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Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.

ABSTRACT: This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours.Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in a 21-day cycle, both in combination with daily pazopanib, were explored.In total, 67 patients were enroled. Pazopanib co-administration caused a substantial increase in exposure to total topotecan (1.7-fold) compared with topotecan alone, which is considered clinically relevant. Topotecan had no effect on pazopanib concentrations. Safety findings were consistent with the known profile of both agents. There were three drug-related deaths, liver failure, tumour haemorrhage and myelosuppression. Two patients experienced dose-limiting toxicities (DLTs; hand-foot syndrome, myelosuppression and diarrhoea) on the weekly topotecan schedule and four patients experienced DLTs (myelosuppression) on the daily-times-five topotecan schedule. When combined with pazopanib, 800?mg daily, the recommended doses for oral topotecan are: 8?mg weekly and 2.5?mg daily-times-five. Seven of eight patients with partial response had platinum-resistant ovarian cancer. In addition, 54% of patients had stable disease with 22% stable for 6 months.Total topotecan exposure is 1.7-fold higher when co-administered with pazopanib. Both schedules of administration were tolerated and would permit further evaluation, especially the weekly schedule.

SUBMITTER: Kerklaan BM

PROVIDER: S-EPMC4559826 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.

Kerklaan B Milojkovic BM Lolkema M P J MP Devriese L A LA Voest E E EE Nol-Boekel A A Mergui-Roelvink M M Langenberg M M Mykulowycz K K Stoebenau J J Lane S S Legenne P P Wissel P P Smith D A DA Giantonio B J BJ Schellens J H M JH Witteveen P O PO

British journal of cancer 20150820 5

<h4>Background</h4>This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics of two dosing schedules of oral topotecan in combination with pazopanib in patients with advanced solid tumours.<h4>Methods</h4>Stage I of this study was to determine whether there was an impact of pazopanib on topotecan exposure. In stage II, the MTD and safety profile of oral topotecan given weekly on days 1, 8 and 15 in a 28-day cycle; or daily-times-five on days 1-5 in ...[more]

PMID: 26291057

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Project description:Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

Dataset Information

Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.

Publications

Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours.

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