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Cancer Chemotherapy and Pharmacology

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01-03-2012 | Original Article

A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors

Authors: Matthew G. Fury, Eric Sherman, Sofia Haque, Susan Korte, Donna Lisa, Ronglai Shen, Nian Wu, David Pfister

Published in: Cancer Chemotherapy and Pharmacology | Issue 3/2012

Abstract

Purpose

Preclinical studies demonstrate synergistic anti-tumor activity with the combination of everolimus and cisplatin. We conducted a phase I study to establish the recommended phase II of oral everolimus to be given with low-dose weekly intravenous cisplatin.

Methods

Part A used a standard 3 + 3 dose escalation scheme. There were 4 planned dose levels of everolimus: 2.5, 5, 7.5, and 10 mg/day. Subjects received oral everolimus during days 1–21 and cisplatin 20 mg/m² intravenously (fixed dose) on days 1, 8, and 15 of a 28-day cycle. Pharmacokinetic (PK) blood samples were collected on day 1 and day 8 of cycle 1 in Part A. After the phase II recommended dose was established (Part A), 6 additional subjects were enrolled in an expansion cohort (Part B). Response was assessed by RECIST q 2 cycles for all subjects.

Results

Thirty patients were enrolled (18 male, 12 female) and 29 were treated. Median age was 61 years (31–79) and the median number of prior cytotoxic chemotherapy regimens was 2 (0–3). Eighty-three percent of subjects had received prior RT. DLTs occurred at dose level 1 (sudden death of unclear cause in a patient with melanoma metastatic to liver) and dose level 2 (bowel obstruction). No DLTs occurred at dose levels 3 and 4. The most common adverse events (≥grade 3) among 28 patients evaluable for toxicity were lymphopenia (36%), hyperglycemia (11%), fatigue (11%), and venous thrombosis (11%). PK analysis of everolimus demonstrated dose-proportional increases in C _max (mean 91.9 ng/ml) and AUC_0-INF (mean 680.5 h*ng/ml) at dose level 4. Three partial responses were seen (metastatic pulmonary carcinoid, n = 2; metastatic sinus carcinoma, n = 1). Prolonged stable disease ≥6 cycles occurred in subjects with pulmonary carcinoid, oropharyngeal squamous cell carcinoma, basal cell carcinoma, papillary thyroid carcinoma, and esthesioneuroblastoma (n = 1 each).

Conclusion

The phase II recommended dose is everolimus 10 mg/day (days 1–21) + cisplatin 20 mg/m² (days 1, 8, and 15) of a 28-day cycle. PK data demonstrate dose-proportional increases in exposure, as previously described for everolimus monotherapy. Anti-tumor activity was observed in several tumor types.

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Title: A phase I study of daily everolimus plus low-dose weekly cisplatin for patients with advanced solid tumors
Authors: Matthew G. Fury
Eric Sherman
Sofia Haque
Susan Korte
Donna Lisa
Ronglai Shen
Nian Wu
David Pfister
Publication date: 01-03-2012
Publisher: Springer-Verlag
Published in: Cancer Chemotherapy and Pharmacology / Issue 3/2012
Print ISSN: 0344-5704
Electronic ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-011-1734-5

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Abstract

Purpose

Methods

Results

Conclusion

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