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A phase I trial of temsirolimus and erlotinib in patients with refractory solid tumors
Haeseong Park1,2, Kerry Williams1,3, Nikolaos A Trikalinos1,2
1Division of Oncology, Washington University School of Medicine, St. Louis, MO, USA.
Purpose:
Resistance to treatment with inhibitors of mammalian target of rapamycin (mTOR) is partially mediated by activation of epidermal growth factor receptor (EGFR). We conducted a phase I study to determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLT) of temsirolimus (mTOR inhibitor) combined with erlotinib (EGFR inhibitor) in patients with refractory solid tumors.
Methods:
Standard "3 + 3" design was used for dose escalation. An expansion cohort at RP2D included only patients with squamous histology or mutations relevant to PI3K or EGFR pathway activation. Patients started daily erlotinib 7 days prior to starting temsirolimus on cycle 1. Intravenous temsirolimus was then administered weekly. Starting dose levels were 15 mg for temsirolimus and 100 mg for erlotinib.
Results:
Forty-four patients received treatment on this study (28 in dose escalation and 16 in the expansion cohort). The RP2D was temsirolimus 25 mg IV weekly and erlotinib 100 mg orally daily. Two patients experienced DLTs (G3 dehydration and G4 renal failure). The most common drug-related adverse events (all grades) were rash, mucositis/stomatitis, diarrhea, nausea and fatigue. No complete or partial responses were observed. The median duration on this study was 69 days (range 3-770) for escalation and 88 days (range 25-243) for expansion cohorts. Among 11 response-evaluable patients in the expansion cohort, 9 (82%) had stable disease and 2 (18%) had progressive disease.
Conclusion:
The combination of temsirolimus and erlotinib at the RP2D was well tolerated, and the regimen resulted in prolonged disease stabilization in selected patients (NCT00770263).
Insights
This phase I study found that combining temsirolimus (an mTOR inhibitor) with erlotinib (an EGFR inhibitor) was well-tolerated in patients with refractory solid tumors. The combination demonstrated prolonged disease stabilization in select patients.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Resistance to mammalian target of rapamycin (mTOR) inhibitors can be mediated by epidermal growth factor receptor (EGFR) activation.
- Investigating combination therapies targeting these pathways is crucial for overcoming treatment resistance in solid tumors.
Purpose of the Study:
- To determine the recommended phase II dose (RP2D) and dose-limiting toxicities (DLTs) of combining temsirolimus (mTOR inhibitor) with erlotinib (EGFR inhibitor).
- To evaluate the safety and tolerability of this combination in patients with refractory solid tumors.
Main Methods:
- A phase I clinical trial using a standard "3+3" dose escalation design.
- Patients received daily erlotinib for 7 days followed by weekly intravenous temsirolimus.
- An expansion cohort included patients with squamous histology or PI3K/EGFR pathway alterations.
Main Results:
- The RP2D was established as temsirolimus 25 mg weekly and erlotinib 100 mg daily.
- The combination was generally well-tolerated, with common adverse events including rash, mucositis, diarrhea, nausea, and fatigue.
- No complete or partial responses were observed; however, 82% of response-evaluable patients in the expansion cohort achieved stable disease.
Conclusions:
- The combination of temsirolimus and erlotinib at the RP2D is well-tolerated.
- This regimen demonstrated potential for prolonged disease stabilization in selected patients with refractory solid tumors.
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