Alberta Aikin

Proton Magnetic Resonance Spectroscopic Imaging in Children With Recurrent Primary Brain Tumors

PURPOSE Proton magnetic resonance spectroscopic imaging ((1)H-MRSI) is a noninvasive technique for spatial characterization of biochemical markers in tissues. We measured the relative tumor concentrations of these biochemical markers in children with recurrent brain tumors and evaluated their potential prognostic significance. PATIENTS AND METHODS (1)H-MRSI was performed on 27 children with recurrent primary brain tumors referred to our institution for investigational drug trials. Diagnoses included high-grade glioma (n = 10), brainstem glioma (n = 7), medulloblastoma/peripheral neuroectodermal tumor (n = 6), ependymoma (n = 3), and pineal germinoma (n = 1). (1)H-MRSI was performed on 1. 5-T magnetic resonance imagers before treatment. The concentrations of choline (Cho) and N-acetyl-aspartate (NAA) in the tumor and normal brain were quantified using a multislice multivoxel method, and the maximum Cho:NAA ratio was determined for each patients tumor. RESULTS The maximum Cho:NAA ratio ranged from 1.1 to 13.2 (median, 4.5); the Cho:NAA ratio in areas of normal-appearing brain tissue was less than 1.0. The maximum Cho:NAA ratio for each histologic subtype varied considerably; approximately equal numbers of patients within each tumor type had maximum Cho:NAA ratios above and below the median. Patients with a maximum Cho:NAA ratio greater than 4.5 had a median survival of 22 weeks, and all 13 patients died by 63 weeks. Patients with a Cho:NAA ratio less than or equal to 4.5 had a projected survival of more than 50% at 63 weeks. The difference was statistically significant (P =.0067, log-rank test). CONCLUSION The maximum tumor Cho:NAA ratio seems to be predictive of outcome in children with recurrent primary brain tumors and should be evaluated as a prognostic indicator in newly diagnosed childhood brain tumors.

Vandetanib in Children and Adolescents with Multiple Endocrine Neoplasia Type 2B Associated Medullary Thyroid Carcinoma

Purpose: Medullary thyroid carcinoma (MTC) is a manifestation of multiple endocrine neoplasia type 2 (MEN2) syndromes caused by germline, activating mutations in the RET (REarranged during Transfection) proto-oncogene. Vandetanib, a VEGF and EGF receptor inhibitor, blocks RET tyrosine kinase activity and is active in adults with hereditary MTC. Experimental Design: We conducted a phase I/II trial of vandetanib for children (5–12 years) and adolescents (13–18 years) with MTC to define a recommended dose and assess antitumor activity. The starting dose was 100 mg/m2 administered orally, once daily, continuously for 28-day treatment cycles. The dose could be escalated to 150 mg/m2/d after two cycles. Radiographic response to vandetanib was quantified using RECIST (v1.0), biomarker response was measured by comparing posttreatment serum calcitonin and carcinoembryonic antigen (CEA) levels to baseline, and a patient-reported outcome was used to assess clinical benefit. Results: Sixteen patients with locally advanced or metastatic MTC received vandetanib for a median (range) 27 (2–52) cycles. Eleven patients remain on protocol therapy. Diarrhea was the primary dose-limiting toxicity. In subjects with M918T RET germline mutations (n = 15) the confirmed objective partial response rate was 47% (exact 95% confidence intervals, 21%–75%). Biomarker partial response was confirmed for calcitonin in 12 subjects and for CEA in 8 subjects. Conclusion: Using an innovative trial design and selecting patients based on target gene expression, we conclude that vandetanib 100 mg/m2/d is a well-tolerated and highly active new treatment for children and adolescents with MEN2B and locally advanced or metastatic MTC. Clin Cancer Res; 19(15); 4239–48. ©2013 AACR.

Phase I Study of O6-Benzylguanine and Temozolomide Administered Daily for 5 Days to Pediatric Patients With Solid Tumors

PURPOSE This pediatric phase I trial of O6-benzylguanine (O6BG) and temozolomide (TMZ) on a daily schedule for 5 days, every 28 days was performed to determine the maximum-tolerated dose of TMZ when given with a biologically active dose of O6BG and to define the toxicity profile of the combination in children with solid tumors. PATIENTS AND METHODS Patients < or = 21 years old with refractory solid tumors were eligible. O6BG was administered intravenously over 60 minutes daily for 5 days. TMZ was administered orally 30 minutes after completion of each O6BG infusion. Starting doses of O6BG and TMZ were 60 mg/m2/d and 28 mg/m2/d, respectively. O6BG was escalated to 90 and 120 mg/m2/d; TMZ was subsequently escalated to 40, 55, 75, and 100 mg/m2/d. Cycles were repeated every 28 days. RESULTS Forty-one patients were enrolled; 32 patients were assessable for toxicity. The combination of O6BG and TMZ was tolerable at TMZ doses less than half of the conventional dose of 200 mg/m2/d. Myelosuppression occurred sporadically at all dose levels and was the dose-limiting toxicity (DLT) at 100 mg/m2/d of TMZ combined with 120 mg/m2/d O6BG. Nonhematologic toxicities were generally mild. Evidence of antitumor activity was observed at 120 mg/m2/d O6BG combined with TMZ doses of 55 mg/m2/d and above. CONCLUSION The recommended doses of O6BG administered with TMZ on a 5-day schedule in children are 120 mg/m2/d of O6BG and 75 mg/m2/d of TMZ. Evidence of activity was observed at these doses. Myelosuppression was the DLT.

Intrathecal mafosfamide: a preclinical pharmacology and phase I trial.

PURPOSE Preclinical studies of mafosfamide, a preactivated cyclophosphamide analog, were performed to define a tolerable and potentially active target concentration for intrathecal (IT) administration. A phase I and pharmacokinetic study of IT mafosfamide was performed to determine a dose for subsequent phase II trials. PATIENTS AND METHODS In vitro cytotoxicity studies were performed in MCF-7, Molt-4, and rhabdomyosarcoma cell lines. Feasibility and pharmacokinetic studies were performed in nonhuman primates. These preclinical studies were followed by a phase I trial in patients with neoplastic meningitis. There were five dose levels ranging from 1 mg to 6.5 mg. Serial CSF samples were obtained for pharmacokinetic studies in a subset of patients with Ommaya reservoirs. RESULTS The cytotoxic target exposure for mafosfamide was 10 micromol/L. Preclinical studies demonstrated that this concentration could be easily achieved in ventricular CSF after intraventricular dosing. In the phase I clinical trial, headache was the dose-limiting toxicity. Headache was ameliorated at 5 mg by prolonging the infusion rate to 20 minutes, but dose-limiting headache occurred at 6.5 mg dose with prolonged infusion. Ventricular CSF mafosfamide concentrations at 5 mg exceeded target cytotoxic concentrations after an intraventricular dose, but lumbar CSF concentrations 2 hours after the dose were less than 10 micromol/L. Therefore, a strategy to alternate dosing between the intralumbar and intraventricular routes was tested. Seven of 30 registrants who were assessable for response had a partial response, and six had stable disease. CONCLUSION The recommended phase II dose for IT mafosfamide, administered without concomitant analgesia, is 5 mg over 20 minutes.

Pharmacokinetically Guided Phase 1 Trial of the IGF-1 Receptor Antagonist RG1507 in Children with Recurrent or Refractory Solid Tumors

Purpose: This pediatric phase I study was designed to identify the doses of RG1507, a monoclonal antibody against the Type 1 Insulin-like Growth Factor Receptor (IGF1R), that achieves exposures equivalent to those achieved in adults at recommended doses. Experimental Design: Children with relapsed or refractory solid tumors were treated using the same doses and administration schedules of RG1507 (3 and 9 mg/kg/wk, and 16 mg/kg every 3 weeks [q3W]) as those studied in adults. Detailed pharmacokinetic (PK) sampling was performed after the first dose; selected peak and trough levels were subsequently obtained. Target exposures were ≥85% of mean areas under concentration x time curves (AUCs) in adults at doses of 9 mg/kg/wk and 16 mg/kg q3W. A maximum tolerated dose could be identified if dose-limiting toxicities (DLT) occurred. Results: Thirty-one evaluable patients aged 3–17 years were enrolled at 3 mg/kg/wk (n = 3), 9 mg/kg/wk (n = 18), or 16 mg/kg q3W (n = 10). There were no DLTs. At 9 mg/kg/wk the mean AUC0–7d (21,000 μg h/mL) exceeded the target (16,000 μg h/mL). At 16 mg/kg q3W, the mean AUC021d (70,000 μg h/mL) exceeded the target (59,400 μg h/mL). Clearance normalized to body weight was age dependent. There were no objective responses. Seven patients had stable disease for >12 weeks, including two patients with osteosarcoma with stable disease for 52+ and 78+ weeks. Conclusions: The recommended doses of RG1507 in children with solid tumors are 9 mg/kg/wk and 16 mg/kg q3W. This flexible design is well suited for trials of agents associated with limited toxicity. Clin Cancer Res; 17(3); 611–9. ©2010 AACR.

A phase I trial and pharmacokinetic study of a 24-hour infusion of trabectedin (Yondelis®, ET-743) in children and adolescents with relapsed or refractory solid tumors†‡

The objectives of this phase I study were to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics of a 24‐hour continuous intravenous infusion of trabectedin administered to children and adolescents with refractory or relapsed solid tumors.

Randomized Trial and Pharmacokinetic Study of Pegfilgrastim versus Filgrastim after Dose-Intensive Chemotherapy in Young Adults and Children with Sarcomas

Purpose: To compare the effectiveness, tolerance, and pharmacokinetics of a single dose of pegfilgrastim to daily filgrastim in children and young adults with sarcomas treated with dose-intensive combination chemotherapy. Experimental Design: Patients were randomized to receive a single dose of 100 mcg/kg of pegfilgrastim s.c. or 5 mcg/kg/day of filgrastim s.c., daily until neutrophil recovery after two treatment cycles with vincristine, doxorubicin, and cyclophosphamide (VDC) and two cycles of etoposide and ifosfamide (IE). The duration of severe neutropenia (absolute neutrophil count, ≤500/mcL) during cycles 1 to 4 and cycle duration for all cycles were compared. Pharmacokinetics of pegfilgrastim and filgrastim and CD34+ stem cell mobilization were studied on cycle 1. Growth factor–related toxicity, transfusions, and episodes of fever and neutropenia and infections were collected for cycles 1 to 4. Results: Thirty-four patients (median age, 20 years; range 3.8-25.8) were enrolled, and 32 completed cycles 1 to 4. The median (range) duration of absolute neutrophil count of <500/mcL was 5.5 (3-8) days for pegfilgrastim and 6 (0-9) days for filgrastim (P = 0.76) after VDC, and 1.5 (0-4) days for pegfilgrastim and 3.75 (0-6.5) days for filgrastim (P = 0.11) after IE. More episodes of febrile neutropenia and documented infections occurred on the filgrastim arm. Serum pegfilgrastim concentrations were highly variable. Pegfilgrastim apparent clearance (11 mL/h/kg) was similar to that reported in adults. Conclusion: A single dose per cycle of pegfilgrastim was well tolerated and may be as effective as daily filgrastim based on the duration of severe neutropenia and number of episodes of febrile neutropenia and documented infections after dose-intensive treatment with VDC and IE. (Clin Cancer Res 2009;15(23):7361–7)

111In-Octreotide Scintigraphy for Identification of Metastatic Medullary Thyroid Carcinoma in Children and Adolescents

CONTEXT Most medullary thyroid cancers (MTC) express somatostatin receptors; therefore, (111)In-octreotide somatostatin receptor scintigraphy (SRS) may be useful in detecting sites of metastases in children with MTC. OBJECTIVE The aim of the study was to evaluate tumor metastases in children and adolescents with MTC using SRS in comparison to conventional imaging. DESIGN AND SETTING A case series was conducted as part of baseline evaluation for cancer treatment protocol at the National Institutes of Health Clinical Center. PATIENTS Eleven patients with a median age of 15 (range, 9-17) yr participated in the study, 10 with histologically proven, metastatic MTC due to the M918T mutation of the RET protooncogene, and one with a known RET polymorphism. INTERVENTION After receiving 0.086 mCi/kg (111)Indium-pentreotide, patients were examined with a single photon emission computed tomography scan 4 and 24 h after injection. Baseline conventional imaging, including computed tomography (neck, chest, abdomen, ± pelvis, adrenals), magnetic resonance imaging (neck), and bone scan, was performed on all patients. MAIN OUTCOME MEASURES SRS results were compared with conventional imaging. RESULTS Five of the 11 patients had abnormal findings on SRS. Of the 53 total target lesions present in the patients, only 24.5% were accurately identified through SRS. CONCLUSIONS SRS appears to be less sensitive than conventional imaging at detecting the full extent of metastatic disease in children and adolescents with hereditary MTC. SRS incompletely identified sites of tumor and failed to visualize small sites of tumor or liver and lung metastases, and it has a limited role in the evaluation of metastatic disease in pediatric MTC patients.

Pediatric Phase I Trial Design Using Maximum Target Inhibition as the Primary Endpoint

The extent to which a drug inhibits a target responsible for a therapeutic effect is a more rational primary endpoint for dose-finding studies of more selective anticancer drugs than the conventional endpoint of dose-limiting toxicity (DLT) used for cytotoxic agents. An adaptive phase I trial design incorporating maximum target inhibition as the primary endpoint was developed to define the optimal dose of talabostat, a dipeptidyl peptidase (DPP) inhibitor, in children with relapsed or refractory solid tumors. The relationship between dose and effect (percent inhibition of serum DPP-4) was assessed using a maximum effect model. Maximum target inhibition was defined as greater than 90% DPP-4 inhibition in five or more of six patients 24 hours post-dose. If DLT was to occur, the trial would adapt to a traditional phase I design with a more conservative dose escalation. At the 600 microg/m(2) dose level, serum DPP-4 inhibition at 24 hours was 85%. No talabostat-related DLT occurred. The maximum effect model predicted that 1200 microg/m(2) of talabostat would maximally inhibit DPP-4. This adaptive trial design appears to be feasible, safe, and efficient and warrants further evaluation for development of molecularly targeted agents.