Cancer Chemother Pharmacol (2014) 73:1071–1078 DOI 10.1007/s00280-014-2443-7
Original Article
A phase I study of oral ixabepilone in patients with advanced solid tumors John F. Deeken · John L. Marshall · Michael J. Pishvaian · Jimmy Hwang · Christoph M. Ahlers · Pamela L. Clemens · Susan M. Parker · Lisa Iacono · Patricia M. LoRusso
Received: 25 April 2013 / Accepted: 10 March 2014 / Published online: 25 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Background Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors. Patients and methods Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1–5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects. Results The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 J. F. Deeken (*) · J. L. Marshall Inova Comprehensive Cancer and Research Center, 3300 Gallows Road, Falls Church, VA 22042, USA e-mail: [email protected] M. J. Pishvaian · J. Hwang Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA C. M. Ahlers · P. L. Clemens · S. M. Parker · L. Iacono Bristol-Myers Squibb, Princeton, NJ, USA P. M. LoRusso Karmanos Cancer Institute, Detroit, MI, USA
ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine. Conclusions The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted. Keywords Ixabepilone · Oral · Pharmacokinetics · Advanced solid tumors
Introduction Ixabepilone, a semisynthetic analog of epothilone B, is an effective treatment option for patients with advanced breast cancer and has been assessed in various other solid tumor types [1–5]. Intravenous (IV) infusion of this agent has been approved by the Food and Drug Administration (FDA) in combination with capecitabine to treat metastatic or locally advanced breast cancer resistant to anthracycline and taxane therapy, or taxane-resistant disease in patients ineligible for further anthracycline therapy. Ixabepilone IV monotherapy is approved by the FDA for patients with metastatic or locally advanced breast cancer resistant or refractory to anthracyclines, taxanes, and capecitabine. The approved dose of ixabepilone for the treatment of metastatic breast cancer, either alone or in combination with capecitabine, is 40 mg/m2 administered as a 3 h IV infusion once every 3 weeks [5]. An alternative oral formulation of ixabepilone, comprised of enteric-coated beadlets, was developed with the goal of providing a more
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convenient route of administration, while maintaining acceptable efficacy and safety profiles. Additional phase I studies have been conducted in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic (PK) profile of this oral formulation of ixabepilone [6, 7]. A study that prospectively evaluated intra- and inter-patient variability of two separate single 30 mg oral doses of ixabepilone, given to 30 patients with at least 7 days between each dose, reported increased variability in exposure to the novel oral formulation compared with standard IV administration; intra-patient variability was lower than inter-patient variability [6]. In a subsequent phase I study, newly formulated oral ixabepilone was administered to patients at baseline (0 h), 6, and 12 h on day 1 of a 21-day cycle, initially at a dose of 30 mg (three patients), which was then escalated to 40 mg (nine patients), followed by 50 mg (six patients) [7]. Two DLTs were reported: grade 4 febrile neutropenia (40 mg dose) and grade 4 neutropenic sepsis (50 mg dose). Subsequently, the 40 mg dose level was defined as the MTD. Investigators observed high PK variability that could potentially affect both the safety and efficacy of ixabepilone, although this variability was not prospectively assessed. The current phase I study was designed to evaluate the safety of oral ixabepilone administered once daily at a dose of 5–30 mg/day for the first five consecutive days of a 21-day cycle. This study also assessed the PK profile and explored the effects of food and famotidine (a histamine H2 receptor antagonist that inhibits gastric acid secretion) on the PK of a single oral dose of ixabepilone.
Patients and methods Patients Patients 18 years of age or older were required to have a histologically or cytologically confirmed diagnosis of solid tumor malignancy unresponsive to currently available therapies or for which there was no known curative therapy. Other eligibility criteria included measurable or non-measurable disease, as defined by Response Evaluation Criteria in Solid Tumors; an Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. A period of at least 3 weeks had to have elapsed since the last major surgery or radiation therapy, at least 4 weeks since the last dose of chemotherapy, and at least 2 weeks since the last hormonal or biological therapy. Patients with symptomatic central nervous system malignancy or signs and symptoms suggestive of brain metastases were excluded; however, patients with controlled brain
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Cancer Chemother Pharmacol (2014) 73:1071–1078
metastases (i.e., no radiographic progression following radiation and/or surgical treatment and no neurological signs or symptoms) were eligible. Patients were excluded if they had an uncontrolled medical disorder or active infection, current or recent (within 3 months) gastrointestinal disease or any gastrointestinal surgery that would impact the absorption of the drug, or a prior history of grade ≥3 neuropathy. Patients with existing motor or sensory neuropathy greater than grade 1 in severity were excluded. Other exclusion criteria included prior exposure to ixabepilone, use of cytochrome P450 3A4 inhibitors or inducers, and use of steroids except for antiemetic purposes. The study protocol was approved by all recruiting sites’ institutional review boards and independent ethics committees, and all patients had to provide written informed consent in order to participate in the study. The study was conducted in accordance with the 1964 Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was registered on www.clinicaltrials.gov as NCT00422097. Study design This was an open-label, phase I dose-escalation study in which ixabepilone was administered orally (5, 10, 15, 20, 25, or 30 mg/day) on days 1–5 of a 21-day cycle. Planned enrollment was for approximately 40 patients: three to six patients treated at each dose level and 18–22 patients treated at the MTD. Six to eight patients treated at the MTD were to participate in assessments of the effects of food and gastric pH on the PK of oral ixabepilone. The primary objective was to determine the MTD and DLTs of ixabepilone administered orally as described above. Secondary objectives were to assess the overall safety profile and plasma PK of orally administered ixabepilone and also to assess the effect of food and famotidine on the PK of orally administered ixabepilone. Determination of the MTD was based on cycle 1 data only and was defined as the maximum dose which could be given to six patients such that not more than one patient experienced a DLT (or
Original Article
A phase I study of oral ixabepilone in patients with advanced solid tumors John F. Deeken · John L. Marshall · Michael J. Pishvaian · Jimmy Hwang · Christoph M. Ahlers · Pamela L. Clemens · Susan M. Parker · Lisa Iacono · Patricia M. LoRusso
Received: 25 April 2013 / Accepted: 10 March 2014 / Published online: 25 March 2014 © Springer-Verlag Berlin Heidelberg 2014
Abstract Background Intravenous infusion of ixabepilone is Food and Drug Administration-approved for treatment of patients with metastatic breast cancer. The aim of this study was to establish the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), safety, and pharmacokinetics (PK) of a novel oral formulation of ixabepilone in patients with advanced solid tumors. Patients and methods Forty-four patients received one of six daily doses of oral ixabepilone (5, 10, 15, 20, 25, or 30 mg) on days 1–5 of a 21-day cycle. PK parameters were evaluated in cycle 1 for all treated patients and in cycle 1 and cycle 2 for patients participating in assessments of food and gastric pH effects. Results The most common DLTs (reported in at least one patient) were neutropenia, neutropenic fever, diarrhea, ileus, and hypokalemia. The MTD of oral ixabepilone was 25 mg. Plasma concentrations of ixabepilone showed high variability; coefficients of variation for the area under the curve and the peak plasma concentration ranged from 61 to 131 % and from 17 to 172 %, respectively. The mean half-life of ixabepilone calculated after day 5 of cycle 1 J. F. Deeken (*) · J. L. Marshall Inova Comprehensive Cancer and Research Center, 3300 Gallows Road, Falls Church, VA 22042, USA e-mail: [email protected] M. J. Pishvaian · J. Hwang Georgetown Lombardi Comprehensive Cancer Center, Washington, DC, USA C. M. Ahlers · P. L. Clemens · S. M. Parker · L. Iacono Bristol-Myers Squibb, Princeton, NJ, USA P. M. LoRusso Karmanos Cancer Institute, Detroit, MI, USA
ranged from 24 to 47 h. Ixabepilone exposure was higher when administered with a low-fat meal compared with the fasted state, and when administered 2 h after the histamine H2 receptor antagonist famotidine. Conclusions The MTD of oral ixabepilone when administered once daily for five consecutive days every 21 days was 25 mg. Ixabepilone exposure was highly variable; therefore, safety and efficacy of this novel oral formulation might not be reliably predicted. Keywords Ixabepilone · Oral · Pharmacokinetics · Advanced solid tumors
Introduction Ixabepilone, a semisynthetic analog of epothilone B, is an effective treatment option for patients with advanced breast cancer and has been assessed in various other solid tumor types [1–5]. Intravenous (IV) infusion of this agent has been approved by the Food and Drug Administration (FDA) in combination with capecitabine to treat metastatic or locally advanced breast cancer resistant to anthracycline and taxane therapy, or taxane-resistant disease in patients ineligible for further anthracycline therapy. Ixabepilone IV monotherapy is approved by the FDA for patients with metastatic or locally advanced breast cancer resistant or refractory to anthracyclines, taxanes, and capecitabine. The approved dose of ixabepilone for the treatment of metastatic breast cancer, either alone or in combination with capecitabine, is 40 mg/m2 administered as a 3 h IV infusion once every 3 weeks [5]. An alternative oral formulation of ixabepilone, comprised of enteric-coated beadlets, was developed with the goal of providing a more
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convenient route of administration, while maintaining acceptable efficacy and safety profiles. Additional phase I studies have been conducted in patients with advanced solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and pharmacokinetic (PK) profile of this oral formulation of ixabepilone [6, 7]. A study that prospectively evaluated intra- and inter-patient variability of two separate single 30 mg oral doses of ixabepilone, given to 30 patients with at least 7 days between each dose, reported increased variability in exposure to the novel oral formulation compared with standard IV administration; intra-patient variability was lower than inter-patient variability [6]. In a subsequent phase I study, newly formulated oral ixabepilone was administered to patients at baseline (0 h), 6, and 12 h on day 1 of a 21-day cycle, initially at a dose of 30 mg (three patients), which was then escalated to 40 mg (nine patients), followed by 50 mg (six patients) [7]. Two DLTs were reported: grade 4 febrile neutropenia (40 mg dose) and grade 4 neutropenic sepsis (50 mg dose). Subsequently, the 40 mg dose level was defined as the MTD. Investigators observed high PK variability that could potentially affect both the safety and efficacy of ixabepilone, although this variability was not prospectively assessed. The current phase I study was designed to evaluate the safety of oral ixabepilone administered once daily at a dose of 5–30 mg/day for the first five consecutive days of a 21-day cycle. This study also assessed the PK profile and explored the effects of food and famotidine (a histamine H2 receptor antagonist that inhibits gastric acid secretion) on the PK of a single oral dose of ixabepilone.
Patients and methods Patients Patients 18 years of age or older were required to have a histologically or cytologically confirmed diagnosis of solid tumor malignancy unresponsive to currently available therapies or for which there was no known curative therapy. Other eligibility criteria included measurable or non-measurable disease, as defined by Response Evaluation Criteria in Solid Tumors; an Eastern Cooperative Oncology Group performance status of 0 or 1; and adequate bone marrow, hepatic, and renal function. A period of at least 3 weeks had to have elapsed since the last major surgery or radiation therapy, at least 4 weeks since the last dose of chemotherapy, and at least 2 weeks since the last hormonal or biological therapy. Patients with symptomatic central nervous system malignancy or signs and symptoms suggestive of brain metastases were excluded; however, patients with controlled brain
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Cancer Chemother Pharmacol (2014) 73:1071–1078
metastases (i.e., no radiographic progression following radiation and/or surgical treatment and no neurological signs or symptoms) were eligible. Patients were excluded if they had an uncontrolled medical disorder or active infection, current or recent (within 3 months) gastrointestinal disease or any gastrointestinal surgery that would impact the absorption of the drug, or a prior history of grade ≥3 neuropathy. Patients with existing motor or sensory neuropathy greater than grade 1 in severity were excluded. Other exclusion criteria included prior exposure to ixabepilone, use of cytochrome P450 3A4 inhibitors or inducers, and use of steroids except for antiemetic purposes. The study protocol was approved by all recruiting sites’ institutional review boards and independent ethics committees, and all patients had to provide written informed consent in order to participate in the study. The study was conducted in accordance with the 1964 Declaration of Helsinki and the International Conference on Harmonization Guidelines for Good Clinical Practice. The study was registered on www.clinicaltrials.gov as NCT00422097. Study design This was an open-label, phase I dose-escalation study in which ixabepilone was administered orally (5, 10, 15, 20, 25, or 30 mg/day) on days 1–5 of a 21-day cycle. Planned enrollment was for approximately 40 patients: three to six patients treated at each dose level and 18–22 patients treated at the MTD. Six to eight patients treated at the MTD were to participate in assessments of the effects of food and gastric pH on the PK of oral ixabepilone. The primary objective was to determine the MTD and DLTs of ixabepilone administered orally as described above. Secondary objectives were to assess the overall safety profile and plasma PK of orally administered ixabepilone and also to assess the effect of food and famotidine on the PK of orally administered ixabepilone. Determination of the MTD was based on cycle 1 data only and was defined as the maximum dose which could be given to six patients such that not more than one patient experienced a DLT (or
