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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Thalidomide
* Drug: TAS-102


Participation Criteria
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Eligibility Criteria
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Have histological or cytological documentation of adenocarcinoma of the colon or rectum (mCRC). 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. 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 β- Human chorionic gonadotropin (β- 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: Platelet count ≥75 × 109 /L Hemoglobin level ≥90 g/L 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 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. 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. Peripheral neuropathy > grade 1 (adverse events per CTCAE v5.0). History of uncontrolled or medicated heart disease. Seizure disorder requiring medication. Known history of human immunodeficiency virus (HIV) infection. Patients with an active infection. Other uncontrolled concurrent diseases determined by the researchers as not meeting the study conditions. Patients with ascites and pleural effusion with clinical symptoms requiring treatment. Known allergy to any of the study drug ingredients. Unable to swallow oral medication. Prior exposure to TAS-102 or thalidomide. Patients who have brain metastases.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TAS-102+Thalidomide<br>Thalidomide 100mg PO BID+TAS-102 35mg/m2, po, bid, d1-5, d8-12, q4wks | Drug: Thalidomide<br>* For the experimental group, the intervention was thalidomide（100mg PO Bid)<br>* Other names: Thalidomide Tablets produced by Changzhou Pharmaceutical Factory Co. LTD;Drug: TAS-102<br>* TAS-102<br>|
| Active Comparator: TAS-102<br>TAS-102 35mg/m2, po, bid, d1-5, d8-12, q4wks | Drug: TAS-102<br>* TAS-102<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 |