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A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies.

Goss GD, Jonker DJ, Laurie SA, Weberpals JI, Oza AM, Spaans JN, la Porte C, Dimitroulakos J - J Transl Med (2016)

Bottom Line: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib.In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.

View Article: PubMed Central - PubMed

Affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada. ggoss@toh.on.ca.

ABSTRACT

Background: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours.

Methods: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day × 2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.

Results: All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1 ≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.

Conclusions: The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.

No MeSH data available.


Related in: MedlinePlus

Pharmacokinetic analysis of Schedule A patients. a Serum erlotinib levels were determined for these patients at day 6 (erlotinib alone, left panel) and at day 14 (erlotinib + rosuvastatin treatments) every 2 h following drug administration for 24 h. b For the 5 evaluable patients (14–18), area under the curve (AUC) values showed no statistical difference between the two treatments with respect to serum erlotinib exposure. P value determined by T test. c Serum rosuvastatin levels were determined for these patients at day 14 (erlotinib +1 mg/mg/day rosuvastatin treatments) every 2 h following drug administration for 24 h
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Fig3: Pharmacokinetic analysis of Schedule A patients. a Serum erlotinib levels were determined for these patients at day 6 (erlotinib alone, left panel) and at day 14 (erlotinib + rosuvastatin treatments) every 2 h following drug administration for 24 h. b For the 5 evaluable patients (14–18), area under the curve (AUC) values showed no statistical difference between the two treatments with respect to serum erlotinib exposure. P value determined by T test. c Serum rosuvastatin levels were determined for these patients at day 14 (erlotinib +1 mg/mg/day rosuvastatin treatments) every 2 h following drug administration for 24 h

Mentions: Pharmacokinetic analysis of erlotinib serum levels was performed at day 6 (erlotinib alone) and at day 14 (erlotinib and 1 mg/kg/day rosuvastatin treatments) in the 6 patients enrolled in Schedule A (Fig. 1). The erlotinib levels at each time-point for each patient are depicted in Fig. 3a. In the five evaluable patients who received both erlotinib and rosuvastatin, the area under the curve (AUC) for erlotinib did not differ significantly between day 6 and day 14 (Fig. 3b). Furthermore, the maximum concentration observed for each patient (Cmax) and the time to obtain the Cmax (Tmax) were also similar in both treatments (Table 3). The half-life of erlotinib was also consistent and was unaffected by the addition of rosuvastatin. Pharmacokinetic analysis of rosuvastatin serum levels was also performed at day 14 (erlotinib and 1 mg/kg/day rosuvastatin treatments; single dose) in the five evaluable patients who received both erlotinib and rosuvastatin, the area under the curve (AUC) for rosuvastatin is presented (Fig. 3c). As expected the nM serum concentrations are elevated compared to the hypercholesterolemia dose (approximately 1/2 to 1/4 the dose employed in this study) [39]. Patient variability has been consistently demonstrated irrespective of dose [39] and is observed in this study as well, however, due to the treatment schedule employed a comparison in the same patients of rosuvastatin serum levels with or without erlotinib treatment were not evaluated.Fig. 3


A phase I study of high-dose rosuvastatin with standard dose erlotinib in patients with advanced solid malignancies.

Goss GD, Jonker DJ, Laurie SA, Weberpals JI, Oza AM, Spaans JN, la Porte C, Dimitroulakos J - J Transl Med (2016)

Pharmacokinetic analysis of Schedule A patients. a Serum erlotinib levels were determined for these patients at day 6 (erlotinib alone, left panel) and at day 14 (erlotinib + rosuvastatin treatments) every 2 h following drug administration for 24 h. b For the 5 evaluable patients (14–18), area under the curve (AUC) values showed no statistical difference between the two treatments with respect to serum erlotinib exposure. P value determined by T test. c Serum rosuvastatin levels were determined for these patients at day 14 (erlotinib +1 mg/mg/day rosuvastatin treatments) every 2 h following drug administration for 24 h
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4815068&req=5

Fig3: Pharmacokinetic analysis of Schedule A patients. a Serum erlotinib levels were determined for these patients at day 6 (erlotinib alone, left panel) and at day 14 (erlotinib + rosuvastatin treatments) every 2 h following drug administration for 24 h. b For the 5 evaluable patients (14–18), area under the curve (AUC) values showed no statistical difference between the two treatments with respect to serum erlotinib exposure. P value determined by T test. c Serum rosuvastatin levels were determined for these patients at day 14 (erlotinib +1 mg/mg/day rosuvastatin treatments) every 2 h following drug administration for 24 h
Mentions: Pharmacokinetic analysis of erlotinib serum levels was performed at day 6 (erlotinib alone) and at day 14 (erlotinib and 1 mg/kg/day rosuvastatin treatments) in the 6 patients enrolled in Schedule A (Fig. 1). The erlotinib levels at each time-point for each patient are depicted in Fig. 3a. In the five evaluable patients who received both erlotinib and rosuvastatin, the area under the curve (AUC) for erlotinib did not differ significantly between day 6 and day 14 (Fig. 3b). Furthermore, the maximum concentration observed for each patient (Cmax) and the time to obtain the Cmax (Tmax) were also similar in both treatments (Table 3). The half-life of erlotinib was also consistent and was unaffected by the addition of rosuvastatin. Pharmacokinetic analysis of rosuvastatin serum levels was also performed at day 14 (erlotinib and 1 mg/kg/day rosuvastatin treatments; single dose) in the five evaluable patients who received both erlotinib and rosuvastatin, the area under the curve (AUC) for rosuvastatin is presented (Fig. 3c). As expected the nM serum concentrations are elevated compared to the hypercholesterolemia dose (approximately 1/2 to 1/4 the dose employed in this study) [39]. Patient variability has been consistently demonstrated irrespective of dose [39] and is observed in this study as well, however, due to the treatment schedule employed a comparison in the same patients of rosuvastatin serum levels with or without erlotinib treatment were not evaluated.Fig. 3

Bottom Line: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib.In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.

View Article: PubMed Central - PubMed

Affiliation: Ottawa Hospital Research Institute, Centre for Cancer Therapeutics, Ottawa, Canada. ggoss@toh.on.ca.

ABSTRACT

Background: Synergistic cytotoxicity with high-dose statins and erlotinib has been demonstrated in preclinical models across a number of tumour types. In this phase I study, we evaluated the safety and potential anti-tumour activity of escalating doses of rosuvastatin in combination with the standard clinical dose of erlotinib in heavily pretreated patients with advanced solid tumours.

Methods: This was a single-center, phase I open-label study to determine the safety and recommended phase two dose (RPTD) of rosuvastatin in combination with 150 mg/day standard dose of erlotinib. Using a 3 + 3 study design and 28-day cycle, escalating doses of rosuvastatin from 1 to 8 mg/kg/day × 2 weeks (cycle 1) and 3 weeks (subsequent cycles) given concurrently with erlotinib were evaluated. In order to expand the experience and to gain additional safety and pharmacokinetic data, two expansions cohorts using concurrent or alternating weekly dosing regimens at the RPTD were also evaluated.

Results: All 24 patients enrolled were evaluable for toxicity, and 22 for response. The dose-limiting toxicity (DLT) of reversible muscle toxicity was seen at the 2 mg/kg/day dose level. Maximal tolerated dose (MTD) was determined to be 1 mg/kg/day. Thirty-three percent of patients developed at least 1 ≥ grade 2 muscle toxicity (rhabdomyolysis: 1/24, myalgia: 7/24) resulting in one study-related death. Durable stable disease for more than 170 days was seen in 25 % of patients that received concurrent treatment and were evaluable for response (n = 16). Plasma erlotinib levels on study were unaffected by the addition of rosuvastatin.

Conclusions: The observed disease stabilization rate of 25 % with combination therapy in this heavily pretreated population is encouraging, however, the high levels of muscle toxicities observed limited this combination strategy.

No MeSH data available.


Related in: MedlinePlus