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Background: Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer., Methods: Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1., Results: One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension., Conclusions: The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society., (© 2018 American Cancer Society.)

S-CKD602 is a pegylated liposomal formulation of CKD-602. This study is the first to evaluate the factors affecting the high interpatient variability in the pharmacokinetic disposition of S-CKD602. S-CKD602 was administered intravenously (i.v.) every 3 weeks as part of a phase I study. Pharmacokinetics studies of the liposomal encapsulated and released CKD-602 in plasma were performed. The pharmacokinetic variability of S-CKD602 is associated with both linear and nonlinear clearances. Patients > or =60 years of age have a 2.7-fold higher exposure of S-CKD602 as compared with patients <60 years of age (P = 0.02). Patients with a lean body composition have a higher plasma exposure of S-CKD602 (P = 0.02). Patients who have received prior therapy with pegylated liposomal doxorubicin (PLD) have a 2.2-fold higher exposure of S-CKD602 as compared with patients who have not received PLD (P = 0.045). Prolonged exposure of the encapsulated drug in plasma over 1-2 weeks provides significant pharmacologic advantages. The high interpatient variability in the pharmacokinetic disposition of S-CKD602 was associated with age, body composition, saturable clearance, and prior PLD therapy.

Background: Rubitecan (RFS-2000, 9NC, Orathecin) is an orally bioavailable camptothecin analogue, with evidence of preclinical activity in colon cancer cell lines. We evaluated oral rubitecan (5 days on, 2 days rest per week) on a continuous schedule, in patients with advanced colorectal cancer (CRC), who progressed after 5-fluorouracil based chemotherapy., Patients and Results: Fourteen eligible patients were treated with rubitecan at 1.5 mg/m2/day on a 5 day/week continuous schedule. Therapy was well tolerated with most adverse events in the mild to moderate category. Grade 3/4 toxicity consisting of anemia, diarrhea and elevated bilirubin was seen in 4 patients. No responses were seen in 13 evaluable patients. Overall median survival (95% confidence interval) was 10.1 (range 3.1-12.6) months, and median time to progression was 2.1 months., Conclusions: Administration of rubitecan was well tolerated, but this schedule does not appear to have clinical activity in patients with advanced previously treated CRC.

The camptothecins provide a novel class of effective anticancer agents that exert their action against DNA topoisomerase I. Members of the camptothecins include topotecan, irinotecan, 9-aminocamptothecin, and 9-nitrocamptothecin, which are analogs of the plant alkaloid 20(S)-camptothecin. These agents vary in their antitumor efficacy and toxicity. Several pharmacokinetic and pharmacodynamic factors including cellular efflux, modulation of topoisomerases I and II, lactone stability, alterations in metabolism, and drug-drug interactions, influence the antitumor response and toxicity of these agents. Preclinical studies suggest that protracted schedules of administration produce greater antitumor effect than bolus administration. However, the optimal treatment regimens and administration schedules of these agents have yet to be established in clinical studies.

Irinotecan (IRN), a topoisomerase I interactive agent, has significant antitumor activity in early Phase I studies in children with recurrent solid tumors. However, the disposition of IRN and its metabolites, SN-38 and APC, in children has not been reported. Children with solid tumors refractory to conventional therapy received IRN by a 1-h i.v. infusion at either 20, 24, or 29 mg/m2 daily for 5 consecutive days for 2 weeks. Serial blood samples were collected after doses 1 and 10 of the first course. IRN, SN-38, and APC lactone concentrations were determined by an isocratic high-performance liquid chromatography assay. A linear four-compartment model was fit simultaneously to the IRN, SN-38, and APC plasma concentration versus time data. Systemic clearance rate for IRN was 58.7 +/- 18.8 liters/h/m2 (mean +/- SD). The mean +/- SD ng/ml x h single-day lactone SN-38 area under the concentration-time curve (AUC(0-->6) was 90.9 +/- 96.4, 103.7 +/- 62.4, and 95.3 +/- 63.9 at IRN doses of 20, 24, and 29 mg/m2, respectively. The relative extent of IRN conversion to SN-38 and metabolism to APC measured after dose 1 were 0.49 +/- 0.33 and 0.29 +/- 0.17 (mean +/- SD). No statistically significant intrapatient difference was noted for SN-38 area under the concentration-time curve. Large interpatient variability in IRN and metabolite disposition was observed. The relative extent of conversion and the SN-38 systemic exposure achieved with this protracted schedule of administration were much greater than reported in adults or children receiving larger intermittent doses.

Purpose: In a preclinical model of neuroblastoma, administration of irinotecan daily 5 days per week for 2 consecutive weeks ([qd x 5] x 2) resulted in greater antitumor activity than did a single 5-day course with the same total dose. We evaluated this protracted schedule in children., Patients and Methods: Twenty-three children with refractory solid tumors were enrolled onto a phase I study. Cohorts received irinotecan by 1-hour intravenous infusion at 20, 24, or 29 mg/m(2) (qd x 5) x 2 every 21 days., Results: The 23 children (median age, 14.1 years; median prior regimens, two) received 84 courses. Predominant diagnoses were neuroblastoma (n = 5), osteosarcoma (n = 5), and rhabdomyosarcoma (n = 4). The dose-limiting toxicity was grade 3/4 diarrhea and/or abdominal cramps in six of 12 patients treated at 24 mg/m(2), despite aggressive use of loperamide. The maximum-tolerated dose (MTD) on this schedule was 20 mg/m(2)/d. Five patients had partial responses and 16 had disease stabilization. On day 1, the median systemic exposure to SN-38 (the active metabolite of irinotecan) at the MTD was 106 ng-h/mL (range, 41 to 421 ng-h/mL)., Conclusion: This protracted schedule is well tolerated in children. The absence of significant myelosuppression and encouraging clinical responses suggest compellingly that irinotecan be further evaluated in children using the (qd x 5) x 2 schedule, beginning at a dose of 20 mg/m(2). These results imply that data obtained from xenograft models can be effectively integrated into the design of clinical trials.

Irinotecan, administered i.v. on days 1-5 and 8-12 [(dx5)2 i.v.] has demonstrated significant activity against advanced human tumor xenografts. To explore the feasibility of prolonged oral administration of irinotecan, we compared the efficacy of oral and i.v. irinotecan on the (dx5)2 schedule. We also evaluated oral therapy for 12 consecutive weeks [(dx5)12] at 25 and 50 mg/kg and two consecutive 5-day courses repeated every 21 days for up to four cycles ([(dx5)2]4) at 50 and 75 mg/kg/dose in a series of human colon carcinoma xenograft lines. In addition, we evaluated the effect of a sensitive (HC1) and resistant (ELC2) human colon adenocarcinoma xenograft on irinotecan and SN-38 lactone disposition after administration of irinotecan 10 mg/kg i.v. and 10 and 25 mg/kg p.o. Irinotecan i.v. at 40 mg/kg and oral at 50 and 75 mg/kg on the (dx5)2 schedule had similar activity against the panel of adult colon adenocarcinoma xenografts. Irinotecan given p.o. also demonstrated significant activity against a topotecan-resistant derivative, VRC5/TOPO. Oral administration of 75 mg/kg [(dx5)2]4 and 50 mg/kg (dx5)12 achieved complete response in five of seven xenograft lines evaluated. After i.v. administration, mice bearing HC1 xenografts had 43% greater SN-38 lactone systemic exposure compared to those with ELC2 xenografts and non-tumor-bearing mice. After oral (10 mg/kg) administration, there was a 5-fold higher molar formation of SN-38 lactone compared to i.v. (10 mg/kg) administration in tumor and non-tumor-bearing mice. SN-38 systemic exposure associated with the lowest oral dose (25 mg/kg) achieving complete response for HC1 was 942.6 ng/ml x h. These results emphasize the importance of pharmacokinetic studies as part of tumor response studies in xenograft models.

The antitumor activity of irinotecan in vitro primarily results from its hydrolysis by carboxylesterase to the active metabolite SN-38. The present study was conducted to evaluate the effect of human neuroblastoma xenografts on irinotecan and SN-38 disposition after i.v. and oral irinotecan administration. Non-tumor-bearing mice and mice bearing three different human neuroblastoma xenograft lines (NB1691, NB1643, and NBEB) were given irinotecan (10 mg/kg) by short i.v. injection into the tail vein or by oral gavage. Serial plasma samples were obtained, processed to isolate irinotecan and SN-38 lactone, and assayed with a sensitive and specific high-performance liquid chromatography assay. Noncompartmental and compartmental pharmacokinetic analyses were performed. A four-compartment model was used for analysis of irinotecan and SN-38 concentration-time data after i.v. administration. The presence of tumor increased irinotecan systemic exposure (1.2-3.8-fold; P < 0.05) after i.v. and oral administration in mice bearing neuroblastoma xenografts compared to non-tumor-bearing mice. Moreover, SN-38 systemic exposures were higher (1.3-3.8-fold; P < 0.05) in mice bearing human neuroblastoma xenografts as compared to non-tumor-bearing mice, with the greatest effect observed after oral administration of irinotecan. A schematic model is presented to provide a mechanistic basis for our observations. These results emphasize the need to perform preclinical pharmacokinetic studies to evaluate the influence of tumor on drug disposition.

The efficacy of the topoisomerase I inhibitor, 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11), administered by oral gavage has been examined against a panel of six independently derived neuroblastoma xenografts. Irinotecan was administered either daily for 5 days on 12 consecutive weeks ¿(d x 5)12¿ or for 5 days on two consecutive weeks repeated every 21 days for 4 cycles ¿[(d x 5)2]4¿. Given on the (d x 5)12 schedule the maximum tolerated dose (MTD) was 50 mg/kg. For intermittent scheduling ¿[(d x 5)2]4¿, the MTD was 75 mg/kg, resulting in the same total dose being administered (3 g/kg) over the period of treatment. At the MTD for the 12 consecutive week schedule there were two of 42 toxicity related deaths, whereas intermittent scheduling at the MTD resulted in none of 42 deaths. The intermittent schedule ¿[(d x 5)2]4¿ was less toxic than therapy given (d x 5)12, as at the end of treatment mice weighed 92 +/- 4% (SD; n = 6 experiments) and 81 +/- 4% (SD; n = 6 experiments) of their body weight at the start of therapy, respectively. The latter schedule was associated with loose feces starting around week 8 of therapy, broken teeth and a high incidence of swelling of the orbital conjunctiva that developed late in the course of therapy. Given (d x 5)12, irinotecan caused complete regressions of all six neuroblastoma xenograft lines. Because mice tolerate significantly greater systemic exposure to SN-38 lactone than do patients (as determined by plasma AUC at the respective MTD), we evaluated the intermittent schedule of administration, reducing the dose/administration to determine the lowest dose levels that produced objective regressions of these neuroblastoma xenografts and determined the daily systemic exposure associated with these dose levels. In four lines examined objective responses were obtained at dose levels of 12.5 or 6.25 mg/kg. The daily plasma AUC exposures associated with minimum dose achieving response in NB1691 (12.5 mg/kg), NB1643 (6.25 mg/kg) and NBEB (12.5 mg/kg) for irinotecan lactone were 219, 152 and 653 ng-h/ml, respectively; and for SN-38 lactone were 704, 418 and 987 ng-h/ml, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by oral administration and therapeutic activity is similar to i.v. irinotecan administered on similar schedules.

The efficacy of the topoisomerase I inhibitor 7-ethyl-10-(4-[1-piperidino]-1-piperidino)-carbonyloxy-camptotheci n (irinotecan, CPT-11) has been examined against a panel of six independently derived neuroblastoma xenografts. Intensive courses of therapy, where irinotecan was administered i.v. daily 5 days per week for two consecutive weeks [(dx5)2; defined as 1 cycle], were compared to more protracted low-dose schedules where cycles were repeated every 21 days for a total of three courses ¿abbreviated [(dx5)2]3¿. When administered (dx5)2 for a single cycle, the maximum tolerated daily dose was 40 mg/kg. Irinotecan induced a high frequency of complete regressions (CRs) in four of the six lines examined; however, most tumors achieving CR regrew during the period of observation (12 weeks). Furthermore, there was no advantage in high-dose regimens as compared to low dose (10 mg/kg) on the same schedule. Protracted schedules of administration, where three courses of therapy were given at 21-day intervals ¿[(dx5)2]3¿ i.v. were examined at 10 and 5 mg/kg/dose. Even at the lower dose level, irinotecan caused 100% CR in all tumor lines that were maintained at 12 weeks. To determine the minimum dose levels required to induce objective regressions of neuroblastoma xenografts, decreasing doses were examined using the [(dx5)2]3 i.v. schedule. At 2.5 mg/kg/dose, >90% of NB-1643, NB-1691, NB-1382.2, and NB-EB xenografts demonstrated CR, whereas at 1.25 mg/kg/dose, all six tumor lines evaluated demonstrated objective regressions (>/=50% volume reduction), with a high frequency of CRs in four tumor lines. The 10-hydroxy-7-ethyl CPT lactone single-day systemic exposure measured with the minimum dose (2.5 mg/kg) associated with complete response was 198, 257, and 228 ng.h/ml for mice bearing NB-1643, NB-1691, and NB-EB tumors, respectively. These results indicate that childhood neuroblastoma xenografts are highly sensitive to irinotecan given by parenteral administration, and that efficacy is schedule dependent.

The present study was conducted to quantitate the disposition of irinotecan lactone and its active metabolite SN-38 lactone in mice following oral and intravenous administration, and to evaluate the systemic exposure of irinotecan lactone and SN-38 lactone associated with antitumor doses of irinotecan lactone in mice bearing human tumor xenografts. Nontumor-bearing mice were given a single oral or intravenous irinotecan dose (5, 10, 40, or 75 mg/kg), and serial plasma samples were subsequently obtained. Irinotecan and SN-38 lactone plasma concentrations were measured using an isocratic HPLC assay with fluorescence detection. The disposition of intravenous irinotecan lactone was modeled using a two-compartment pharmacokinetic model, and the disposition of oral irinotecan and SN-38 lactone was modeled with noncompartmental methods. Irinotecan lactone showed biphasic plasma disposition following intravenous dosing with a terminal half-life ranging between 1.1 to 3 h. Irinotecan lactone disposition was linear at lower doses (5 and 10 mg/kg), but at 40 mg/kg irinotecan lactone clearance decreased and a nonlinear increase in irinotecan lactone AUC was observed. The steady-state volume of distribution ranged from 19.1 to 48.1 l/m2. After oral dosing, peak irinotecan and SN-38 lactone concentrations occurred within 1 h, and the irinotecan lactone bioavailability was 0.12 at 10 mg/kg and 0.21 at 40 mg/kg. The percent unbound SN-38 lactone in murine plasma at 1000 ng/ml was 3.4 +/- 0.67%, whereas at 100 ng/ml the percent unbound was 1.18 +/- 0.14%. Irinotecan and SN-38 lactone AUCs in micebearing human neuroblastoma xenografts were greater than in nontumor-bearing animals. Systemic exposure to unbound SN-38 lactone in nontumor-bearing animals after a single oral irinotecan dose of 40, 10, and 5 mg/kg was 28.3, 8.6, and 2.9 ng h/ml, respectively. Data from the present study provide important information for the design of phase I studies of oral irinotecan.

Purpose: A phase I trial was conducted in children with refractory solid tumors to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and pharmacodynamics for topotecan administered by a 30-min infusion for 5 consecutive days., Patients and Methods: Forty children with a variety of recurrent solid tumors, including nine patients with neuroblastoma and 10 with brain tumors, were given topotecan as a 30-min infusion for 5 consecutive days, beginning with a dose of 1.4 mg/m2/day. The dose was escalated in 20% increments after establishing that DLT was not present at the prior dose. Drug toxicity was graded using standard criteria. Dose-limiting toxicity was defined as grade 3 or 4 nonhematopoietic toxicity or grade 4 hematopoietic toxicity lasting > 7 days. Pharmacokinetic studies were performed during the first infusion course., Results: The DLT was hematopoietic and involved both platelets and neutrophils. Grade 4 hematopoietic toxicity of brief duration was seen at all dose levels. Over half of the patients received red blood cell transfusion support, and 19/40 received platelet transfusions. Hospital admissions for fever and neutropenia or for documented infections occurred in 32 of 169 courses of therapy. Gastrointestinal symptoms with nausea and vomiting or diarrhea were mild to moderate in 12 of the 40 patients. Antitumor responses were seen in three patients with neuroblastoma. An additional four patients (one with neuroblastoma, two with anaplastic astrocytomas, one with Ewing) had stable disease with continued therapy for > 6 months. Using a limited sampling model, pharmacokinetic studies were performed in 36 of the 40 patients. Topotecan lactone and total clearance were similar to those reported in other pediatric populations receiving topotecan by continuous infusion. A pharmacodynamic relation between systemic exposure to topotecan lactone and myclosuppression was observed., Conclusions: In heavily pretreated children, the MTD for topotecan given by intermittent 30-min infusion for 5 days is 1.4 mg/m2 without GCSF and 2.0 mg/m2/day with GCSF. The dose-limiting toxicity is hematopoietic. Data from this study provide the basis for further studies of topotecan in children with cancer.