Clinical trial NCT04683965: Pemetrexed and TAS-102 in Combination With Bevacizumab in Refractory Colorectal Cancer
Official title: A Single Arm, Open Label, Exploratory Study of Pemetrexed and TAS-102 in Combination With Bevacizumab in Patients Who Have Progressed After Standard Second Line Therapy
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Colorectal Neoplasms
Lead sponsor: The First Affiliated Hospital with Nanjing Medical University
Sponsor class: OTHER
Collaborators: name: Jiangsu Hansoh Pharmaceutical Co., Ltd.
First posted: 2020-12-24
Enrollment: 27
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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. TAS-102 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.


Eligibility criteria: 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* Subjects who have withdrawn from standard treatment due to unacceptable toxicity and precluding retreatment with the same agent prior to progression of disease will also be allowed.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 0-2.
* 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 TAS-102, 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.

Primary outcomes:
measure: Objective response rate(ORR)
timeFrame: 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 outcomes:
measure: Progression-free Survival(PFS)
timeFrame: 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
measure: Overall Survival (OS)
timeFrame: From assignment of the first subject until 40 death events observed, up to 2 years.
measure: Disease control rate (DCR)
timeFrame: 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
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 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
Other outcomes:
Locations:
city: Nanjing
country: China
facility: the First Affiliated Hospital of Nanjing Medical University
state: Jiangsu
Study officials:
References:
citation: 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.
citation: 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.
citation: 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.
citation: Yu Z, Wang J, Cai X, Gao Z, Wang S, Gu Y. Analysis of pemetrexed-based chemotherapy in the treatment of advanced colorectal cancer. Ann Transl Med. 2020 Nov;8(21):1368. doi: 10.21037/atm-20-1095.