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

View Article: PubMed Central - PubMed

ABSTRACT

Background:: 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.

Methods:: 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.

Results:: 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.

Conclusions:: 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.

No MeSH data available.


Mean (s.d.) plasma concentration–time curves of pazopanib (A) and total topotecan (B) during part 1 (P1) following single administration of pazopanib (day 14, n=7), single administration of topotecan (day 1, n=6) and concomitant administration of pazopanib and topotecan (day 15); (C) Plasma concentration–time curves per patient treated with 8 mg topotecan weekly and 800 mg pazopanib daily in P2A and (D) treated with 2.5 mg topotecan daily-times-five and 800 mg pazopanib daily in P2B.
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fig1: Mean (s.d.) plasma concentration–time curves of pazopanib (A) and total topotecan (B) during part 1 (P1) following single administration of pazopanib (day 14, n=7), single administration of topotecan (day 1, n=6) and concomitant administration of pazopanib and topotecan (day 15); (C) Plasma concentration–time curves per patient treated with 8 mg topotecan weekly and 800 mg pazopanib daily in P2A and (D) treated with 2.5 mg topotecan daily-times-five and 800 mg pazopanib daily in P2B.

Mentions: The pharmacokinetic population included data from patients who received all doses in P1 and received all MTD doses in P2 (Table 4). Figure 1 shows the mean plasma concentration–time curves of pazopanib (A) and total topotecan (B) of patients treated in the drug–drug interaction study (P1) and individual total topotecan concentration–time curves in the MTD part of the study (P2) for weekly (C) and daily-times-five (D) schedules. Because of the safety reasons and one of the drugs dose delay/interruption, only 50% of patients from P2 expansion phase had paired available Pharmacokinetics (PK) measurements. No differences in pazopanib plasma concentration can be seen following pazopanib dose alone vs co-administration with topotecan (Figure 1A). However, a marked increase in mean total topotecan exposure was observed on the sampling day when topotecan was co-administered with pazopanib, compared with dosing alone (Figure 1B–D). Pazopanib exposure on both schedules was similar with or without co-administration of topotecan (figures not shown). Detailed pharmacokinetic data are summarised in Table 4 and Table 5. Total topotecan exposure was increased when co-administered with pazopanib. Total topotecan Cmax increased ∼1.9-fold in P1 and both schedules in P2, whereas AUC(0–∞) increased between 1.5- and 1.7-fold depending on study part and schedule. Individual increases in ratios ranged from 0.58 to 3.5 and 0.66 to 2.9 for Cmax and AUC(0–∞), respectively, for the topotecan 4 mg single dose in P1, from 1.0 to 3.0 and 1.5 to 2.1 for Cmax and AUC(0–∞), respectively, for 8.0 mg on weekly schedule and from 1.0 to 3.6 and 1.1 to 1.9 for Cmax and AUC(0–∞), respectively, for the topotecan 2.5 mg daily-times-five schedule. The minor differences between the three doses and schedules were likely due to the small sample sizes. Total topotecan mean t½ values were ∼4–5 h and were similar whether topotecan was dosed alone or with pazopanib. PK analysis of the two patients with severe liver toxicity did not suggest any significant difference in plasma drug exposure to other patients.


Phase I and pharmacological study of pazopanib in combination with oral topotecan in patients with advanced solid tumours
Mean (s.d.) plasma concentration–time curves of pazopanib (A) and total topotecan (B) during part 1 (P1) following single administration of pazopanib (day 14, n=7), single administration of topotecan (day 1, n=6) and concomitant administration of pazopanib and topotecan (day 15); (C) Plasma concentration–time curves per patient treated with 8 mg topotecan weekly and 800 mg pazopanib daily in P2A and (D) treated with 2.5 mg topotecan daily-times-five and 800 mg pazopanib daily in P2B.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4559826&req=5

fig1: Mean (s.d.) plasma concentration–time curves of pazopanib (A) and total topotecan (B) during part 1 (P1) following single administration of pazopanib (day 14, n=7), single administration of topotecan (day 1, n=6) and concomitant administration of pazopanib and topotecan (day 15); (C) Plasma concentration–time curves per patient treated with 8 mg topotecan weekly and 800 mg pazopanib daily in P2A and (D) treated with 2.5 mg topotecan daily-times-five and 800 mg pazopanib daily in P2B.
Mentions: The pharmacokinetic population included data from patients who received all doses in P1 and received all MTD doses in P2 (Table 4). Figure 1 shows the mean plasma concentration–time curves of pazopanib (A) and total topotecan (B) of patients treated in the drug–drug interaction study (P1) and individual total topotecan concentration–time curves in the MTD part of the study (P2) for weekly (C) and daily-times-five (D) schedules. Because of the safety reasons and one of the drugs dose delay/interruption, only 50% of patients from P2 expansion phase had paired available Pharmacokinetics (PK) measurements. No differences in pazopanib plasma concentration can be seen following pazopanib dose alone vs co-administration with topotecan (Figure 1A). However, a marked increase in mean total topotecan exposure was observed on the sampling day when topotecan was co-administered with pazopanib, compared with dosing alone (Figure 1B–D). Pazopanib exposure on both schedules was similar with or without co-administration of topotecan (figures not shown). Detailed pharmacokinetic data are summarised in Table 4 and Table 5. Total topotecan exposure was increased when co-administered with pazopanib. Total topotecan Cmax increased ∼1.9-fold in P1 and both schedules in P2, whereas AUC(0–∞) increased between 1.5- and 1.7-fold depending on study part and schedule. Individual increases in ratios ranged from 0.58 to 3.5 and 0.66 to 2.9 for Cmax and AUC(0–∞), respectively, for the topotecan 4 mg single dose in P1, from 1.0 to 3.0 and 1.5 to 2.1 for Cmax and AUC(0–∞), respectively, for 8.0 mg on weekly schedule and from 1.0 to 3.6 and 1.1 to 1.9 for Cmax and AUC(0–∞), respectively, for the topotecan 2.5 mg daily-times-five schedule. The minor differences between the three doses and schedules were likely due to the small sample sizes. Total topotecan mean t½ values were ∼4–5 h and were similar whether topotecan was dosed alone or with pazopanib. PK analysis of the two patients with severe liver toxicity did not suggest any significant difference in plasma drug exposure to other patients.

View Article: PubMed Central - PubMed

ABSTRACT

Background:: 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.

Methods:: 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.

Results:: 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.

Conclusions:: 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.

No MeSH data available.