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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

Patient responses on study. a Days on study for each evaluable patient segregated into concurrent treatments (Cohorts 1 and 2-dose escalation and Schedule A) and the alternating weekly schedule (Schedule B). b Days on study based on tumour type in the concurrent treatments. c Kaplan-Meir curve evaluating progression free survival in all evaluable patients. d Waterfall plot of the number of days on study of evaluable patients in this study
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Fig2: Patient responses on study. a Days on study for each evaluable patient segregated into concurrent treatments (Cohorts 1 and 2-dose escalation and Schedule A) and the alternating weekly schedule (Schedule B). b Days on study based on tumour type in the concurrent treatments. c Kaplan-Meir curve evaluating progression free survival in all evaluable patients. d Waterfall plot of the number of days on study of evaluable patients in this study

Mentions: Twenty-four eligible patients were enrolled on study with two patients not evaluable for response due to early study withdrawal during the first cycle. In addition to these two patients, another five patients did not complete cycle 1 due to progressive disease. No objective responses were seen employing RECIST criteria [36]. Patients were analyzed based on whether they received concurrent treatments with these two agents (Cohorts 1 and 2 and Schedule A, a total of 16 evaluable patients) or were treated with alternating weekly does of rosuvastatin and erlotinib treatments (Schedule B, 6 evaluable patients). Of particular interest, 4/16 evaluable patients treated concurrently were on study for greater than 170 days, with 3 patients on study for greater than 275 days (Fig. 2a). The tumour types of patients displaying durable stable disease were 2/4 NSCLC patients, 1/2 pancreatic cancer (responsive patient; neuroendocrine tumour) and 1/4-genitourinary (GU) cancer patients (vaginal squamous epithelial carcinoma) (Fig. 2b). This stable disease is highlighted by the Thorax CT scans of one of the NSCLC patients that was on study, the pre-treatment scan at-15 days and a subsequent scan at 218 days on study are shown (Additional file 1: Figure S1). Further, of the patients that came off study with progressive disease (n = 19), a subset of these patients also displayed prolonged progression free survival of greater than 175 days (Fig. 2c) and a waterfall plot of patient days on study also highlight the subset of patients with stable disease (Fig. 2d).Fig. 2


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)

Patient responses on study. a Days on study for each evaluable patient segregated into concurrent treatments (Cohorts 1 and 2-dose escalation and Schedule A) and the alternating weekly schedule (Schedule B). b Days on study based on tumour type in the concurrent treatments. c Kaplan-Meir curve evaluating progression free survival in all evaluable patients. d Waterfall plot of the number of days on study of evaluable patients in this study
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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

Fig2: Patient responses on study. a Days on study for each evaluable patient segregated into concurrent treatments (Cohorts 1 and 2-dose escalation and Schedule A) and the alternating weekly schedule (Schedule B). b Days on study based on tumour type in the concurrent treatments. c Kaplan-Meir curve evaluating progression free survival in all evaluable patients. d Waterfall plot of the number of days on study of evaluable patients in this study
Mentions: Twenty-four eligible patients were enrolled on study with two patients not evaluable for response due to early study withdrawal during the first cycle. In addition to these two patients, another five patients did not complete cycle 1 due to progressive disease. No objective responses were seen employing RECIST criteria [36]. Patients were analyzed based on whether they received concurrent treatments with these two agents (Cohorts 1 and 2 and Schedule A, a total of 16 evaluable patients) or were treated with alternating weekly does of rosuvastatin and erlotinib treatments (Schedule B, 6 evaluable patients). Of particular interest, 4/16 evaluable patients treated concurrently were on study for greater than 170 days, with 3 patients on study for greater than 275 days (Fig. 2a). The tumour types of patients displaying durable stable disease were 2/4 NSCLC patients, 1/2 pancreatic cancer (responsive patient; neuroendocrine tumour) and 1/4-genitourinary (GU) cancer patients (vaginal squamous epithelial carcinoma) (Fig. 2b). This stable disease is highlighted by the Thorax CT scans of one of the NSCLC patients that was on study, the pre-treatment scan at-15 days and a subsequent scan at 218 days on study are shown (Additional file 1: Figure S1). Further, of the patients that came off study with progressive disease (n = 19), a subset of these patients also displayed prolonged progression free survival of greater than 175 days (Fig. 2c) and a waterfall plot of patient days on study also highlight the subset of patients with stable disease (Fig. 2d).Fig. 2

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