Abstract
Purpose
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).
Methods
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.
Results
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%).
Conclusions
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.
Keywords
Abbreviations:
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)To read this article in full you will need to make a payment
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Article Info
Publication History
Published online: May 23, 2022
Accepted:
May 19,
2022
Received in revised form:
May 13,
2022
Received:
March 5,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
