A Phase I Clinical Trial of Trametinib in Combination with TAS-102 in Patients with Chemotherapy-Resistant RAS-Mutated (PIK3CA/PTEN-Wild Type) Metastatic Colorectal Cancer

  • Jeremy Chuang
    Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Jun Gong
    Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA
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  • Sierra Min Li
    Department of Biostatistics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Chongkai Wang
    Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA
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  • Marwan Fakih
    Address for correspondence: Marwan Fakih, Department of Medical Oncology and Therapeutics Research, Judy and Bernard Briskin Distinguished Director of Clinical Research, Clinical Sciences, Briskin Center for Clinical Research, GI Medical Oncology, Gastrointestinal Cancer Program, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Road, Duarte, California, 91010.
    Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, Duarte, CA
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      We conducted a phase I study to evaluate the maximum tolerated dose (MTD), safety, and efficacy of trametinib in combination with TAS-102 in patients with chemotherapy-refractory KRAS-mutant, wild-type PIK3CA/PTEN metastatic colorectal cancer (mCRC).


      A 3+3 dose de-escalation single arm phase I clinical trial was performed in patients with chemorefractory mCRC without priorTAS-102 exposure. Patients received fixed dosing of trametinib 2mg oral daily along with de-escalating doses of TAS-102 beginning at 35 mg/m2 twice daily on days 1-5 and days 8-12 every 28 days. Primary endpoint was evaluation of MTD.


      25 eligible patients were enrolled in this study. During the dose de-escalation phase, no dose-limiting toxicities (DLT) were observed at the full doses of trametinib/TAS-102 and the MTD was determined to be TAS-102 35 mg/m2 orally twice daily on days 1 to5 and days 8 to12 every 28 days with continuous trametinib dosing at 2mg orally daily. No patients achieved a partial or complete response. 5 of 21 evaluable patients (23.81%) achieved a stable disease response. Median PFS was two months (95% confidence interval [CI] 1.70-4.82) while median OS was 7 months (95% CI 6.36-11.48). Treatments were well tolerated with most common grade ≥ 3 adverse events being anemia (20%), neutropenia (12%), leukopenia (8%), diarrhea (8%), rash (4%), and fatigue (4%).


      Trametinib in combination with TAS-102 demonstrated a manageable safety profile. However, this combination did not achieve meaningful clinical benefit in patients with RAS-mutated PIK3CA and PTEN wild-type refractory mCRC. Clinical trial information: NCT03317119.



      COH (City of Hope), IRB (institutional review board), CRC (colorectal cancer), mCRC (metastatic colorectal cancer), MTD (maximum tolerable dose), DLT (dose-limiting toxicity), OS (overall survival), PS (performance status), ECOG (Eastern Cooperative Oncology Group), PFS (progression-free survival), PD (progressive disease), SD (stable disease), PR (partial response), RECIST (Response Evaluation Criteria in Solid Tumors), CTCAE (Common Terminology Criteria for Adverse Events), HR (hazard ratio), CI (confidence interval), CPK (creatine phosphokinase), LFT (liver function test), GERD (gastroesophageal reflux disease)
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