Dataset Information

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study.

ABSTRACT:

Background

Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of VAN + EV in patients with advanced solid cancers and the effect of combination therapy on cancer cell proliferation and intracellular pathways.

Patients and methods

Patients with refractory solid tumors were enrolled in a phase I dose-escalation trial testing VAN (100-300 mg orally daily) + EV (2.5-10 mg orally daily). Objective responses were evaluated using RECIST v1.1. RET mutant cancer cell lines were used in cell-based studies.

Results

Among 80 patients enrolled, 72 (90%) patients were evaluable: 7 achieved partial response (PR) (10%) and 37 had stable disease (SD) (51%; duration range: 1-27 cycles). Clinical benefit (SD or PR ≥ 6 months) was observed in 26 evaluable patients [36%, 95% confidence intervals (CI) (25% to 49%)]. In 80 patients, median overall survival (OS) was 10.5 months [95% CI (8.5-16.1)] and median progression-free survival (PFS) 4.1 months [95% CI (3.4-7.3)]. Six patients (7.5%) experienced DLTs and 20 (25%) required dose modifications. VAN + EV was safe, with fatigue, rash, diarrhea, and mucositis being the most common toxicities. In cell-based studies, combination therapy was superior to monotherapy at inhibiting cancer cell proliferation and intracellular signaling.

Conclusions

The MTDs and RP2Ds of VAN + EV are 300 mg and 10 mg, respectively. VAN + EV combination is safe and active in refractory solid tumors. Further investigation is warranted in RET pathway aberrant tumors.

SUBMITTER: Cascone T

PROVIDER: S-EPMC7973128 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study.

Cascone T T Sacks R L RL Subbiah I M IM Drobnitzky N N Piha-Paul S A SA Hong D S DS Hess K R KR Amini B B Bhatt T T Fu S S Naing A A Janku F F Karp D D Falchook G S GS Conley A P AP Sherman S I SI Meric-Bernstam F F Ryan A J AJ Heymach J V JV Subbiah V V

ESMO open 20210312 2

<h4>Background</h4>Preclinical studies suggest that combining vandetanib (VAN), a multi-tyrosine kinase inhibitor of rearranged during transfection (RET) proto-oncogene, vascular endothelial growth factor receptor (VEGFR), and epidermal growth factor receptor (EGFR), with everolimus (EV), a mammalian target of rapamycin (mTOR) inhibitor, may improve antitumor activity. We determined the safety, maximum tolerated dose (MTD), recommended phase II dose (RP2D), and dose-limiting toxicities (DLTs) of ...[more]

PMID: 33721621

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Project description:PurposeCopanlisib in combination with immune checkpoint inhibitors demonstrated synergy and favorable antitumor immune responses in preclinical models. This study evaluated copanlisib plus nivolumab in adults with advanced solid tumors.Patients and methodsIn this phase Ib, nonrandomized, open-label, dose-escalation study, patients received intravenous nivolumab 240 mg (day 15 of cycle 1 and days 1 and 15 of subsequent cycles) plus intravenous copanlisib (45 or 60 mg on days 1, 8, and 15 of each cycle) in 28-day cycles. The primary objective was to determine the MTD and/or recommended phase II dose of copanlisib plus nivolumab. Secondary objectives were safety, tolerability, and efficacy. Exploratory objectives included evaluation of potentially predictive biomarkers.ResultsOverall, 16 patients were treated [copanlisib: 45 mg (n = 5); 60 mg (n = 11)]. The most common cancer types at baseline were bladder (25.0%) and oropharyngeal (18.8%) cancers. No dose-limiting toxicities were observed; copanlisib 60 mg was deemed the recommended phase II dose in combination with nivolumab 240 mg. Grade 3 and 4 treatment-emergent adverse events were reported in 56.3% and 12.5% of patients, respectively; one grade 5 event was reported (unrelated to treatment). Overall, 18.8% of patients achieved a partial response. Evaluations of potential biomarkers did not correlate with response, but copanlisib-modulated biomarker changes were observed before nivolumab administration and were consistent and dose-dependent.ConclusionsNo new safety concerns were identified with this combination, and preliminary efficacy indicated an antitumor effect. Data supported an immunomodulatory effect of copanlisib, suggesting that this combination may enhance the efficacy of immune checkpoint inhibitors.SignificanceThe combination of copanlisib and nivolumab was well tolerated and showed antitumor effects in patients with advanced solid tumors. The number of circulating myeloid-derived suppressive cells decreased 24 to 48 hours after treatment with copanlisib. Further investigation of copanlisib and nivolumab is warranted as a novel strategy to enhance the efficacy of checkpoint inhibitors.

Dataset Information

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study.

Background

Patients and methods

Results

Conclusions

Publications

Safety and activity of vandetanib in combination with everolimus in patients with advanced solid tumors: a phase I study.

Similar Datasets

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