Single-arm Prospective Trial. J Cancer. 2018 Jul 30;9(16):2910-2915. doi: 10.7150/jca.24948. eCollection 2018.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2019
• Primary Completion (Anticipated): November 1, 2021
• Study Completion (Anticipated): May 1, 2022

Study Registration Dates

• First Submitted: February 14, 2019
• First Submitted That Met QC Criteria: February 14, 2019
• First Posted (Actual): February 18, 2019

Study Record Updates

• Last Update Posted (Actual): July 25, 2022
• Last Update Submitted That Met QC Criteria: July 20, 2022
• Last Verified: July 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Folic Acid Antagonists; Bevacizumab; Pemetrexed
• Other Study ID Numbers: KEEP-G 02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes