Few effective options are available for the treatment of unresectable hepatocellular carcinoma (HCC). Several phase I trials suggest promising activity of a combination of gemcitabine and docetaxel.
Patients with unresectable or metastatic HCC were treated with docetaxel 40 mg/m2 (later reduced to 30 mg/m2) and gemcitabine 800 mg/m2 on days 1, 8 every 3 weeks. Twenty-five patients were enrolled in 26 months. Median age was 64 (range 27-78), 17 were male, 14 had liver-only disease and, 11 had extrahepatic disease.
Of 25 patients evaluable for the primary endpoint (response), 2 (8%) have a confirmed partial response. The median TTP is 2.76 months (95% CI 1.84-6.64 months). Median survival was 12.8 months (95% CI: 5.26-28.00). Two patients died on-study due to adverse events (1 hepatic and 1 renal failure), neither of which were attributed to the study medications. Twenty patients (81%) have experienced grade 3+ adverse events, including 11 with grade 4+ adverse events, primarily neutropenia, thrombocytopenia, diarrhea, and fatigue.
While this combination appears to have potential benefit, as measured by overall survival, its toxicity and the recent introduction of sorafenib has further limited the use of chemotherapy. Approaches other than chemotherapy are likely to be of the greatest potential benefit.
Aflibercept is a novel decoy receptor that efficiently neutralizes circulating vascular endothelial growth factor (VEGF). A pediatric phase 1 trial was performed to define the dose limiting toxicities (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of aflibercept.
Cohorts of 3–6 children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5 or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were performed with the initial dose.
21 eligible patients were enrolled; 18 were fully evaluable for toxicity. One of 6 patients receiving 2.0 mg/kg/dose developed dose-limiting intra-tumoral hemorrhage and 2 of 6 receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the 6 patients receiving 2.5 mg/kg/dose developed DLT, defining this as the MTD. The most common non-dose limiting toxicities were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free to bound aflibercept serum concentration was 2.10 on day 8, but only 0.44 by day 15. A rapid decrease in VEGF (p<0.05) and increase in PlGF (p<0.05) from baseline was observed in response to aflibercept by day 2.
The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower that the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of anti-tumor activity, but were dose-limiting.
Aflibercept; pediatric; pharmacokinetics; angiogenesis; VEGF
A phase I/II study of cixutumumab (IMC-A12) in children with refractory solid tumors was conducted. This study was designed to assess the toxicities, pharmacokinetics, and pharmacodynamics of cixutumumab in children to determine a recommended phase II dose and to assess antitumor activity in Ewing sarcoma (ES).
Patients and Methods
Pediatric patients with relapsed or refractory solid tumors were treated with cixutumumab as a 1-hour intravenous infusion once per week. Two dose levels—6 and 9 mg/kg—were evaluated using a standard three-plus-three cohort design. Patients with refractory ES were treated in an expanded phase II cohort at each dose level.
Forty-seven eligible patients with a median age of 15 years (range, 4 to 28 years) were enrolled. Twelve patients were treated in the dose-finding phase. Hematologic and nonhematologic toxicities were generally mild and infrequent. Dose-limiting toxicities included grade 4 thrombocytopenia at 6 mg/kg and grade 3 dehydration at 9 mg/kg. Mean trough concentration (± standard deviation) at 9 mg/kg was 106 ± 57 μg/mL, which exceeded the effective trough concentration of 60 μg/mL observed in xenograft models. Three patients with ES had confirmed partial responses: one of 10 at 6 mg/kg and two of 20 at 9 mg/kg. Serum insulin-like growth factor I (IGF-I) levels consistently increased after one dose of cixutumumab. Tumor IGF-I receptor expression by immunohistochemistry did not correlate with response in patients with ES.
Cixutumumab is well tolerated in children with refractory solid tumors. The recommended phase II dose is 9 mg/kg. Limited single-agent activity of cixutumumab was seen in ES.
To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma.
Patients received 7 days of fenretinide: 2475 mg/m2/day divided TID (<18 years) or 1800 mg/m2/day divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in Stratum 1 (measurable disease on CT/MRI +/− bone marrow and/or MIBG avid sites) and Stratum 2 (bone marrow and/or MIBG avid sites only).
Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in Stratum 1 (n=38) and Stratum 2 (n=24). One partial response (PR) was seen in Stratum 2 (n=24 evaluable). No responses were seen in Stratum 1 (n=35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in Stratum 1 and 6 patients in Stratum 2 for 4–45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for Stratum 1 and 48 days (range 17–892) for Stratum 2. Mean 4-HPR steady state trough plasma concentrations were 7.25 µM (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible.
Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric Phase I studies.
fenretinide; neuroblastoma; Phase II; ANBL0321
A phase I trial of ABT-888 (veliparib), a poly(ADP-ribose) polymerase (PARP inhibitor), in combination with topotecan, a topoisomerase I–targeted agent, was performed to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed, and levels of poly(ADP-ribose) (PAR) and the DNA-damage marker, γH2AX, were measured in tumor and peripheral blood mononuclear cells (PBMCs). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to co-administer ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m2/day and ABT-888 10 mg BID on days 1–5 of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We demonstrate a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I–mediated DNA damage in the clinic.
ABT-888; topotecan; clinical trial; phase I; PARP inhibitor
Sunitinib is an oral multi-targeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary anti-tumor activity of sunitinib in a pediatric population.
Patients 2-21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m2/day were evaluated, with dose escalation based on a 3+3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle.
Twenty-three patients were treated (median age 13.9 years; range, 3.9 – 20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with prior exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose was 15 mg/m2/day. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 - 9 cycles.
Cardiac toxicity precluded determination of a recommended dose for pediatric patients with prior anthracycline or cardiac radiation exposure. The maximum tolerated dose of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m2/day for 28 days followed by a 14-day break.
sunitinib; pediatric; pharmacokinetics; angiogenesis; VEGF
SR13668, an orally active AKT pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability.
Patients and Methods
Healthy adult volunteers were randomly assigned to receive a single, 38 mg oral dose of SR13668 in one of five different formulations, with or without food. Based on existing animal data, SR13668 in a PEG400/Labrasol® oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC0-∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size.
Participants (N=20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC0-∞ values were highest in the fed state (range = 122–439 ng/mL × hours) and were statistically significantly different across formulations (p = 0.007), with Solutol® HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2 – 6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation dependent.
Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.
Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors.
Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hour decitabine infusion for 7 days, followed by doxorubicin (45mg/m2) and cyclophosphamide (1g/m2) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells.
The maximum-tolerated dose of decitabine was 5 mg/m2/d for 7 days. Dose-limiting toxicities at 10 mg/m2/d were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for ≥4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16 respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis.
Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deactelyase inhibitors should be explored.
demethylation; decitabine; pediatric solid tumor; neuroblastoma
The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children.
Patients and Methods
Vorinostat was administered orally daily starting at 180 mg/m2/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC).
Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination.
In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.
In pre-clinical models, temozolomide and vincristine are additive or synergistic with irinotecan. We examined this 3-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea.
Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses.
On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m2/day × 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with dose-limiting toxicity. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml*h. Activity was seen in sarcoma patients, and overall 8 patients received ≥ 6 courses.
The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.
temozolomide; oral irinotecan; SN-38; vincristine; cefixime
Irinotecan has radiosensitizing effects and shows synergism with nitrosoureas. We performed a Phase II study of RT and irinotecan, followed by BCNU plus irinotecan in newly-diagnosed GBM. The MTD for patients receiving enzyme-inducing anticonvulsants (EIAC) was as follows: irinotecan 400 mg/m2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1, and irinotecan, 400 mg/m2 on Days 1, 8, 22 and 29, every 6 weeks. The MTD for non-EIAC patients was as follows: irinotecan 125 mg/m2/week on Days 1, 8, 22 and 29 during RT, followed by BCNU 100 mg/m2 Day 1 and irinotecan 75 mg/m2 Days 1, 8, 22 and 29, every 6 weeks. Median OS was 10.8 mos. (95% CI: 7.7–14.9); OS at 12 months was 44.6% (95% CI: 33.3–59.8) and PFS 6 was 28.6% (95% CI: 18.9–43.2). Patients went off treatment due to adverse events (7%), refusal (11%), progressive disease (48%), death (9%), and other (9%); 16% completed protocol treatment. Survival was similar in patients with variant (6/7 or 7/7) and wild-type (6/6) UGT1A1*28 genotypic alleles. Grade 3–4 toxicity was more common in non-EIAC patients with variant alleles. SN-38 Cmax and AUC in EIAC patients receiving 400 mg/m2 irinotecan were 20.9 ng/ml and 212 ng/ml h, and in non-EIAC patients receiving 125 mg/m2, 15.5 ng/ml and 207 ng/ml h. SN-38 AUC varied by UGT1A1*28 status in non-EIAC patients. This regimen was not significantly active and radiosensitization was not observed. Non-EIAC patients with UGT1A1*28 variant alleles appear particularly sensitive to toxicity from irinotecan.
Glioblastoma; BCNU; Nitrosourea; Irinotecan; NCCTG; UGT1A1; Enzyme-inducing anticonvulsant
Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM).
Patients and Methods
Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period.
A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02).
Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.
Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial.
The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial.
Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21or 28 days with 3.2 mg/m2 topotecan i.v. on days1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization.
The lapatinib/topotecan combination is well tolerated and warrants further study.
The purpose of this study was to determine the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, and intratumor and brain distribution of motexafin gadolinium (MGd) with involved field radiation therapy in children with newly diagnosed intrinsic pontine gliomas. MGd was administered as a 5-min intravenous bolus 2–5 h prior to standard radiation. The starting dose was 1.7 mg/kg. After first establishing that 5 doses/week for 6 weeks was tolerable, the dose of MGd was escalated until dose-limiting toxicity was reached. Radiation therapy was administered to 54 Gy in 30 once-daily fractions. Forty-four children received MGd at doses of 1.7 to 9.2 mg/kg daily prior to radiation therapy for 6 weeks. The maximum tolerated dose was 4.4 mg/kg. The primary dose-limiting toxicities were grade 3 and 4 hypertension and elevations in serum transaminases. Median elimination half-life and clearance values were 6.6 h and 25.4 ml/kg/h, respectively. The estimated median survival was 313 days (95% confidence interval, 248–389 days). The maximum tolerated dose of MGd and the recommended phase II dose was 4.4 mg/kg when administered as a daily intravenous bolus in conjunction with 6 weeks of involved field radiation therapy for pediatric intrinsic pontine gliomas.
motexafin gadolinium; pontine glioma; radiation therapy
1-methyl-D-tryptophan (D-1MT) reverses the immunosuppressive effect of indoleamine 2,3-dioxygenase (IDO), and it is currently being developed both as a vaccine adjuvant and as an immunotherapeutic agent for combination with chemotherapy. The present study examined the pharmacokinetics and toxicity of D-1MT in preparation for clinical trials. Incubation of D-1MT in rat plasma for 24 h produced no significant degradation, with <15% of D-1MT being bound to plasma protein. Following oral administration, D-1MT exhibited a larger AUC and Vd, longer elimination t1/2, and slower clearance in rats than in dogs. When oral doses of D-1MT exceeded levels of 600 mg/m2/day in rats, or 1200 mg/m2/day in dogs, the Cmax and AUC values decreased, resulting in a corresponding decrease in oral bioavailability. Thus, the doses were indicative of the lowest saturating doses in dogs and rats corresponding with an elimination t1/2 of 6.0 h and 28.7 h, a Tmax of 1 h and 8 h, and a bioavailability of 47% and 92%, respectively. Tissue concentrations of D-1MT in mice were highest in the kidney, followed by the liver, muscle, heart, lung, and spleen, respectively; 48 h post dosing, D-1MT was excreted in the urine (35.1%) and feces (13.5%). Oral administration of D-1MT in rats from 150 to 3000 mg/m2/day (25 to 500 mg/kg/day) and in dogs from 600 to 1200 mg/m2/day (30 and 60 mg/kg/day) for 28 consecutive days did not lead to mortality, adverse events, histopathological lesions, or significant changes in hematology, clinical chemistry, and body weight. These results suggested that 3000 and 1200 mg/m2/day were the no-observed-adverse-effect levels in rats and dogs, respectively. Mean plasma concentrations of D-1MT (600 and 1200 mg/m2/day) in dogs 1 h post dosing were 54.4 and 69.5 μg/ml on Day 1, respectively, and 53.1 and 66.6 μg/ml on Day 28, respectively; thus, indicating no increase in plasma D-1MT with a change in dose. In conclusion, D-1MT has little toxicity when administered orally to rats and dogs. Exceeding the saturating dose of D-1MT is unlikely to cause systemic toxicity, since any further increase in D-1MT plasma levels would be minimal.
1-methyl-[D]-tryptophan; indoleamine 2,3-dioxygenase; pharmacokinetics; toxicity; saturating absorption
The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment.
Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal.
There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3–4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 cleareance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule.
Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.
Enzyme-inducing antiepileptic drugs; Dexamethasone; Irinotecan; Pharmacokinetics; Recurrent gliomas
To determine the tolerability and serum concentration of epratuzumab, a humanized monoclonal antibody targeting CD22, administered alone and in combination with reinduction chemotherapy in children with relapsed acute lymphoblastic leukemia (ALL), and to preliminarily assess tumor targeting and efficacy.
Patients and Methods
Therapy consisted of a single-agent phase (epratuzumab 360 mg/m2/dose intravenously twice weekly × four doses), followed by four weekly doses of epratuzumab in combination with standard reinduction chemotherapy. Morphologic and minimal residual disease (MRD) responses were determined at the end of this 6-week period. Serum concentrations of epratuzumab were determined before and 30 minutes after infusions, and CD22 targeting efficiency was determined by quantifying changes in CD22 expression after epratuzumab administration.
Fifteen patients (12 fully assessable for toxicity) with first or later CD22-positive ALL marrow relapse enrolled on the feasibility portion of this study from December 2005 to June 2006. Two dose-limiting toxicities occurred: one grade 4 seizure of unclear etiology and one asymptomatic grade 3 ALT elevation. In all but one patient, surface CD22 was not detected by flow cytometry on peripheral blood leukemic blasts within 24 hours of drug administration, indicating effective targeting of leukemic cells by epratuzumab. Nine patients achieved a complete remission after chemoimmunotherapy, seven of whom were MRD negative.
Treatment with epratuzumab plus standard reinduction chemotherapy is feasible and acceptably tolerated in children with relapsed CD22-positive ALL. CD22 targeting was efficient, and the majority of patients achieved favorable early responses.
The cyclooxygenase-2 (COX-2) enzyme appears to be an important target for cancer chemoprevention. Given the recent emergence of potentially serious cardiovascular toxicity associated with selective COX-2 inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs), which inhibit both COX-1 and COX-2, have received renewed attention as candidate chemoprevention agents. Sulindac has demonstrated consistent chemopreventive potential in preclinical studies, as well as in a limited number of clinical trials reported to date. For the current pharmacokinetic study, sulindac capsules were prepared to facilitate ample agent supplies for future intervention studies. Encapsulation of the parent compound (sulindac sulfoxide) can be readily accomplished, but the effects of alternate formulations on bioavailability have not been rigorously examined. In the present single-dose, two-period crossover trial, we conducted pharmacokinetic analyses of sulindac in capsule (test) versus tablet (reference) formulations. Overall, bioavailability appeared to be higher for the capsule compared to the tablet formulation, based on test-to-reference pharmacokinetic parameter ratios for the parent compound. However, additional analyses based on the sulfide and sulfone metabolites of sulindac with the same pharmacokinetic parameters indicated similar chemopreventive exposures between the capsule and tablet formulations. These data support the use of sulindac capsules, which can be readily prepared with matching placebos, in future blinded chemoprevention trials.
Caspases are cysteine proteases that are essential for cytokine maturation and apoptosis. To facilitate the dissection of caspase function in vitro and in vivo, we have synthesized irreversible caspase inhibitors with biotin attached via linker arms of various lengths (12a–d) and a 2,4-dinitrophenyl labeled inhibitor (13). Affinity labeling of apoptotic extracts followed by blotting reveals that these affinity probes detect active caspases. Using the strong affinity of avidin for biotin, we have isolated affinity-labeled caspase-6 from apoptotic cytosolic extracts of cells overexpressing procaspase 6 by treatment with 12c, which contains biotin attached to the Nε-lysine of the inhibitor by a 22.5 Å linker arm, followed by affinity purification on monomeric avidin-Sepharose beads. 13 has proven sufficiently cell permeable to rescue cells from apoptotic execution. These novel caspase inhibitors should provide powerful probes for the study of the active caspase proteome during apoptosis both in vitro and in vivo.
Pancreatic cancer is one of the deadliest of all human malignancies with limited options for therapy. Here, we report the development of an optimized targeted drug delivery system to inhibit advanced stage pancreatic tumor growth in an orthotopic mouse model.
Targeting specificity in vitro was confirmed by preincubation of the pancreatic cancer cells with C225 as well as Nitrobenzylthioinosine (NBMPR - nucleoside transporter (NT) inhibitor). Upon nanoconjugation functional activity of gemcitabine was retained as tested using a thymidine incorporation assay. Significant stability of the nanoconjugates was maintained, with only 12% release of gemcitabine over a 24-hour period in mouse plasma. Finally, an in vivo study demonstrated the inhibition of tumor growth through targeted delivery of a low dose of gemcitabine in an orthotopic model of pancreatic cancer, mimicking an advanced stage of the disease.
We demonstrated in this study that the gold nanoparticle-based therapeutic containing gemcitabine inhibited tumor growth in an advanced stage of the disease in an orthotopic model of pancreatic cancer. Future work would focus on understanding the pharmacokinetics and combining active targeting with passive targeting to further improve the therapeutic efficacy and increase survival.
Vorinostat (V) at levels >2.5 μM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis.
One week before combination treatment, V alone was given daily for 3d (cycle −1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15–17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied.
34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m2 over 30 min and 30 mg/m2 over 4 h. V Cmax at the 800 mg dose was 4.8 μM (± 2.8). V Cmax ≥2.5 μM was achieved in 86% of patients at the MTD. F increased the Cmax of V by 27% (95% CI 11%–43%). F Cmax of ≥2 μM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6–13.2 m).
Intermittent high dose oral V in combination with F is feasible and achieves target serum levels >2.5 μM. V concentrations higher than previously reported with oral dosing were achieved.
CDKs and CDK inhibitors; Histone deacetylase inhibitors; Phase I trials; Combination chemotherapy; Pharmacokinetics
Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution.
Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum.
Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both IP and IV administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting.