A phase I study of perifosine with temsirolimus for recurrent pediatric solid tumors

BackgroundThe PI3K/AKT/mTOR pathway is aberrantly activated in many pediatric solid tumors including gliomas and medulloblastomas. Preclinical data in a pediatric glioma model demonstrated that the combination of perifosine (AKT inhibitor) and temsirolimus (mTOR inhibitor) is more potent at inhibiting the axis than either agent alone. We conducted this study to assess pharmacokinetics and identify the maximum tolerated dose for the combination.ProcedureWe performed a standard 3+3 phase I, open‐label, dose‐escalation study in patients with recurrent/refractory pediatric solid tumors. Four dose levels of perifosine (25–75 mg/m2/day) and temsirolimus (25–75 mg/m2 IV weekly) were investigated.ResultsTwenty‐three patients (median age 8.5 years) with brain tumors (diffuse intrinsic pontine glioma [DIPG] n = 8, high‐grade glioma n = 6, medulloblastoma n = 2, ependymoma n = 1), neuroblastoma (n = 4), or rhabdomyosarcoma (n = 2) were treated. The combination was generally well tolerated and no dose‐limiting toxicity was encountered. The most common grade 3 or 4 toxicities (at least possibly related) were thrombocytopenia (38.1%), neutropenia (23.8%), lymphopenia (23.8%), and hypercholesterolemia (19.0%). Pharmacokinetic findings for temsirolimus were similar to those observed in the temsirolimus single‐agent phase II pediatric study and pharmacokinetic findings for perifosine were similar to those in adults. Stable disease was seen in 9 of 11 subjects with DIPG or high‐grade glioma; no partial or complete responses were achieved.ConclusionsThe combination of these AKT and mTOR inhibitors was safe and feasible in patients with recurrent/refractory pediatric solid tumors.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137302/1/pbc26409.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137302/2/pbc26409_am.pd

Alveolar soft part sarcoma of the bladder with ASPSCR1-TFE3 gene fusion as a secondary malignancy

Alveolar soft part sarcoma (ASPS) represents <1% of all soft tissue sarcomas and harbors the ASPSCR1-TFE3 translocation, which is found in pediatric renal cell carcinomas arising after chemotherapy. We present the case of a female patient, treated for metastatic retinoblastoma (Rb) with surgery, radiation, and chemotherapy at age 21 months, who was diagnosed with ASPS of the bladder 5 years later when imaging revealed a polypoid mass arising from the left bladder wall. Endoscopic biopsy and tumor resection were performed. After histopathologic confirmation of ASPSCR1-TFE3 fusion-positive ASPS, negative margins were achieved with wide local excision. At 18 months post-surgery, she remains recurrence-free

Outcome of pediatric pineoblastoma after surgery, radiation and chemotherapy

Introduction Pineoblastomas are a category of supratentorial primitive neuroectodermal tumors (sPNETs) occurring in the pineal gland; some studies support the impression that patients with pineoblastomas have a worse prognosis than those with other sPNETs. Methods We reviewed the medical records and tissue sections of all patients with the diagnosis of pineoblastoma that were treated at the Dana-Farber Cancer Institute/Children's Hospital Boston Pediatric Brain Tumor Program between 1986 and 2005. Results Thirteen patients with the pathologic diagnosis of pineoblastoma were treated at our Hospital; 11 of these cases had complete records suitable for study. The median age was 8 years 8 months (5 F, 6 M). Surgical, radiation and chemotherapeutic regimens varied from case to case. Three patients had gross total resection and are alive and free of disease, versus four of eight with subtotal resection or biopsy only. Patients who received CSI and multi-agent chemotherapy had improved overall survival. Conclusions Seven of eleven patients with pineoblastoma are currently alive and free of disease, reflecting an improved outcome and longer survival than previously appreciated. Gross total surgical resection appeared to correlate with improved survival, as did treatment with craniospinal irradiation and multi-agent chemotherapy. Further study of this group of patients as a distinct diagnostic entity will be necessary to determine optimal therapy

Rare but Recurrent ROS1 Fusions Resulting From Chromosome 6q22 Microdeletions are Targetable Oncogenes in Glioma

PURPOSE: Gliomas, a genetically heterogeneous group of primary central nervous system tumors, continue to pose a significant clinical challenge. Discovery of chromosomal rearrangements involving kinase genes has enabled precision therapy, and improved outcomes in several malignancies. EXPERIMENTAL DESIGN: Positing that similar benefit could be accomplished for patients with brain cancer, we evaluated The Cancer Genome Atlas (TCGA) glioblastoma dataset. Functional validation of the oncogenic potential and inhibitory sensitivity of discovered ROS1 fusions was performed using three independent cell-based model systems, and an in vivo murine xenograft study. RESULTS: In silico analysis revealed previously unreported intrachromosomal 6q22 microdeletions that generate ROS1-fusions from TCGA glioblastoma dataset. ROS1 fusions in primary glioma and ependymoma were independently corroborated from MSK-IMPACT and Foundation Medicine clinical datasets. GOPC-ROS1 is a recurrent ROS1 fusion in primary central nervous system (CNS) tumors. CEP85L-ROS1 and GOPC-ROS1 are transforming oncogenes in cells of astrocytic lineage, and amenable to pharmacologic inhibition with several ROS1 inhibitors even when occurring concurrently with other cancer hotspot aberrations frequently associated with glioblastoma. Oral monotherapy with a brain-permeable ROS1 inhibitor, lorlatinib, significantly prolonged survival in an intracranially xenografted tumor model generated from a ROS1 fusion-positive glioblastoma cell line. CONCLUSIONS: Our findings highlight that CNS tumors should be specifically interrogated for these rare intrachromosomal 6q22 microdeletion events that generate actionable ROS1 fusions. ROS1 fusions in primary brain cancer may be amenable for clinical intervention with kinase inhibitors, and this holds the potential of novel treatment paradigms in these treatment-refractory cancer types, particularly in glioblastoma

A phase I study of single-agent perifosine for recurrent or refractory pediatric CNS and solid tumors

<div><p>The PI3K/Akt/mTOR signaling pathway is aberrantly activated in various pediatric tumors. We conducted a phase I study of the Akt inhibitor perifosine in patients with recurrent/refractory pediatric CNS and solid tumors. This was a standard 3+3 open-label dose-escalation study to assess pharmacokinetics, describe toxicities, and identify the MTD for single-agent perifosine. Five dose levels were investigated, ranging from 25 to 125 mg/m2/day for 28 days per cycle. Twenty-three patients (median age 10 years, range 4–18 years) with CNS tumors (DIPG [n = 3], high-grade glioma [n = 5], medulloblastoma [n = 2], ependymoma [n = 3]), neuroblastoma (n = 8), Wilms tumor (n = 1), and Ewing sarcoma (n = 1) were treated. Only one DLT occurred (grade 4 hyperuricemia at dose level 4). The most common grade 3 or 4 toxicity at least possibly related to perifosine was neutropenia (8.7%), with the remaining grade 3 or 4 toxicities (fatigue, hyperglycemia, fever, hyperuricemia, and catheter-related infection) occurring in one patient each. Pharmacokinetics was dose-saturable at doses above 50 mg/m²/day with significant inter-patient variability, consistent with findings reported in adult studies. One patient with DIPG (dose level 5) and 4 of 5 patients with high-grade glioma (dose levels 2 and 3) experienced stable disease for two months. Five subjects with neuroblastoma (dose levels 1 through 4) achieved stable disease which was prolonged (≥11 months) in three. No objective responses were noted. In conclusion, the use of perifosine was safe and feasible in patients with recurrent/refractory pediatric CNS and solid tumors. An MTD was not defined by the 5 dose levels investigated. Our RP2D is 50 mg/m2/day.</p></div

Perifosine dose level 2 (~50 mg/m²/day).

<p>Perifosine dose level 2 (~50 mg/m²/day).</p