Purpose: This study was designed to establish the maximum tolerated dose (MTD) and to evaluate tolerability, pharmacokinetics, and antitumor activity of etirinotecan pegol.
Experimental Design: Patients with refractory solid malignancies were enrolled and assigned to escalating-dose cohorts. Patients received 1 infusion of etirinotecan pegol weekly 3 times every 4 weeks (w × 3q4w), or every 14 days (q14d), or every 21 days (q21d), with MTD as the primary end point using a standard 3 + 3 design.
Results: Seventy-six patients were entered onto 3 dosing schedules (58–245 mg/m2). The MTD was 115 mg/m2 for the w × 3q4w schedule and 145 mg/m2 for both the q14d and q21d schedules. Most adverse events related to study drug were gastrointestinal disorders and were more frequent at higher doses of etirinotecan pegol. Late onset diarrhea was observed in some patients, the frequency of which generally correlated with dose density. Cholinergic diarrhea commonly seen with irinotecan treatment did not occur in patients treated with etirinotecan pegol. Etirinotecan pegol administration resulted in sustained and controlled systemic exposure to SN-38, which had a mean half-life of approximately 50 days. Overall, the pharmacokinetics of etirinotecan pegol are predictable and do not require complex dosing adjustments. Confirmed partial responses were observed in 8 patients with breast, colon, lung (small and squamous cell), bladder, cervical, and neuroendocrine cancer.
Conclusion: Etirinotecan pegol showed substantial antitumor activity in patients with various solid tumors and a somewhat different safety profile compared with the irinotecan historical profile. The MTD recommended for phase II clinical trials is 145 mg/m2 q14d or q21d. Clin Cancer Res; 19(1); 268–78. ©2012 AACR.
Etirinotecan pegol is a unique, long acting topoisomerase I inhibitor that provides prolonged systemic exposure to SN-38. In this study, 76 patients with refractory tumors were treated on various dose levels and schedules. Dose limiting toxicities included late, noncholinergic diarrhea and neutropenia, both manageable with dose modifications. In this phase I trial, 25 (32.9%) patients showed some type of antitumor effect; 8 (11%) had a confirmed partial response to treatment including 1 patient with colon cancer who had experienced disease progression on a prior irinotecan based regimen. Two (2.6%) additional patients had an unconfirmed partial response. The benefit of the prolonged SN-38 t1/2 of 50 days following etirinotecan pegol administration appears to be translational to the clinic. The agent is being actively studied in ongoing phase II and III trials.
Etirinotecan pegol is a unique, long acting topoisomerase I inhibitor that provides prolonged systemic exposure to SN-38 the active metabolite of irinotecan, which is primarily responsible for its efficacy (1), at the site of the tumor. Irinotecan, an antineoplastic agent of the topoisomerase I inhibitor class, is widely used to treat patients with colorectal cancer and other solid tumors (1–10). SN-38 binds to and stabilizes the topoisomerase I-DNA complex, leading to single- and double-stranded DNA breaks and inhibiting DNA repair. Irinotecan and SN-38 have terminal elimination half-lives (t1/2) of 9 to 12 hours and 12 to 47 hours, respectively (1, 11). Irinotecan treatment can be associated with severe diarrhea and severe neutropenia, limiting the frequency with which it can be administered to patients. Therefore, irinotecan is typically administered every 14 to 21 days, which results in a better safety profile than the weekly administration of irinotecan.
Etirinotecan pegol is designed to reduce maximal SN-38 systemic concentrations while providing continuous exposure to tumors, even when administered in 14- or 21-day cycles. The pharmacokinetic (PK) profile of etirinotecan pegol leads to both improved efficacy and safety compared with irinotecan in preclinical models of cancer.
In mouse models of human tumors, etirinotecan pegol resulted in marked dose-related and sustained tumor growth inhibition in colorectal, lung, breast, and ovarian cancers (2, 12). Tumor growth inhibition in all of these cancers was significantly greater than that observed at equivalent doses of irinotecan (2). Pharmacokinetic studies in mice, rats, and dogs showed lower maximum concentration (Cmax) and clearance values for SN-38 and correspondingly greater systemic exposure to SN-38, following etirinotecan pegol dosing, compared with irinotecan. These animal studies suggest that etirinotecan pegol may be more efficacious than irinotecan because of greater topoisomerase I inhibition resulting from prolonged tumor cell exposure to SN-38 (12).
The primary objectives of this first-in-human phase 1 clinical trial were to characterize the safety profile and establish a maximum tolerated dose (MTD) of etirinotecan pegol following 3 separate dosing regimens in patients with refractory solid tumors. Secondary objectives included the determination of the plasma PKs and metabolites, as well as an evaluation of clinical antitumor activity of etirinotecan pegol.
Materials and Methods
Eligible patients had histologically confirmed, evaluable, or measurable malignant solid tumors, metastatic or unresectable, for which standard curative or palliative treatments do not exist. All were required to be 18 years or more of age, have an Eastern Cooperative Oncology Group performance status of 0 or 1, with an estimated life expectancy of 12 weeks or more. Other eligibility criteria included adequate organ/bone marrow function, absolute neutrophil count 1,500/mm3 or more without colony-stimulating support for 3 weeks, white blood cell count 3,000/mm3 or more, platelet count 100,000/mm3 or more, hemoglobin 9 g/dL or more without transfusion support, total bilirubin 2 mg/dL or less, aspartate transaminase, and alanine transaminase 3 times or less upper limit of normal (ULN; ≤5 × ULN if liver metastasis is confirmed), creatinine ≤1.5 × ULN or creatinine clearance 60 mL/min or more.
Patients were excluded from the trial if they had received chemotherapy, including any investigational agents or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before the commencement of dosing. In addition, they must have recovered to at least a grade 1 toxicity, as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0, (CTCv3.0); alopecia of any grade was allowed. Additional exclusion criteria included major surgery within 4 weeks; pregnant or nursing; unstable symptoms from brain metastases; serologically positive for hepatitis B or C, or history of human immunodeficiency virus; cerebrovascular accident or transient ischemia; and history of hypersensitivity to irinotecan, other camptothecin derivatives, or pegylated drugs. The presence of the UGT1A1*28 allele was assessed for heterozygosity or homozygosity, but it was not exclusionary. The study received approval by the Western Institutional Review Board and each institutional ethics board. The study was conducted in accordance with the provisions of the Declaration of Helsinki (13).
Etirinotecan pegol was manufactured by Nektar Therapeutics, and supplied in amber glass vials containing lyophilized etirinotecan pegol powder equivalent to 100 mg irinotecan. Each patient's dose was reconstituted with 5% Dextrose Injection, USP (D5W), total volume 500 mL, to final concentrations of 0.12 to 2.8 mg irinotecan equivalents/mL, and administered via intravenous (i.v.) infusion over 90 minutes. The reconstituted drug required protection from direct ambient lighting at room temperature (15°C–30°C) for up to 2 hours before the start of infusion and drug could also be stored protected from direct lighting at 2°C to 8°C for up to 8 hours before the start of infusion. A central venous catheter was not required for drug administration.
The protocol recommended that patients receive premedication with antiemetic agents including dexamethasone given in conjunction with a 5-HT3 at least 30 minutes before administration of etirinotecan pegol, and written instructions for aggressive antidiarrheal treatment.
This was a multicenter, first-in-human, open-label, phase 1, dose-escalation study of etirinotecan pegol in patients with advanced refractory tumors. All patients received the study drug by i.v. infusion over 90 minutes. Three etirinotecan pegol treatment schedules were evaluated: (i) in treatment group 1, 3 doses of etirinotecan pegol 58 mg/m2 were administered on days 1, 8, and 15 of a 28-day [weekly 3 times every 4 weeks (w × 3q4w)] period [dose escalations in increments of 58 mg/m2 were allowed if there were no dose-limiting toxicities (DLT)]; (ii) in treatment group 2, 1 dose of etirinotecan pegol 145 mg/m2 administered on day 1 of a 21-day (q21d) period (dose escalations in increments of 25 mg/m2 were allowed if there were no DLTs); and (iii) in treatment group 3, 1 dose of etirinotecan pegol 145 mg/m2 administered on day 1 of a 14-day (q14d) period (dose escalations in increments of 25 mg/m2 were allowed if there were no DLTs).
Etirinotecan pegol doses were escalated according to the standard 3 + 3 rule. Intrapatient dose escalations were not allowed. Adverse events were defined and graded according to CTCv3.0. A DLT was defined as the following adverse events related to etirinotecan pegol during cycle 1: grade 4 neutropenia lasting more than 3 days in the absence of growth factor support; grade 4 neutropenia associated with fever more than 38.5°C; any other grade 4 hematologic toxicity; grade 3 thrombocytopenia with hemorrhage; grade 3 or grade 4 nausea, vomiting, or diarrhea despite prophylaxis or treatment with an optimal antiemetic or antidiarrheal regimen; any other grade 3 or higher nonhematologic toxicity that occurred during the study, unless it was clearly unrelated to etirinotecan pegol (e.g., because of disease progression); or a toxicity within the first 21 days of cycle 1 in the treatment group 1 (w × 3q4w) and treatment group 2 (q21d) dosing schedules or within the first 14 days of cycle 1 in the treatment group 3 (q14d) dosing schedule that made the administration of the study drug impossible. The highest dose of etirinotecan pegol in which less than 33% of patients experienced a DLT was considered the MTD (14). Once the MTD was determined, additional patients were accrued at that dose to further characterize its safety and tolerability in the dosing schedule.
The initial w × 3q4w schedule was chosen based on prior clinical experience with irinotecan. Subsequent expansions of the schedule to q14d and q21d were driven by clinical observations at each dose/schedule combination, and by initial PK data suggesting that disposition and elimination in humans were notably slower than observed in animals.
Patient eligibility screening was conducted within 14 days of enrollment. Safety assessments included physical examination, DLTs, and the clinical laboratory parameters (hematology, serum chemistry, and urinalysis) for adverse events, vital sign measurements, and a 12-lead electrocardiogram. Patients also underwent radiologic examinations [computed tomography (CT) or magnetic resonance imaging] at screening, at the completion of each alternate treatment cycle, and at the end of study treatment. After completion of every other treatment cycle, tumor assessment was conducted by CT scan and interpreted according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 (15). All partial or complete tumor responses to treatment required confirmation by repeat assessment of tumor measurements no less than 4 weeks apart. Patients with a partial or complete tumor response or with stable disease were continued on regimen if adverse events were tolerable.
Etirinotecan pegol and its metabolites irinotecan, SN-38, SN-38-glucuronide (SN-38-G), aminopentane carboxylic acid, 7-ethyl-10-(4-N-(5-aminopentanoic acid)-1-piperidine)carbonyloxycamptothecin (APC), and primary amine metabolite of irinotecan, 7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin (NPC), were assayed using validated liquid chromatography–mass spectrometry methods. Beginning preinfusion, plasma samples were collected at scheduled times during cycles 1 and 3, and were continued daily for the first week and then weekly before each subsequent dose and up to 4 weeks after final dosing. Each patient's observed concentration-time data for etirinotecan pegol and its metabolites were fit with PK equations using nonlinear mixed effects modeling (Monolix 2.3, INRIA Saclay) to predict a concentration-time profile for the duration of dosing. The resulting model-predicted concentration-time profiles were subsequently analyzed with noncompartmental methods to estimate customary PK parameters, such as Cmax, time to maximum plasma concentration (Tmax), area under the plasma concentration curve (AUC), total plasma clearance (CL), volume of distribution (V), and t1/2. To allow comparisons between etirinotecan pegol and irinotecan, plasma irinotecan and SN-38 concentration-time profiles after irinotecan administration were simulated using a population PK model for irinotecan (16).
The safety population included all enrolled patients who received at least 1 dose (or partial dose) of etirinotecan pegol. Safety, PK, and tumor evaluation data were summarized using descriptive statistics.
The demographics of patients in this study were similar across the 3 treatment schedules (Table 1). A total of 76 patients with a wide variety of solid tumors were enrolled in this trial. The most commonly represented anatomical locations for the primary tumor were lung (n = 18), colorectal (n = 17), pancreas (n = 5), ovary (n = 5), cervix (n = 5), esophagus (n = 5), and breast (n = 4).
Treatment group 1 (w × 3q4w) enrolled 32 patients, treatment group 2 (q21d) enrolled 25 patients, and treatment group 3 (q14d) enrolled 19 patients. A total of 73 patients (96.1%) had tumors measurable to assess for response by RECIST 1.0. All patients who received at least 1 dose (or partial dose) of etirinotecan pegol were included in the response and safety analysis.
Aside from the time since prior systemic chemotherapy, other trends in the patients' medical histories were similar across the 3 treatment arms.
In treatment group 1 (w × 3q4w), dose escalation continued until the maximum administered dose of 230 mg/m2 was reached. Patients in the first 3 ascending dosing cohorts (58, 115, and 173 mg/m2, respectively) did not experience DLTs. The DLTs were first observed in this schedule at a dose of 230 mg/m2, when 3 patients had grade 3 diarrhea. Per the protocol, dose reduction evaluations with an expanded number of patients being treated continued until a dose free from DLTs was observed. Overall, the dose of 115 mg/m2 was found to be well tolerated with less than 33% of patients experiencing a DLT and was subsequently declared the MTD for treatment group 1.
In treatment group 2 (q21d), the dose was escalated to 245 mg/m2, and in treatment group 3 (q14d), the dose was escalated to 220 mg/m2. In both of these groups, a similar dose deescalation with expanded dose cohorts occurred until the dose level of 170 mg/m2 was reached. Only 2 of 12 patients experienced a DLT at the 170 mg/m2 dose in both schedules combined. However, because of the long terminal half-life of SN-38 and the observation that 4 of 12 patients experienced grade 3 diarrhea after the protocol defined DLT window limited to the first cycle, the investigators and sponsor agreed to reduce the MTD to the next lower dose level of 145 mg/m2 in both the 14- and 21-day schedules. Additional patients were not added as 0 of the 3 treated at the 145 mg/m2 dose level in treatment groups 2 and 3 experienced a DLT.
All patients experienced 1 or more treatment-emergent adverse events during the study. The most clinically significant adverse events related to study drug across all cycles of treatment were gastrointestinal disorders, including diarrhea, nausea, and vomiting (Table 2). In treatment group 1, at doses 115 mg/m2 or more, 7 of 9 (78%) patients' reported diarrhea (1 with grade 3) and nausea with only 3 of 9 (33%) reporting vomiting. However, as the dose escalated to 145 mg/m2 or more, all patients treated reported diarrhea from grade 1 to 3 along with a higher incidence of nausea and vomiting. In treatment group 2, 7 patients (78%) experienced diarrhea and 6 patients (67%) experienced nausea at doses of 170 mg/m2 or less, with 2 patients (22%) having grade 3 diarrhea. In treatment group 3, 6 patients (67%) experienced fatigue, diarrhea, and nausea at doses of 170 mg/m2 or less, with 1 patient (11%) having grade 3 fatigue and 4 patients (44%) having grade 3 diarrhea. Prevention and management of diarrhea included prompt initiation of loperamide 4 mg orally, at the first change in bowel habits, then 2 mg every 2 hours during the day and 4 mg every 4 hours at night until the patient was free of diarrhea for at least 12 hours (17). Other interventions included Lomotil, activated charcoal (18), octreotide (19), tincture of opium, and neomycin (20, 21). Management of persistent diarrhea in some patients treated at doses above the MTD included hospitalization, bowel rest, aggressive IV hydration, total parenteral nutrition support, and continuous infusion of high doses of octreotide (22). The occurrence of neutropenia was reported in treatment group 1 (22% of the patients treated with a dose ≥145 mg/m2) and in group 2 (16% of the patients treated with a dose ≥195 mg/m2), but it was not reported in group 3. Unlike with irinotecan, the presence of a UGT1A1 variant allele, either homozygous or heterozygous, did not correlate with the occurrence of neutropenia or diarrhea. No other adverse event was correlated with the presence of this allele. No patients in the cohorts establishing MTD were homozygous for UGT1A1*28. Other observed treatment-emergent adverse events were not unexpected and were of a random nature throughout the patient population. No changes in the electrocardiogram, including prolongation of the corrected QT intervals, were observed. Over the course of the study, 11 deaths were reported. Two of the deaths were considered to be related to the study drug; the remaining 9 were not, with 8 attributed to disease progression, and 1 attributed to cardiopulmonary arrest (probable result of malignancy related pulmonary embolus or aspiration). The 2 deaths related to the study drug were attributed to neutropenic sepsis (n = 1; 245 mg/m2 q21d) and diarrhea (n = 1; 220 mg/m2 q14d). Nine patients experienced unexpected adverse events, including involuntary muscle contractions and twitching, but all of these were painless and resolved within 24 hours. The underlying mechanism for these adverse events is unclear, and these patients had no significant electrolyte abnormalities. Drug-related blurred vision, grade 1, that was transient and that resolved spontaneously occurred in 10 patients (13%).
Plasma PK data were obtained for every (n = 76) patient in the trial. Observed and model-predicted concentration-time profiles for representative patients receiving etirinotecan pegol at a dosing schedule of w × 3q4w, q21d, or q14d are shown in Fig. 1. In all patients, etirinotecan pegol was slowly metabolized to irinotecan and its known metabolites SN-38, SN-38-G, APC, and NPC, with the magnitude of concentration in the following order: etirinotecan pegol >>> irinotecan ≥ SN-38-G > APC > SN-38. Plasma NPC concentrations were near the limit of quantitation and patient variable, precluding meaningful PK analysis of this metabolite. Steep declines in concentrations during the initial disposition phase were observed for etirinotecan pegol and irinotecan, whereas SN-38, SN-38-G, and APC showed more shallow declines from maximal concentrations (see Fig. 1).
Importantly, trough concentrations of irinotecan, SN-38, SN-38-G, and APC were detectable after etirinotecan pegol dosing with all 3 schedules, providing evidence of sustained exposure between dosing intervals even when administered q21d. The exposure pattern for etirinotecan pegol is different from those for irinotecan and SN-38 after irinotecan administration where concentrations fall below quantitation limits before the next dose is administered.
In general, the plasma concentrations of all analytes increased in proportion to the etirinotecan pegol dose, independent of the dosing schedule, with Cmax after the first dose increasing linearly with the size of the first dose and cumulative AUC increasing linearly with the total dose administered for etirinotecan pegol, irinotecan, and SN-38 (Fig. 2A). Similar plots were obtained for the remaining metabolites.
Comparisons of model-predicted concentration-time profiles for irinotecan and SN-38 after the administration of 350 mg/m2 irinotecan q21d (approved dose and schedule) or 145 mg/m2 etirinotecan pegol q21d at the recommended phase 2 dose (RP2D), show that irinotecan Cmax after administration of etirinotecan pegol is approximately 35-fold lower compared with irinotecan administration, whereas total irinotecan AUC is reduced 4-fold (Fig. 2B).
Mean PK parameter values are presented in Table 3. Because patients received different doses using different schedules and for different durations, and because all analytes exhibited dose-linear PK, mean Cmax and AUC values are presented after normalization for dose.
Etirinotecan pegol and metabolites followed biphasic disposition kinetics with terminal disposition half-lives of 21, 27, 50, 61, and 53 days for etirinotecan pegol, irinotecan, SN-38, SN-38-G, and APC, respectively.
As expected, etirinotecan pegol Cmax values were observed shortly after the end of infusion. Etirinotecan pegol CL, V, and t1/2 values were independent of dose and schedule, which is consistent with the observed dose linearity of Cmax and AUC.
Among etirinotecan pegol metabolites, Cmax values decreased in the following order: irinotecan ≥ SN-38-G > APC > SN-38. Tmax increased in relation to the proposed metabolic progression (irinotecan < SN-38 < SN-38-G < APC), providing further evidence that etirinotecan pegol results in prolonged exposure. As observed with etirinotecan pegol, irinotecan, SN-38, SN-38-G, and APC, CL/F, V/F and t1/2 values were independent of dose and schedule.
The reported interpatient variability for SN-38 after irinotecan administration ranges between 40% and 58% (16, 23), which is similar to the interpatient variability observed for SN-38 after administration of etirinotecan pegol.
Evidence of response
Seventy-three of the 76 patients (96.1%) with a variety of solid tumors had measurable disease at baseline and were, therefore, assessable for response by RECIST 1.0. Twenty-five (32.9%) patients showed some type of antitumor response; 8 (11%) had a partial response to treatment confirmed by RECIST 1.0, including 2 patients in treatment group 1 (6.5%; 2/31), 1 patient in treatment group 2 (4.3%; 1/23), and 5 patients in treatment group 3 (26.3%; 5/19). Two (2.6%) additional patients had an unconfirmed partial response. The median duration of response was 86 days (range, 60–273 days; Table 4). The longest observed confirmed partial response of 9 months was seen in a 47-year-old male with a neuroendocrine tumor of the sinus. The anatomical locations of primary tumors for patients with confirmed partial responses were lung (n = 2), colorectal (n = 1), pancreas (n = 1), breast (n = 1), cervix (n = 1), bladder (n = 1), and head and neck (n = 1). The assessments, which did not meet formal RECIST guidelines, revealed that in the 17 patients with signs of antitumor response, 2 (colorectal and ovarian tumors) had unconfirmed partial responses, 3 (esophagus, ovarian, and breast tumors) had declines in tumor markers suggestive of antitumor activity, and 12 had stable disease with durations ranging from 99 days to 343 days.
Excluding stable disease as a measure of antitumor activity, more antitumor activity was seen in patients treatment group 1 (15.6%; 5/32) and treatment group 3 (36.8%; 7/19) than in treatment group 2 (4.0%; 1/25). However, in general, there were too few patients in each group to conduct comparative analyses.
Etirinotecan pegol, is a unique long acting topoisomerase I inhibitor that provides prolonged systemic exposure to SN-38. This first-in-human study shows that etirinotecan pegol has significant antitumor activity in patients with various solid tumors and some differences in safety profile compared with the irinotecan historical profile. Data from this study presents the versatility of etirinotecan pegol to provide several successful therapeutic regimens.
Because of the long t1/2 of etirinotecan pegol, defining the MTD based on the first cycle of treatment was challenging. The protocol stipulated that only adverse events in the first cycle were considered DLT's. The cycle lengths varied between schedules from 2 to 4 weeks. It was not until patients received additional cycles that we started seeing rather severe diarrhea. As a result, we evaluated successive downward dose reductions in additional patients. For treatment group 1 (w × 3q4w), dosing went from 58→115→173→230→173→145→115 mg/m2, which was the determined dose that could be tolerated for multiple cycles. Patients in treatment groups 2 (q21d) and 3 (q14d), had similar experiences with doses of 145→170→195→220→245→220→195→170 mg/m2, and 145→170→195→220→195→170 mg/m2, respectively. Overall, the MTD for treatment group 1 (w × 3q4w), was declared to be 115 mg/m2. The MTD for both for treatment group 2 (q21d) and treatment group 3 (q14d) was 145 mg/m2.
All 3 therapeutic regimens were found to be well tolerated at the defined MTD dose levels and most importantly, resulted in sustained and controlled systemic exposure to SN-38 with preliminary evidence of antitumor activity. These findings are consistent with in vitro and in vivo studies in tumor-bearing mice which showed the unique properties of etirinotecan pegol and found that topoisomerase I inhibitors displayed exposure time–dependent rather than concentration-dependent cytotoxicity (23–27). In preclinical studies, the antitumor activity of etirinotecan pegol was much greater than irinotecan when studied at equivalent, as well as lower doses, in various xenograft models in mice. Animals treated with etirinotecan pegol displayed durable tumor growth suppression at and below the maximum feasible dose administered, whereas animals treated with irinotecan at MTD had temporary tumor growth inhibition as their best response. The prolonged tumor cell exposure to SN-38 following etirinotecan pegol administration is greater than the intermittent exposure produced by all existing topoisomerase I inhibitor therapies. These results confirm the hypothesis that etirinotecan pegol, as designed, would provide prolonged cellular exposure to SN-38 and as a result would result in greater DNA damage.
Both etirinotecan pegol and irinotecan can cause significant diarrhea that is successfully treated with prompt aggressive clinical intervention. However, unlike irinotecan, etirinotecan pegol did not exhibit cholinergic symptoms that indicated premedication with atropine was needed and neutropenia was significantly less common. Diarrhea was more frequent and severe at doses above the RP2D with onset greater than 24 hours after study drug administration. The plasma concentrations of both irinotecan and SN-38 following etirinotecan pegol administration resulted in sustained and controlled systemic exposure, which likely contributed to the observed reductions in cholinergic diarrhea and neutropenia while maintaining evidence of antitumor response.
The sustained and controlled systemic exposure to irinotecan and SN-38 is the result of the molecular design of etirinotecan pegol. The MTD of 145 mg/m2 for etirinotecan pegol resulted in approximately the same plasma SN-38 AUC as the 350 mg/m2 dose of irinotecan with 1 cycle of therapy, but exposure was continuous rather than intermittent and maximal concentrations were approximately 10-fold less (16). Following the administration of etirinotecan pegol, an elimination t1/2 for SN-38 (∼50 days) was measured that is significantly different than that for SN-38 after irinotecan administration (∼12 to 47 hours; refs. 1, 11).
PK modeling and simulation using results from this study, as well as published irinotecan data, showed plasma SN-38 concentrations were sustained throughout a 21-day dosing interval after etirinotecan pegol was administered at 145 mg/m2 which translates into continuous and sustained antitumor activity. This is not the case following irinotecan (350 mg/m2) administration where 70% of the 21-day dosing interval was drug free. The simulation also shows some accumulation of SN-38 as would be expected after q21d administration of a drug having a terminal disposition half-life of approximately 50 days. SN-38 AUC after 4 cycles (Fig 2B) is approximately 80% of the predicted steady-state AUC; therefore neither rapid nor extensive additional accumulation is expected when the recommended q21d schedule is used.
Once etirinotecan pegol is metabolized to irinotecan, the irinotecan metabolic profile is the same as that for irinotecan administration. However, the rates of formation for each metabolite are much slower and the proportions formed are very different than those after administration of irinotecan. These differences can be characterized as a shift away from hepatic oxidation of irinotecan to APC and NPC via CYP3A4. This may be secondary to protection of irinotecan from metabolism while bound to the polymer core, as well as a corresponding greater proportion of irinotecan metabolized to SN-38 once released from the polymer core.
Diarrhea is an ongoing concern in the development of new topoisomerase I inhibitors as SN-38 levels in the intestinal lumen play a key role in the delayed diarrhea that limits dose intensification and efficacy. Encouraging work is being done to identify potent and selective inhibitors of bacterial b-glucuronidases to eliminate the GI toxicity of irinotecan without killing the bacterial symbiotes required for intestinal health (28). These developments, if successful, may enhance the efficacy and tolerability of this class of antineoplastic.
In conclusion, in this first-in-human study, the MTD was established for the administration of etirinotecan pegol following 3 different dosing schedules. Etirinotecan pegol showed antitumor activity in a broad spectrum of cancers. An optimal response profile was seen with sustained exposure to SN-38 throughout a 21-day dosing interval in patients with lower peak concentration. An improved safety profile regarding hematologic toxicity was noted when compared historically to irinotecan, most likely because of reduced irinotecan exposure secondary to slow release from etirinotecan pegol. Overall, etirinotecan pegol administration to patients with cancer results in sustained and controlled systemic exposure to SN-38. The pharmacokinetics of etirinotecan pegol and metabolites are predictable and do not require complex dosing adjustments. Etirinotecan pegol is being studied in phase II and III trials of patients with cancers that have failed prior chemotherapy treatment, including patients with platinum-resistant ovarian cancer, phase II, (29) and metastatic breast cancer, phase II (30) and III. The benefit of the prolonged SN-38 t1/2 of 50 days following etirinotecan pegol administration may offer future research opportunities exploring alternative dosing schedules, including a model of induction and subsequent maintenance therapy.
Disclosure of Potential Conflicts of Interest
M.A. Eldon reported major support from Nektar, Inc. (employment). Lee S. Rosen received a commercial research grant from Nektar. No other potential conflicts of interest were disclosed by the other authors.
Conception and design: J.T. Hamm, L.S. Rosen, M.A. Eldon
Development of methodology: L.S. Rosen, M.A. Eldon
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): G.S. Jameson, J.T. Hamm, G.J. Weiss, C. Alemany, S. Anthony, M. Basche, R.K. Ramanathan, M.J. Borad, R. Tibes, A. Cohn, I. Hinshaw, R. Jotte, L.S. Rosen, K. Schroeder, E. White
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): G.S. Jameson, G.J. Weiss, M.J. Borad, R. Tibes, A. Cohn, L.S. Rosen, U. Hoch, M.A. Eldon, E. White
Writing, review, and/or revision of the manuscript: G.S. Jameson, J.T. Hamm, G.J. Weiss, C. Alemany, S. Anthony, R.K. Ramanathan, M.J. Borad, R. Tibes, A. Cohn, R. Jotte, L.S. Rosen, U. Hoch, M.A. Eldon, R. Medve, D.D. Von Hoff
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): R. Tibes
Study supervision: S. Anthony, R.K. Ramanathan, A. Cohn, R. Jotte, L.S. Rosen, K. Schroeder, D.D. Von Hoff
Commercial research funding was provided to each participating institution by Nektar Therapeutics.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The authors thank the patients and their families for their participation in this trial.
Prior presentations: This study was presented at 2008 EORTC-NCI-AACR Symposium, Poster 595. The study abstract was presented at the 2008 ASCO Annual Meeting (abstract 13518).
- Received April 27, 2012.
- Revision received October 17, 2012.
- Accepted October 22, 2012.
- ©2012 American Association for Cancer Research.