Paula Schaiquevich

Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report

PURPOSE 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/m(2)/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). RESULTS Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/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/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x 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. CONCLUSION In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Local and Systemic Toxicity of Intravitreal Melphalan for Vitreous Seeding in Retinoblastoma: A Preclinical and Clinical Study

PURPOSE Intravitreal melphalan is emerging as an effective treatment for refractory vitreous seeds in retinoblastoma, but there is limited understanding regarding its toxicity. This study evaluates the retinal and systemic toxicity of intravitreal melphalan in retinoblastoma patients, with preclinical validation in a rabbit model. DESIGN Clinical and preclinical, prospective, cohort study. PARTICIPANTS In the clinical study, 16 patient eyes received 107 intravitreal injections of 30 μg melphalan given weekly, a median of 6.5 times (range, 5-8). In the animal study, 12 New Zealand/Dutch Belt pigmented rabbits were given 3 weekly injections of 15 μg of intravitreal melphalan or vehicle to the right eye. METHODS Electroretinogram (ERG) responses were recorded in both humans and rabbits. For the clinical study, ERG responses were recorded at baseline, immediately before each injection, and at each follow-up visit; 82 of these studies were deemed evaluable. Median follow-up time was 5.2 months (range, 1-11). Complete blood counts (CBCs) were obtained on the day of injection at 46 patient visits. In the animal study, ERG responses were obtained along with fluorescein angiography, CBCs, and melphalan plasma concentration. After humane killing, the histopathology of the eyes was evaluated. MAIN OUTCOME MEASURES For the clinical study, we measured peak-to-peak ERG amplitudes in response to 30-Hz photopic flicker stimulation with comparisons between ERG studies before and after intravitreal melphalan. For the animal study, we collected ERG parameters before and after intravitreal melphalan injections with histopathologic findings. RESULTS By linear regression analysis, over the course of weekly intravitreal injections in retinoblastoma patients, for every additional injection, the ERG amplitude decreased by approximately 5.8 μV. The ERG remained stable once the treatment course was completed. In retinoblastoma patients, there were no grade 3 or 4 hematologic events. One week after the second injection in rabbits, the a- and b-wave amplitude declined significantly in the melphalan treated eyes compared with vehicle-treated eyes (P<0.05). Histopathology revealed severely atrophic retina. CONCLUSIONS Weekly injections of 30 μg of melphalan can result in a decreased ERG response, which is indicative of retinal toxicity. These findings are confirmed at an equivalent dose in rabbit eyes by ERG measurements and by histopathologic evidence of severe retinal damage. Systemic toxicity with intravitreal melphalan at these doses in humans or rabbits was not detected.

Phase I Trial of Lapatinib in Children With Refractory CNS Malignancies: A Pediatric Brain Tumor Consortium Study

PURPOSE To estimate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic properties of lapatinib, a selective epidermal growth factor receptor (EGFR) and ERBB2 inhibitor, in children with refractory or recurrent CNS malignancies. PATIENTS AND METHODS Lapatinib was administered orally twice daily at escalating doses starting at 300 mg/m(2) to patients who were not (stratum I) or were (stratum II) receiving steroids. Pharmacokinetic studies were performed during the first two courses. Expression of the four ERBB receptors and downstream signaling elements in tumor tissue was evaluated by immunohistochemistry. RESULTS Fifty-nine patients were enrolled (stratum I, n = 32; stratum II, n = 27). Of 29 patients evaluable for toxicity in stratum I, one experienced a DLT (diarrhea) at 520 mg/m(2) twice daily, and all three receiving 1,150 mg/m(2) twice daily experienced DLTs (one each of rash, diarrhea, and fatigue). Two of 21 patients evaluable for toxicity in stratum II experienced DLTs of rash at 900 mg/m(2) twice daily. Lapatinib dosage was related linearly to area under the [concentration-time] curve from start time to 12 hours later (AUC(0-12)) and dose-normalized maximum serum concentration and AUC values for patients in stratum II were both significantly higher (P = .001) than those for patients in stratum I. Frequent, high-level expression of activated (phosphorylated) EGFR and ERBB2 receptors and downstream signal intermediates were observed in tumors, particularly in ependymomas that displayed prolonged stable disease on lapatinib therapy. CONCLUSION Lapatinib is well tolerated in children with recurrent CNS malignancies, with rash, diarrhea, and fatigue identified as DLTs. The recommended phase II dose, regardless of steroid use, is 900 mg/m(2) twice daily.

Phase I Trial of Lenalidomide in Pediatric Patients With Recurrent, Refractory, or Progressive Primary CNS Tumors: Pediatric Brain Tumor Consortium Study PBTC-018

PURPOSE A phase I trial of lenalidomide was performed in children with recurrent, refractory, or progressive primary CNS tumors to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile and pharmacokinetics. PATIENTS AND METHODS Lenalidomide was administered by mouth daily for 21 days, repeated every 28 days. The starting dose was 15 mg/m(2)/d orally, and the dose was escalated according to a modified continuous reassessment method. Correlative studies included pharmacokinetics obtained from consenting patients on course 1, day 1, and at steady-state (between days 7 and 21). RESULTS Fifty-one patients (median age, 10 years; range, 2 to 21 years) were enrolled. Forty-four patients were evaluable for dose finding, and 49 patients were evaluable for toxicity. The primary toxicity was myelosuppression, but the MTD was not defined because doses up to 116 mg/m(2)/d were well-tolerated during the dose-finding period. Two objective responses were observed (one in thalamic juvenile pilocytic astrocytoma and one in optic pathway glioma) at dose levels of 88 and 116 mg/m(2)/d. Twenty-three patients, representing all dose levels, received ≥ six cycles of therapy. Pharmacokinetic analysis demonstrated that the lenalidomide area under the concentration-time curve from 0 to 24 hours and maximum plasma concentration increased with dosage over the range studied. CONCLUSION Lenalidomide was tolerable in children with CNS tumors at doses of 116 mg/m(2)/d during the initial dose-finding period. The primary toxicity is myelosuppression. Antitumor activity, defined by both objective responses and long-term stable disease, was observed, primarily in patients with low-grade gliomas.

Phase I and Pharmacokinetic Studies of Erlotinib Administered Concurrently with Radiotherapy for Children, Adolescents, and Young Adults with High-Grade Glioma

Purpose: To estimate the maximum-tolerated dose (MTD) of erlotinib administered during and after radiotherapy, and to describe the pharmacokinetics of erlotinib and its metabolite OSI-420 in patients between 3 and 25 years with newly diagnosed high-grade glioma who did not require enzyme-inducing anticonvulsants. Experimental Design: Five dosage levels (70, 90, 120, 160, and 200 mg/m2 per day) were planned in this phase I study. Dose-limiting toxicities (DLT) were evaluated during first 8 weeks of therapy. Local radiotherapy (dose between 54 and 59.4 Gy) and erlotinib started preferentially on the same day. Erlotinib was administered once daily for a maximum of 3 years. Pharmacokinetic studies were obtained after first dose and on day 8 of therapy. Mutational analysis of EGFR kinase domain, PIK3CA, and PTEN was done in tumor tissue. Results: Median age at diagnosis of 23 patients was 10.7 years (range, 3.7-22.5 years). MTD of erlotinib was 120 mg/m2 per day. Skin rash and diarrhea were generally well controlled with supportive care. Dose-limiting toxicities were diarrhea (n = 1), increase in serum lipase (n = 1), and rash with pruritus (n = 1). The pharmacokinetic variables of erlotinib and OSI-420 in children were similar to those described in adults. However, there was no relationship between erlotinib dosage and drug exposure. No EGFR kinase domain mutations were observed. Two patients with glioblastoma harbored mutations in PIK3CA (n = 1) or PTEN (n = 1). Conclusions: Although the MTD of erlotinib in children with newly diagnosed high-grade glioma was 120 mg/m2 per day, pharmacokinetic studies showed wide interpatient variability in drug exposure.

Using Pharmacokinetic and Pharmacodynamic Modeling and Simulation to Evaluate Importance of Schedule in Topotecan Therapy for Pediatric Neuroblastoma

Purpose: The study aims to use mathematical modeling and simulation to assess the relative contribution of topotecan systemic exposure and scheduling in the activity and myelosuppression of topotecan in pediatric patients with neuroblastoma. Experimental Design: Pharmacokinetic and pharmacodynamic data were obtained from a phase II study for pediatric patients with high-risk neuroblastoma. The topotecan dosage was individualized to attain a topotecan lactone area under the plasma concentration-time curve between 80 and 120 ng/mL h and given over a protracted schedule (i.e., 10 days). Four mathematical models describing topotecan pharmacokinetics, tumor growth, and neutrophil and platelet dynamics were developed. The models were combined to simulate and compare different topotecan treatment strategies with respect to systemic exposure and schedule. Results: The median change in tumor volume was significantly different between schedules (5% increase for D × 5 versus 60% decrease for D × 5 × 2; P < 0.0001) when administering the same total systemic exposure. Whereas protracted schedules showed increased neutropenia (median of 7 versus 12 days below an absolute neutrophil count of 500/μL; P < 0.0001) and thrombocytopenia (median of 3 versus 10 days below a platelet count of 20,000/μL; P < 0.00001), simulations showed that delays in topotecan therapy would not be required. Simulations showed that an increase in topotecan exposure on the D × 5 schedule by 2.4-fold resulted in a modest decrease in tumor volume (i.e., median percentage change tumor volume of 24% versus 3%). Conclusions: The present mathematical model gave an innovative approach to determining relevant topotecan schedules for possible evaluation in the clinic, which could lead to improved tumor response with minimized toxicities.

Subconjunctival carboplatin and systemic topotecan treatment in preclinical models of retinoblastoma

The authors demonstrated previously that the combination of topotecan (TPT) and carboplatin (CBP) was more effective than current chemotherapeutic combinations used to treat retinoblastoma in an orthotopic xenograft model. However, systemic coadministration of these agents is not ideal, because both agents cause dose‐limiting myelosuppression in children.

A phase II trial and pharmacokinetic study of oxaliplatin in children with refractory solid tumors: A Children's Oncology Group study

Platinating agents are used in the treatment of a spectrum of childhood cancers. Oxaliplatin, a third generation platinum compound, may provide less toxicity and be more effective. A phase 2 study was performed to estimate the response rate to single agent oxaliplatin in patients with refractory pediatric solid tumors, and to further describe the toxicities and pharmacokinetics of the drug in this population.

Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma†

Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra‐arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients.

Initial testing (stage 1) of lapatinib by the pediatric preclinical testing program.

Lapatinib is a small molecule reversible tyrosine kinase inhibitor of EGFR and ErbB2 that shows in vitro and in vivo activity against a range of EGFR and ErbB2‐dependent adult cancer cell lines and that has clinical efficacy against ErbB2‐overexpressing breast cancer.