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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

Phase I trial outline. a Schematic of the patient cohorts including patient numbers and treatment regimens evaluated in this study. b Treatment schedules employed in this Phase I study
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Fig1: Phase I trial outline. a Schematic of the patient cohorts including patient numbers and treatment regimens evaluated in this study. b Treatment schedules employed in this Phase I study

Mentions: Two levels of dose-escalation were attempted. One of the last patients enrolled in the second cohort (2 mg/kg/day rosuvastatin) developed Grade 4 rhabdomyolysis, which led to a study related death and established the 1 mg/kg/day dose of rosuvastatin as the MTD and RPTD when used in combination with 150 mg of erlotinib. As a result of this unexpected death, the study was amended to include a second expansion cohort at the RPTD to evaluate the impact of alternating weekly erlotinib and rosuvastatin treatment on the safety of this combination regimen. As detailed in Fig. 1, four patients were enrolled at the first dose (1 mg/kg/day) as the second study patient withdrew consent prior to receiving rosuvastatin and eight patients were enrolled in the second cohort (2 mg/kg/day). At the 2 mg/kg/day escalation dose, 8 patients were enrolled with the original 3 patients to be expanded by another 6 patients due to the development of skin rash in the 3 patients that is associated with erlotinib clinical activity but stopped at a total of 8 patients due to a study related death. An additional 12 patients were accrued to the expansion cohorts, with 6 patients enrolled to into Schedule A (an expansion of Cohort 1 at 1 mg/kg/day rosuvastatin) and 6 patients into Schedule B, which used an alternating weekly schedule of rosuvastatin (1 mg/kg/day) and erlotinib (Fig. 1b). In total, eighteen patients were treated concurrently with erlotinib and rosuvastatin and six with an alternating weekly schedule of rosuvastatin and erlotinib.Fig. 1


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)

Phase I trial outline. a Schematic of the patient cohorts including patient numbers and treatment regimens evaluated in this study. b Treatment schedules employed in this Phase I study
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig1: Phase I trial outline. a Schematic of the patient cohorts including patient numbers and treatment regimens evaluated in this study. b Treatment schedules employed in this Phase I study
Mentions: Two levels of dose-escalation were attempted. One of the last patients enrolled in the second cohort (2 mg/kg/day rosuvastatin) developed Grade 4 rhabdomyolysis, which led to a study related death and established the 1 mg/kg/day dose of rosuvastatin as the MTD and RPTD when used in combination with 150 mg of erlotinib. As a result of this unexpected death, the study was amended to include a second expansion cohort at the RPTD to evaluate the impact of alternating weekly erlotinib and rosuvastatin treatment on the safety of this combination regimen. As detailed in Fig. 1, four patients were enrolled at the first dose (1 mg/kg/day) as the second study patient withdrew consent prior to receiving rosuvastatin and eight patients were enrolled in the second cohort (2 mg/kg/day). At the 2 mg/kg/day escalation dose, 8 patients were enrolled with the original 3 patients to be expanded by another 6 patients due to the development of skin rash in the 3 patients that is associated with erlotinib clinical activity but stopped at a total of 8 patients due to a study related death. An additional 12 patients were accrued to the expansion cohorts, with 6 patients enrolled to into Schedule A (an expansion of Cohort 1 at 1 mg/kg/day rosuvastatin) and 6 patients into Schedule B, which used an alternating weekly schedule of rosuvastatin (1 mg/kg/day) and erlotinib (Fig. 1b). In total, eighteen patients were treated concurrently with erlotinib and rosuvastatin and six with an alternating weekly schedule of rosuvastatin and erlotinib.Fig. 1

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