Trifluridine/Tipiracil (TAS-102) With or Without Thalidomide for the Treatment of Metastatic Colorectal Cancer

Metastatic Colorectal Cancer Clinical Trial

Official title:

TACTIC: a Phase II Study of TAS-102 Monotherapy and Thalidomide Plus TAS-102 as Third-line Therapy and Beyond in Patients With Advanced Colorectal Carcinoma

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05266820
• Other study ID #: TACTIC
• Status: Recruiting
• Phase: Phase 2
• Start date: October 1, 2021
• Est. completion date: December 1, 2023

Study information

• Verified date: January 2022
• Source: Fujian Cancer Hospital
• Contact: Zengqing Guo
• Phone: +86 13860603879
• Email: gzq_005[@]126.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Thalidomide has both anti-angiogenesis and antiemetic effects, and its combined use with TAS-102 may reduce the gastrointestinal reactions associated with TAS-102, while enhancing antitumor efficacy and reducing the side effects of chemotherapy, and its cost is significantly lower than that of bevacizumab, which has higher pharmacoeconomics and greater clinical research application value.

Description:

In the past decade, the use of targeted drugs has greatly improved the overall survival of patients with mCRC. However, there are currently few effective drugs available clinically. Trifluridine/Tipiracil (TAS-102) is a novel cytotoxic antitumor drug taken orally with minor adverse reactions, consisting of trifluridine and tipyrimidine hydrochloride. Tas-102 has been approved for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy; an anti-VEGF biological therapy; and if RAS wild type, an anti-EGFR therapy. Multiple studies have shown that TAS-102 prolongs median OS and PFS in mCRC patients compared with placebo.

Thalidomide is a sedative that was developed in the late 1950s and eventually marketed and prescribed in several countries to pregnant women to alleviate nausea in the late 1950s and early 1960s. The drug, however, caused severe birth defects in more than 10,000 children worldwide and was forced to withdraw from the international market. Further studies found that the S-optical isomer of thalidomide can inhibit neutrophil chemotaxis, produce anti-inflammatory activity, stimulate immune system activation, regulate immunity, anti-angiogenesis, and inhibit the adhesion of cancer cells to stroma, so as to change the microenvironment of the body, and achieve anti-tumor effect.

Thalidomide has both anti-angiogenesis and antiemetic effects, and its combined use with TAS-102 may reduce the gastrointestinal reactions associated with TAS-102, while enhancing antitumor efficacy and reducing the side effects of chemotherapy, and its cost is significantly lower than that of bevacizumab, which has higher pharmacoeconomics and greater clinical research application value.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 120
• Est. completion date: December 1, 2023
• Est. primary completion date: December 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

1. Have histological or cytological documentation of adenocarcinoma of the colon or rectum (mCRC).

2. For patients with disease progression after conventional treatment, TAS-102 is determined as the third-line therapy or beyond according to the routine treatment practice of the researcher.

3. Aged no less than 20 years.

5.Have a measurable disease, according to RECIST version 1.1 6.Eastern Cooperative Oncology Group performance status 0-2. 7.Life expectancy of at least 12 weeks. 8.For women with reproductive potential, serum tests were performed within 7 days before the start of study treatment ß- Human chorionic gonadotropin (ß- HCG) pregnancy test, the result is negative. Women with reproductive potential must agree to take appropriate contraceptive measures with informed consent until at least 6 months after the last use of the study drug.

9.Sufficient bone marrow, liver and kidney functions and meet the following laboratory requirements:

1. Platelet count =75 × 109 /L

2. Hemoglobin level =90 g/L

3. Absolute neutrophil count =1.5× 109 /L

a) Total bilirubin =1.5 × upper limit of normal (ULN) b) Alanine aminotransferase and aspartate aminotransferase =2.5 × ULN (=5 × ULN for patients with liver metastases) d) Serum creatinine =1.5 × ULN e) Glomerular filtration rate =30 ml/min/1.73 m2, according to the modified diet in renal disease abbreviated formula 10.Able to take oral drugs. 11.Have signed written informed consent.

Exclusion criteria

1. With arterial or venous thrombosis or embolic events such as myocardial infarction, cerebral thrombosis, intracerebral hemorrhage, deep venous thrombosis or pulmonary embolism within 6 months before the start of the study.

2. Evidence or history of any bleeding diathesis, irrespective of severity. Any hemorrhage or bleeding event = grade 3 (adverse events per CTCAE v5.0) within 4 weeks prior to the start of treatment.

3. Peripheral neuropathy > grade 1 (adverse events per CTCAE v5.0).

4. History of uncontrolled or medicated heart disease.

5. Seizure disorder requiring medication.

6. Known history of human immunodeficiency virus (HIV) infection.

7. Patients with an active infection.

8. Other uncontrolled concurrent diseases determined by the researchers as not meeting the study conditions.

9. Patients with ascites and pleural effusion with clinical symptoms requiring treatment.

10. Known allergy to any of the study drug ingredients.

11. Unable to swallow oral medication.

12. Prior exposure to TAS-102 or thalidomide.

13. Patients who have brain metastases.

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• Thalidomide
For the experimental group, the intervention was thalidomide(100mg PO Bid)
• TAS-102
TAS-102

Locations

Country	Name	City	State
China	First Affiliated Hospital of Fujian Medical University	Fuzhou
China	Fujian Medical University Cancer Hospital, Fujian Cancer Hospital	Fuzhou	Fujian
China	Fujian Provincial people's Hospital	Fuzhou
China	Fuzhou First Hospital affiliated to Fujian Medical University	Fuzhou
China	Hospital 900 of the Joint Logistic Support Force of the Chinese People's Liberation Army	Fuzhou
China	The Third People's Hospital affiliated to Fujian University of Chinese Medicine	Fuzhou

Sponsors (1)

Lead Sponsor	Collaborator
Fujian Cancer Hospital

Country where clinical trial is conducted

China, 

References & Publications (16)

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Kotani D, Kuboki Y, Horasawa S, Kaneko A, Nakamura Y, Kawazoe A, Bando H, Taniguchi H, Shitara K, Kojima T, Tsuji A, Yoshino T. Retrospective cohort study of trifluridine/tipiracil (TAS-102) plus bevacizumab versus trifluridine/tipiracil monotherapy for metastatic colorectal cancer. BMC Cancer. 2019 Dec 27;19(1):1253. doi: 10.1186/s12885-019-6475-6. — View Citation

Liu H, Ma Y, Xu HC, Huang LY, Zhai LY, Zhang XR. Updates on the Management of Ocular Vasculopathies with VEGF Inhibitor Conbercept. Curr Eye Res. 2020 Dec;45(12):1467-1476. doi: 10.1080/02713683.2020.1781193. Epub 2020 Jul 7. Review. — View Citation

Longo-Muñoz F, Argiles G, Tabernero J, Cervantes A, Gravalos C, Pericay C, Gil-Calle S, Mizuguchi H, Carrato-Mena A, Limón ML, Garcia-Carbonero R. Efficacy of trifluridine and tipiracil (TAS-102) versus placebo, with supportive care, in a randomized, controlled trial of patients with metastatic colorectal cancer from Spain: results of a subgroup analysis of the phase 3 RECOURSE trial. Clin Transl Oncol. 2017 Feb;19(2):227-235. doi: 10.1007/s12094-016-1528-7. Epub 2016 Jul 21. — View Citation

Ma J, Yang QL, Ling Y. Rechallenge and maintenance therapy using cetuximab and chemotherapy administered to a patient with metastatic colorectal cancer. BMC Cancer. 2017 Feb 14;17(1):132. doi: 10.1186/s12885-017-3133-8. — View Citation

Mayer RJ, Van Cutsem E, Falcone A, Yoshino T, Garcia-Carbonero R, Mizunuma N, Yamazaki K, Shimada Y, Tabernero J, Komatsu Y, Sobrero A, Boucher E, Peeters M, Tran B, Lenz HJ, Zaniboni A, Hochster H, Cleary JM, Prenen H, Benedetti F, Mizuguchi H, Makris L, Ito M, Ohtsu A; RECOURSE Study Group. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015 May 14;372(20):1909-19. doi: 10.1056/NEJMoa1414325. — View Citation

Melchert M, List A. The thalidomide saga. Int J Biochem Cell Biol. 2007;39(7-8):1489-99. Epub 2007 Jan 30. Review. — View Citation

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Van Cutsem E, Cervantes A, Adam R, Sobrero A, Van Krieken JH, Aderka D, Aranda Aguilar E, Bardelli A, Benson A, Bodoky G, Ciardiello F, D'Hoore A, Diaz-Rubio E, Douillard JY, Ducreux M, Falcone A, Grothey A, Gruenberger T, Haustermans K, Heinemann V, Hoff P, Köhne CH, Labianca R, Laurent-Puig P, Ma B, Maughan T, Muro K, Normanno N, Österlund P, Oyen WJ, Papamichael D, Pentheroudakis G, Pfeiffer P, Price TJ, Punt C, Ricke J, Roth A, Salazar R, Scheithauer W, Schmoll HJ, Tabernero J, Taïeb J, Tejpar S, Wasan H, Yoshino T, Zaanan A, Arnold D. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016 Aug;27(8):1386-422. doi: 10.1093/annonc/mdw235. Epub 2016 Jul 5. — View Citation

Wallander M, Rolander B, Åvall-Lundqvist E, Elander NO. Real world aspects of palliative trifluridine plus tiperacil (TAS-102) in refractory metastatic colorectal cancer. J Gastrointest Oncol. 2020 Aug;11(4):616-625. doi: 10.21037/jgo-20-43. — View Citation

Yoshida Y, Yamada T, Matsuoka H, Sonoda H, Fukazawa A, Yoshida H, Ishida H, Hirata K, Hasegawa S, Sakamoto K, Otsuka T, Koda K. A Trial Protocol of Biweekly TAS-102 and Bevacizumab as Third-Line Chemotherapy for Advanced/Recurrent Colorectal Cancer: A Phase II Multicenter Clinical Trial (The TAS-CC4 Study). J Anus Rectum Colon. 2019 Jul 30;3(3):136-141. doi: 10.23922/jarc.2018-043. eCollection 2019. — View Citation

Zhang L, Qu X, Teng Y, Shi J, Yu P, Sun T, Wang J, Zhu Z, Zhang X, Zhao M, Liu J, Jin B, Luo Y, Teng Z, Dong Y, Wen F, An Y, Yuan C, Chen T, Zhou L, Chen Y, Zhang J, Wang Z, Qu J, Jin F, Zhang J, Jin X, Xie X, Wang J, Man L, Fu L, Liu Y. Efficacy of Thalidomide in Preventing Delayed Nausea and Vomiting Induced by Highly Emetogenic Chemotherapy: A Randomized, Multicenter, Double-Blind, Placebo-Controlled Phase III Trial (CLOG1302 study). J Clin Oncol. 2017 Nov 1;35(31):3558-3565. doi: 10.1200/JCO.2017.72.2538. Epub 2017 Aug 30. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progression-free survival (PFS)	PFS was defined as the time from randomization until the date of first occurrence of investigator-assessed radiological disease progression or death due to any cause, whichever came first.	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months
Secondary	Overall survival(OS)	OS was defined as the time from the date of randomization to the date of death due to any cause. For subjects who were alive or lost to follow-up by the data analysis cut-off date, survival was censored at the subject's last known survival time.	From date of randomization until the date of death from any cause, whichever came first, assessed up to 100 months
Secondary	Incidence of Treatment-Emergent Adverse Events	Incidence of Treatment-Emergent Adverse Events were evaluated in accordance with the NCI CTC AE Version 5.0	from first dose to within 30 days after the last dose