Srivandana Akshintala

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Based on pre‐clinical and clinical activity in adult refractory tumors, and absence of significant neuro‐, nephro‐, or oto‐toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors.

Outcomes of Children and Adolescents with Advanced Hereditary Medullary Thyroid Carcinoma Treated with Vandetanib

Purpose: Vandetanib is well-tolerated in patients with advanced medullary thyroid carcinoma (MTC). Long-term outcomes and mechanisms of MTC progression have not been reported previously. Experimental Design: We monitored toxicities and disease status in patients taking vandetanib for hereditary, advanced MTC. Tumor samples were analyzed for molecular mechanisms of disease progression. Results: Seventeen patients [8 male, age 13 (9–17)* years] enrolled; 16 had a RET p.Met918Thr germline mutation. The duration of vandetanib therapy was 6.1 (0.1–9.7+)* years with treatment ongoing in 9 patients. Best response was partial response in 10, stable disease in 6, and progressive disease in one patient. Duration of response was 7.4 (0.6–8.7+)* and 4.9 (0.6–7.8+)* years in patients with PR and SD, respectively. Six patients died 2.0 (0.4–5.7)* years after progression. Median progression-free survival (PFS) was 6.7 years [95% confidence interval (CI): 2.3 years–undefined] and 5-year overall survival (OS) was 88.2% (95% CI: 60.6%–96.9%). Of 16 patients with a RET p.Met918Thr mutation, progression-free survival was 6.7 years (95% CI: 3.1–undefined) and 5-year overall survival was 93.8% (95% CI: 63.2%–99.1%). No patients terminated treatment because of toxicity. DNA sequencing of tissue samples (n = 11) identified an increase in copy number alterations across the genome as a potential mechanism of drug resistance [*median (range)]. Conclusions: This study demonstrates that vandetanib is safe and results in sustained responses in children and adolescents with hereditary MTC. Our preliminary molecular data suggest that an increase in copy number abnormalities may be associated with tumor progression in hereditary MTC patients treated with vandetanib. Clin Cancer Res; 24(4); 753–65. ©2017 AACR.

Multiple Endocrine Neoplasia Type 2B Presents Early in Childhood but Often Is Undiagnosed for Years

&NA; We describe the presenting symptoms and signs of multiple endocrine neoplasia type 2B in a cohort of children. Improved awareness of the early nonendocrine signs of multiple endocrine neoplasia type 2B could lead to earlier diagnosis before the development of medullary thyroid cancer and possibly its metastasis.

Pheochromocytoma in children and adolescents with multiple endocrine neoplasia type 2B

Context Multiple endocrine neoplasia type 2B (MEN2B) is characterized by early-onset medullary thyroid cancer in virtually all cases and a 50% lifetime risk of pheochromocytoma (PHEO) development. The literature on PHEO in patients with MEN2B is limited with most data being reported from adult studies that primarily address MEN2A. Objective The aim of the current study is to describe PHEO development in a cohort of pediatric patients with MEN2B. Design Retrospective chart review of patients with MEN2B evaluated at the National Institutes of Health in the period between July 2007 and February 2018. Results A total of 38 patients were identified (21 males and 17 females). Mean age at MEN2B diagnosis was 10.6 ± 3.9 years. Eight patients (21%) developed PHEO in the course of follow-up to date, all of whom were sporadic cases with the classic M918T RET mutation. PHEO was diagnosed based on biochemical and/or imaging screening studies in five patients, whereas three patients presented with symptoms of excess catecholamines. PHEO was diagnosed at a mean age 15.2 ± 4.6 (range, 10 to 25) years and 4.0 ± 3.3 years after MEN2B diagnosis. Only one patient was diagnosed with PHEO as the initial manifestation of MEN2B after she presented with hypertension and secondary amenorrhea. Conclusion Undiagnosed PHEO can be associated with substantial morbidity. Current American Thyroid Association guidelines recommend PHEO screening starting at age 11 for the high-/highest risk group. The youngest patient diagnosed with PHEO in our cohort was an asymptomatic 10-year-old, suggesting that PHEO development may begin before the screening-recommended age of 11, though remains clinically undetectable and thus the current screening guidelines seem appropriate.

Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1

Background Plexiform neurofibromas (PN) in neurofibromatosis 1 (NF1) can cause substantial morbidities. Clinical trials targeting PN have recently described decreases in PN volumes. However, no previous study has assessed the association between changes in PN volumes and PN-related morbidities. Our objective was to assess if increasing PN volume in NF1 is associated with increasing PN-related morbidity. Methods This is a retrospective review of patients enrolled on the NCI NF1 natural history study with ≥7 years of data available. Morbidities including pain, motor dysfunction, vision loss, and PN-related surgery were assessed at time of baseline PN MRI with volumetric analysis and time of MRI with maximum PN volume. Results Forty-one patients (median age at baseline 8 y) with 57 PN were included. At baseline, 40 PN had at least 1 PN-associated morbidity. During the observation period, 27 PN required increasing pain medication, and these PN grew faster per year (median difference 8.3%; 95% CI: 2.4, 13.8%) than those PN which did not. PN resulting in motor impairment at baseline (n = 11) had larger volumes compared with those that did not (median difference 461 mL; 95% CI: 66.9, 820). Conclusions Many NF1 PN were associated with clinically significant morbidity at baseline, highlighting the need for longitudinal morbidity evaluations starting at an early age to capture changes in PN-associated morbidities. Prospective evaluation of standardized patient reported and functional outcomes in clinical trials are ongoing and may allow further characterization of the association of PN volume increase or decrease and clinical changes.

Sleep and pulmonary outcomes for clinical trials of airway plexiform neurofibromas in NF1

Objective: Plexiform neurofibromas (PNs) are complex, benign nerve sheath tumors that occur in approximately 25%–50% of individuals with neurofibromatosis type 1 (NF1). PNs that cause airway compromise or pulmonary dysfunction are uncommon but clinically important. Because improvement in sleep quality or airway function represents direct clinical benefit, measures of sleep and pulmonary function may be more meaningful than tumor size as endpoints in therapeutic clinical trials targeting airway PN. Methods: The Response Evaluation in Neurofibromatosis and Schwannomatosis functional outcomes group reviewed currently available endpoints for sleep and pulmonary outcomes and developed consensus recommendations for response evaluation in NF clinical trials. Results: For patients with airway PNs, polysomnography, impulse oscillometry, and spirometry should be performed to identify abnormal function that will be targeted by the agent under clinical investigation. The functional group endorsed the use of the apnea hypopnea index (AHI) as the primary sleep endpoint, and pulmonary resistance at 10 Hz (R10) or forced expiratory volume in 1 or 0.75 seconds (FEV1 or FEV0.75) as primary pulmonary endpoints. The group defined minimum changes in AHI, R10, and FEV1 or FEV0.75 for response criteria. Secondary sleep outcomes include desaturation and hypercapnia during sleep and arousal index. Secondary pulmonary outcomes include pulmonary resistance and reactance measurements at 5, 10, and 20 Hz; forced vital capacity; peak expiratory flow; and forced expiratory flows. Conclusions: These recommended sleep and pulmonary evaluations are intended to provide researchers with a standardized set of clinically meaningful endpoints for response evaluation in trials of NF1-related airway PNs.

Abstract 3374: Effect of bevacizumab and dexamethasone on plasma ultrafiltrate (UF) and cerebrospinal fluid (CSF) pharmacokinetics (PKs) of carboplatin in a non-human primate (NHP) model.

Background: Bevacizumab and dexamethasone are commonly administered to patients with brain tumors, and may alter the central nervous system penetration of concurrently administered chemotherapeutic agents by affecting vascular permeability and blood brain barrier (BBB) composition. We compared plasma UF and CSF PKs of intravenously (IV) administered carboplatin given alone and in combination with dexamethasone or bevacizumab in a non-tumor bearing NHP model, that has been predictive of human PKs of anti-cancer drugs. Methods: Carboplatin (8.75 mg/kg IV over 1 hour) combined with bevacizumab (12.5 mg/kg IV over 1 hour immediately prior to carboplatin) or dexamethasone (0.4 mg/kg IV bolus given 24 hours and immediately prior to carboplatin), was administered on separate occasions to each of three adult rhesus monkeys. Each monkey received carboplatin alone as control. Serial paired plasma and CSF samples were obtained over 24 hours. Plasma UFs were prepared immediately. Platinum was quantified using a validated atomic absorption spectroscopy assay with a lower limit of quantitation of 0.03 μM. Area under concentration x time curves (AUC) were derived using the linear trapezoidal method. CSF penetration (ratio of CSF AUC 0-∞ : plasma UF AUC 0-∞ ) and CSF penetration relative to control (ratio of the CSF penetration of carboplatin with bevacizumab or dexamethasone to the CSF penetration of carboplatin alone) were calculated. Results: Conclusions: Plasma UF and CSF PK of carboplatin in NHP were similar to previous reports and showed limited inter-subject variability. Bevacizumab and dexamethasone consistently decreased the CSF penetration of carboplatin (median decrease 22% and 12% respectively). In patients with brain tumors and disrupted BBB, these differences may be larger and could be clinically relevant. Citation Format: Srivandana Akshintala, Cynthia M. Lester-McCully, Robert F. Murphy, Brigitte C. Widemann, Katherine E. Warren. Effect of bevacizumab and dexamethasone on plasma ultrafiltrate (UF) and cerebrospinal fluid (CSF) pharmacokinetics (PKs) of carboplatin in a non-human primate (NHP) model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3374. doi:10.1158/1538-7445.AM2013-3374