Publications by authors named "Jodi A Muscal"

21 Publications

  • Page 1 of 1

Phase 1 trial of olaratumab monotherapy and in combination with chemotherapy in pediatric patients with relapsed/refractory solid and central nervous system tumors.

Cancer Med 2021 Feb 20;10(3):843-856. Epub 2021 Jan 20.

Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA.

Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.
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http://dx.doi.org/10.1002/cam4.3658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897905PMC
February 2021

Prevention of Recurrent Mucinous Borderline Ovarian Tumor with Aromatase Inhibitor.

J Pediatr Adolesc Gynecol 2020 Oct 3;33(5):610-612. Epub 2020 Apr 3.

Division of Pediatric and Adolescent Gynecology, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.

Background: Aromatase inhibitors (AIs) are used for estrogen-modulated conditions. Some borderline ovarian tumors (BOT) express estrogen receptors. We present 2 cases of progression from mucinous cystadenoma to mucinous BOT (mBOT) after prior cystectomies in whom an AI was used with recurrence prevention.

Cases: Two patients underwent laparoscopic ovarian cystectomy for mucinous cystadenoma. Serial imaging demonstrated recurrent ovarian cysts for which both underwent fertility sparing surgery (FSS) with ovarian cystectomy for mBOT. Both patients were initiated on an AI and have been without recurrence.

Summary And Conclusion: BOT predominantly occur in reproductive aged females. FSS with cystectomy is an option, but recurrence occurs in 12-36% of cases. The use of AI in prevention of recurrent BOT shows promise, and more studies are needed to explore this treatment.
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http://dx.doi.org/10.1016/j.jpag.2020.03.011DOI Listing
October 2020

BCOR-CCNB3 fusion-positive clear cell sarcoma of the kidney.

Pediatr Blood Cancer 2020 04 26;67(4):e28151. Epub 2019 Dec 26.

Section of Hematology/Oncology, Department of Pediatrics, Texas Children's Hospital/Baylor College of Medicine, Houston, Texas.

Clear cell sarcoma of the kidney (CCSK) is the second most common malignant pediatric renal tumor. Two of the recurrent somatic alterations reported in CCSK are BCL-6 corepressor (BCOR) internal tandem duplication (ITD) and YWHAE-NUTM2B/E gene fusion. A minority of patients with CCSKs have other rare somatic alterations. We report two patients with CCSK showing BCOR-CCNB3 (where CCNB3 is cyclin B3) fusion, who had similar clinical presentation of a large renal mass with tumor thrombus extending through the inferior vena cava into the right atrium and a favorable response to chemotherapy. We recommend BCOR-CCNB3 fusion testing for all patients with CCSK who lack BCOR-ITD or YWHAE-NUTM2B/E gene fusions.
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http://dx.doi.org/10.1002/pbc.28151DOI Listing
April 2020

Salvage sacrococcygeal resection for yolk sac tumors after chemotherapy: report of 2 cases.

J Neurosurg Pediatr 2019 Oct 4:1-8. Epub 2019 Oct 4.

1Division of Pediatric Neurosurgery, Department of Surgery, Texas Children's Hospital, Baylor College of Medicine.

Pediatric germ cell tumors (GCTs) are neoplasms that originate from primordial germ cells and, according to their site of presentation, are classified as gonadal or extragonadal. The most common site of extragonadal GCTs in children is the sacrococcygeal region, and the standard management is multimodal with a focus on chemotherapy. In selected instances, sacrococcygeal resection is performed. Herein, the authors report on 2 patients who presented with presacral yolk sac tumors managed with multimodal treatment. Both patients underwent salvage sacrococcygeal resection for oncological control and surgical removal of the sacral vertebral elements: a 27-month-old girl with a recurrent sacrococcygeal yolk sac tumor following chemotherapy and initial resection and a 24-month-old boy in whom a primary sacrococcygeal yolk sac tumor was resected following chemotherapy. These 2 cases illustrate the complexity in the management of these unusual tumors and will help neurosurgeons with the understanding of yolk sac tumors in the sacrococcygeal region.
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http://dx.doi.org/10.3171/2019.7.PEDS19321DOI Listing
October 2019

Mentors' perspectives on the successes and challenges of mentoring in the COG Young Investigator mentorship program: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2019 10 16;66(10):e27920. Epub 2019 Jul 16.

Division of Pediatric Hematology-Oncology, Children's Hospital of Los Angeles, Los Angeles, California.

Background: Identification and development of young investigators (YI) is critical to the long-term success of research organizations. In 2004, the Children's Oncology Group (COG) created a mentorship program to foster the career development of YIs (faculty <10 years from initial appointment). This study sought to assess mentors' long-term assessment of this program.

Procedure: In 2018, 101 past or current mentors in the COG YI mentorship program completed an online survey. Statistical comparisons were made with the Kruskal-Walis test.

Results: The response rate was 74.2%. As some mentors had multiple mentees, we report on 138 total mentee-mentor pairs. Mentors were 57.4% male, and mentees were 39.1% male. Mentors rated being mentored as a YI as important with a median rating of 90 on a scale of 1-100, interquartile range (IQR) 80-100. Most mentors reported that being mentored themselves helped their own success within COG (78.2%) and with their overall career development (92.1%). Most mentors enjoyed serving in the program (72.3%) and the median success rating (on a scale of 1-100) across the mentor-mentee pairings was 75, IQR 39-90. Success ratings did not differ by mentor/mentee gender, but improved with increased frequency of mentor-mentee interactions (P < .001). Mentor-mentee pairs who set initial goals reported higher success ratings than those who did not (P < .001). Tangible successes included current mentee COG committee involvement (45.7%), ongoing mentor-mentee collaboration (53.6%), and co-authored manuscript publication (38.4%).

Conclusion: These data indicate that mentorship is important for successful professional development. Long-term mentoring success improves when mentors and mentees set goals upfront and meet frequently.
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http://dx.doi.org/10.1002/pbc.27920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707882PMC
October 2019

Concurrent Inhibition of Neurosphere and Monolayer Cells of Pediatric Glioblastoma by Aurora A Inhibitor MLN8237 Predicted Survival Extension in PDOX Models.

Clin Cancer Res 2018 05 20;24(9):2159-2170. Epub 2018 Feb 20.

Laboratory of Molecular Neuro-Oncology, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

Pediatric glioblastoma multiforme (pGBM) is a highly aggressive tumor in need of novel therapies. Our objective was to demonstrate the therapeutic efficacy of MLN8237 (alisertib), an orally available selective inhibitor of Aurora A kinase (AURKA), and to evaluate which model system (monolayer or neurosphere) can predict therapeutic efficacy AURKA mRNA expressions were screened with qRT-PCR. antitumor effects were examined in three matching pairs of monolayer and neurosphere lines established from patient-derived orthotopic xenograft (PDOX) models of the untreated (IC-4687GBM), recurrent (IC-3752GBM), and terminal (IC-R0315GBM) tumors, and therapeutic efficacy through log rank analysis of survival times in two models (IC-4687GBM and IC-R0315GBM) following MLN8237 treatment (30 mg/kg/day, orally, 12 days). Drug concentrations and mechanism of action and resistance were also investigated. AURKA mRNA overexpression was detected in 14 pGBM tumors, 10 PDOX models, and 6 cultured pGBM lines as compared with 11 low-grade gliomas and normal brains. MLN8237 penetrated into pGBM xenografts in mouse brains. Significant extension of survival times were achieved in IC-4687GBM of which both neurosphere and monolayer were inhibited , but not in IC-R0315GBM of which only neurosphere cells responded (similar to IC-3752GBM). Apoptosis-mediated MLN8237 induced cell death, and the presence of AURKA-negative and CD133 cells appears to have contributed to therapy resistance. MLN8237 successfully targeted AURKA in a subset of pGBMs. Our data suggest that combination therapy should aim at AURKA-negative and/or CD133 pGBM cells to prevent tumor recurrence. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-2256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6052861PMC
May 2018

Small molecule inhibitor regorafenib inhibits RET signaling in neuroblastoma cells and effectively suppresses tumor growth .

Oncotarget 2017 Nov 24;8(61):104090-104103. Epub 2017 Oct 24.

Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Neuroblastoma (NB), the most common extracranial pediatric solid tumor, continues to cause significant cancer-related morbidity and mortality in children. Dysregulation of oncogenic receptor tyrosine kinases (RTKs) has been shown to contribute to tumorigenesis in various human cancers and targeting these RTKs has had therapeutic benefit. RET is an RTK which is commonly expressed in NB, and high expression of RET correlates with poor outcomes in patients with NB. Herein we report that RET is required for NB cell proliferation and that the small molecule inhibitor regorafenib (BAY 73-4506) blocks glial cell derived neurotrophic factor (GDNF)-induced RET signaling in NB cells and inhibits NB growth both and . We found that regorafenib significantly inhibited cell proliferation and colony formation ability of NB cells. Moreover, regorafenib suppressed tumor growth in both an orthotopic xenograft NB mouse model and a transgenic NB mouse model. Finally, regorafenib markedly improved the overall survival of transgenic tumor-bearing mice. In summary, our study suggests that RET is a potential therapeutic target in NB, and that using a novel RET inhibitor, like regorafenib, should be investigated as a therapeutic treatment option for children with NB.
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http://dx.doi.org/10.18632/oncotarget.22011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732789PMC
November 2017

Long-term evidence that a pediatric oncology mentorship program for young investigators is feasible and beneficial in the cooperative group setting: A report from the Children's Oncology Group.

Pediatr Blood Cancer 2018 03 28;65(3). Epub 2017 Nov 28.

Children's Hospital of Los Angeles, Los Angeles, California.

Background: Mentorship of junior faculty is an integral component of career development. The Children's Oncology Group (COG) Young Investigator (YI) Committee designed a mentorship program in 2004 whose purpose was to pair YIs (faculty ≤10 years of first academic appointment) with a senior mentor to assist with career development and involvement in COG research activities. This study reports on the committee's ability to achieve these goals.

Procedure: An online survey was sent to YIs who were registered with the program from 2004 to2015, assessing three major domains: (1) overall experience with the mentor pairing, (2) satisfaction with the program, and (3) academic accomplishments of the mentees.

Results: The response rate was 64% (110/171). Overall, YIs rated the success of their mentorship pairing as 7.2 out of 10 (median) (25th, 75th quartile 3.6, 9.6). The direct effects of the mentorship program included 70% YIs reporting a positive effect on their career, 40% reporting any grant or manuscript resulting from the pairing, 47% forming a new research collaboration, and 43% receiving appointment to a COG committee. Respondents reported success in COG with 38% authoring a manuscript on behalf of COG and 65% reporting a leadership position including seven current or past COG discipline chairs and 20 study chairs. Finally, 74% of respondents said they would consider serving as mentors in the program in the future.

Conclusion: The COG YI mentorship program has been well received by the majority of the participants and has helped to identify and train many current leaders in COG.
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http://dx.doi.org/10.1002/pbc.26878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7773146PMC
March 2018

Borderline Ovarian Tumor in the Pediatric and Adolescent Population: A Case Series and Literature Review.

J Pediatr Adolesc Gynecol 2018 Feb 9;31(1):48-54. Epub 2017 Sep 9.

Division of Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas.

Study Objective: To determine the diagnosis, management, and outcome for children and adolescents with borderline ovarian tumor (BOT), and to provide a review of the literature on BOT in children and adolescents.

Design: A retrospective cohort study of female adolescents younger than age 21 years diagnosed with BOT between January 2001 and May 2016.

Setting: Texas Children's Hospital, Houston, Texas.

Participants: Fourteen patients (ages 12 to 18 years) diagnosed with BOT.

Main Outcome Measures: Clinical presentation, preoperative characteristics, surgical technique, cancer stage, histology, treatment, and recurrence.

Results: Median age at diagnosis was 15.5 years, with most postmenarchal. Abdominal mass/pain were the most common presenting symptoms. Median tumor size was 16.6 cm (range, 4-32 cm). Preoperative cancer antigen 125 (CA 125) was elevated in 54% (7/13) of cases. All patients had fertility-preserving surgery, either cystectomy (CY) or unilateral salpingo-oophorectomy (USO): 5 via laparoscopy (LSC) and 9 via laparotomy. Most were stage I with 5 serous and 9 mucinous BOT histology. No one received adjuvant chemotherapy. Two patients had recurrence. One had ipsilateral recurrence 2 months after LSC CY for FIGO stage IC1 mucinous BOT. The second had contralateral recurrence 15 months after laparotomy, right USO for FIGO stage IIIC serous BOT treated with LSC CY, then a second recurrence treated with USO after oocyte cryopreservation for fertility preservation. All patients were alive at last follow-up, 1 with disease.

Conclusions: BOT in children and adolescents can be treated conservatively with fertility-preserving techniques and surveillance with good outcome. The role of adjuvant therapy is not known.
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http://dx.doi.org/10.1016/j.jpag.2017.09.001DOI Listing
February 2018

The second-generation ALK inhibitor alectinib effectively induces apoptosis in human neuroblastoma cells and inhibits tumor growth in a TH-MYCN transgenic neuroblastoma mouse model.

Cancer Lett 2017 08 26;400:61-68. Epub 2017 Apr 26.

Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. Electronic address:

Activating germline mutations of anaplastic lymphoma kinase (ALK) occur in most cases of hereditary neuroblastoma (NB) and the constitutively active kinase activity of ALK promotes cell proliferation and survival in NB. Therefore, ALK kinase is a potential therapeutic target for NB. In this study, we show that the novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time. These results indicate that alectinib may be a promising therapeutic agent for the treatment of NB.
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http://dx.doi.org/10.1016/j.canlet.2017.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502736PMC
August 2017

Novel Src/Abl tyrosine kinase inhibitor bosutinib suppresses neuroblastoma growth via inhibiting Src/Abl signaling.

Oncotarget 2017 Jan;8(1):1469-1480

Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

Neuroblastoma (NB) is the most common extracranial solid tumor in children. Aberrant activation of the non-receptor tyrosine kinases Src and c-Abl contributes to the progression of NB. Thus, targeting these kinases could be a promising strategy for NB therapy. In this paper, we report that the potent dual Src/Abl inhibitor bosutinib exerts anti-tumor effects on NB. Bosutinib inhibited NB cell proliferation in a dose-dependent manner and suppressed colony formation ability of NB cells. Mechanistically, bosutinib effectively decreased the activity of Src/Abl and PI3K/AKT/mTOR, MAPK/ERK, and JAK/STAT3 signaling pathways. In addition, bosutinib enhanced doxorubicin (Dox)- and etoposide (VP-16)-induced cytotoxicity in NB cells. Furthermore, bosutinib demonstrated anti-tumor efficacy in an orthotopic xenograft NB mouse model in a similar mechanism as of that in vitro. In summary, our results reveal that Src and c-Abl are potential therapeutic targets in NB and that the novel Src/Abl inhibitor bosutinib alone or in combination with other chemotherapeutic agents may be a valuable therapeutic option for NB patients.
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http://dx.doi.org/10.18632/oncotarget.13643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352070PMC
January 2017

Childhood and adolescent tracheobronchial mucoepidermoid carcinoma (MEC): a case-series and review of the literature.

Pediatr Surg Int 2016 Apr 20;32(4):417-24. Epub 2016 Jan 20.

Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, 6701 Fannin, Suite 1210, Houston, 77030, TX, USA.

Tracheobronchial mucoepidermoid carcinomas (MEC) are rare in the pediatric population with literature limited primarily to case reports. Here we present our institutional experience treating MEC in three patients and review the literature of 142 pediatric cases previously published from 1968 to 2013. Although rare, tracheobronchial MEC should be included in the differential diagnosis in a child with recurrent respiratory symptoms. Conservative surgical management is often sufficient to achieve complete resection and good outcomes.
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http://dx.doi.org/10.1007/s00383-015-3849-yDOI Listing
April 2016

Novel ALK inhibitor AZD3463 inhibits neuroblastoma growth by overcoming crizotinib resistance and inducing apoptosis.

Sci Rep 2016 Jan 20;6:19423. Epub 2016 Jan 20.

Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas 77030, USA.

ALK receptor tyrosine kinase has been shown to be a therapeutic target in neuroblastoma. Germline ALK activating mutations are responsible for the majority of hereditary neuroblastoma and somatic ALK activating mutations are also frequently observed in sporadic cases of advanced NB. Crizotinib, a first-line therapy in the treatment of advanced non-small cell lung cancer (NSCLC) harboring ALK rearrangements, demonstrates striking efficacy against ALK-rearranged NB. However, crizotinib fails to effectively inhibit the activity of ALK when activating mutations are present within its kinase domain, as with the F1174L mutation. Here we show that a new ALK inhibitor AZD3463 effectively suppressed the proliferation of NB cell lines with wild type ALK (WT) as well as ALK activating mutations (F1174L and D1091N) by blocking the ALK-mediated PI3K/AKT/mTOR pathway and ultimately induced apoptosis and autophagy. In addition, AZD3463 enhanced the cytotoxic effects of doxorubicin on NB cells. AZD3463 also exhibited significant therapeutic efficacy on the growth of the NB tumors with WT and F1174L activating mutation ALK in orthotopic xenograft mouse models. These results indicate that AZD3463 is a promising therapeutic agent in the treatment of NB.
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http://dx.doi.org/10.1038/srep19423DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4726162PMC
January 2016

Mucoepidermoid Carcinoma in Children: A Single Institutional Experience.

Pediatr Blood Cancer 2016 Jan 29;63(1):27-31. Epub 2015 Jul 29.

Texas Children's Cancer and Hematology Centers, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

Purpose And Objective: To determine the clinicopathologic and molecular features and outcome of children with mucoepidermoid carcinoma (MEC).

Methods: A retrospective analysis of clinical and histopathologic findings was performed in patients with MEC diagnosed at Texas Children's Cancer Center between 2000 and 2014.

Results: Ten female and four male patients with median age 12 years (range 7-19 years) were included in the study. Tumors involved major salivary glands, minor salivary glands of the palate, and the tracheobronchial tree. Nine of 11 patients with salivary MEC underwent more than one surgical resection at the time of initial diagnosis to achieve a gross total resection. Three patients with tracheobronchial tumors underwent pulmonary lobectomy. Three patients received postoperative radiation therapy. No patient was treated with chemotherapy. Histopathologic grades were classified as low (n = 2), intermediate (n = 9), and high (n = 3). All 12 patients with tumor tissue available for testing were positive for MECT1/MAML2 fusion transcripts. There were no deaths, metastases, or recurrences in this series, with a median follow-up of 24 months (range 5-96 months).

Conclusions: Low to intermediate histopathologic grade MECs are more common than high grade MEC in children. In contrast to adults, MECT1/MAML2 fusion transcripts occur with a frequency of 100% in our pediatric MEC series. Complete excision is the treatment of choice and is associated with excellent outcome. The role of radiotherapy is unclear, but may be indicated in patients with high grade tumors with positive surgical margins.
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http://dx.doi.org/10.1002/pbc.25681DOI Listing
January 2016

Phase 1 evaluation of EZN-2208, a polyethylene glycol conjugate of SN38, in children adolescents and young adults with relapsed or refractory solid tumors.

Pediatr Blood Cancer 2014 Oct 24;61(10):1792-7. Epub 2014 Jun 24.

Division of Pediatric Hematology/Oncology, University Hospitals Case Medical Center Rainbow Babies & Children's Hospital, Cleveland, Ohio.

Background: EZN-2208 is a water-soluble PEGylated conjugate of the topoisomerase inhibitor SN38, the active metabolite of irinotecan. Compared to irinotecan, EZN-2208 has a prolonged half-life permitting extended exposure to SN38. EZN-2208 has demonstrated clinical tolerability and antitumor activity in adults with advanced solid tumors. This Phase 1 study evaluated the safety, pharmacokinetics, and preliminary antitumor activity of EZN-2208 in children with relapsed or refractory solid tumors.

Procedure: EZN-2208 was administered as a 1-hour intravenous infusion once every 21 days at five dose levels (12-30 mg/m(2) ). Filgrastim or pegfilgrastim was administered 24-48 hours after treatment with EZN-2208. The rolling-six design was used for dose determination.

Results: Thirty eligible patients (15 females; median [range] age 11.5 years [2-21 years]) were treated with EZN-2208. Dose-limiting diarrhea occurred in one patient receiving 16 mg/m(2) and dose-limiting dehydration was seen in one patient receiving 24 mg/m(2) . At dose levels above 16 mg/m(2) , Grade ≥3 myelosuppression was demonstrated in the majority of patients. Additional adverse events included nausea, vomiting, and fatigue. The maximum tolerated dose was identified as 24 mg/m(2) due to dose-limiting thrombocytopenia in two patients receiving 30 mg/m(2) . Two of nine patients with neuroblastoma who were evaluable for response had partial responses. Five patients (four with neuroblastoma) remained on study for ≥8 cycles.

Conclusions: EZN-2208 was generally well-tolerated and was associated with clinical benefit in patients with neuroblastoma.
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http://dx.doi.org/10.1002/pbc.25105DOI Listing
October 2014

A phase I trial of imetelstat in children with refractory or recurrent solid tumors: a Children's Oncology Group Phase I Consortium Study (ADVL1112).

Clin Cancer Res 2013 Dec 4;19(23):6578-84. Epub 2013 Oct 4.

Authors' Affiliations: Texas Children's Cancer Center and Department of Pediatrics; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas; Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Children's Oncology Group, Arcadia; Geron Corporation, Menlo Park, California; Department of Oncology, Mayo Clinic, Rochester; and Department of Pediatrics, Hematology-Oncology, University of Minnesota, Minneapolis, Minnesota.

Purpose: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors.

Experimental Design: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m(2) were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle.

Results: Twenty subjects were enrolled (median age, 14 years; range, 3-21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m(2). Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m(2). Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed.

Conclusions: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m(2).
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4079262PMC
December 2013

A phase I trial of vorinostat and bortezomib in children with refractory or recurrent solid tumors: a Children's Oncology Group phase I consortium study (ADVL0916).

Pediatr Blood Cancer 2013 Mar 9;60(3):390-5. Epub 2012 Aug 9.

Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA.

Background: A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors.

Procedure: Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1.

Results: Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients.

Conclusion: The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors.
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http://dx.doi.org/10.1002/pbc.24271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3511610PMC
March 2013

Additive effects of vorinostat and MLN8237 in pediatric leukemia, medulloblastoma, and neuroblastoma cell lines.

Invest New Drugs 2013 Feb 6;31(1):39-45. Epub 2012 Jun 6.

Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Suite 1220, Houston, TX 77030, USA.

Purpose: Histone deacetylase (HDAC) inhibitors, such as vorinostat, decrease Aurora kinase activity by a variety of mechanisms. Vorinostat and MLN8237, a selective Aurora A kinase inhibitor, disrupt the spindle assembly and the mitotic checkpoint at different points, suggesting that the combination could have increased antitumor activity. The purpose of this study was to determine the cytotoxicity of vorinostat and MLN8237 in pediatric tumor cell lines.

Methods: Cell survival was measured after 72 h of drug treatment using a modified methyl tetrazolium assay. For drug combination experiments, cells were exposed to medium alone (controls), single drug alone, or to different concentrations of the combination of the two drugs, for a total of 36 concentration pairs per plate. The interaction of the drug combination was analyzed using the universal response surface approach.

Results: The cells express the target of MLN8237, Aurora A. For each cell line, the single agent IC(50) for MLN8237 and for vorinostat was in the clinically relevant range. Both drugs inhibited cell survival in a concentration-dependent fashion. At concentrations of MLN8237 exceeding approximately 1 μM, there was a paradoxical increase in viability signal in all three lines that may be explained by inhibition of Aurora B kinase. The combination of MLN8237 and vorinostat showed additive cytotoxicity in all three cell lines and nearly abrogated the paradoxical increase in survival noted at high single-agent MLN8237 concentrations.

Conclusion: MLN8237 and vorinostat are active in vitro against cancer cell lines. These results provide important preclinical support for the development of future clinical studies of MLN8237and vorinostat.
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http://dx.doi.org/10.1007/s10637-012-9831-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3655801PMC
February 2013

Plasma and cerebrospinal fluid pharmacokinetics of thalidomide and lenalidomide in nonhuman primates.

Cancer Chemother Pharmacol 2012 Apr 23;69(4):943-7. Epub 2011 Nov 23.

Texas Children's Cancer Center, Baylor College of Medicine, 1102 Bates Street, Suite 1220, Houston, TX 77030, USA.

Purpose: Thalidomide, originally developed as a sedative, was subsequently identified to have antiangiogenic properties. Lenalidomide is an antiangiogenic and immunomodulatory agent that has been utilized in the treatment of patients with brain tumors. We studied the pharmacokinetics and cerebrospinal fluid (CSF) penetration of thalidomide and lenalidomide in a nonhuman primate model.

Methods: A dose of 50 mg of thalidomide or 20 mg of lenalidomide was administered once orally to each of three rhesus monkeys. Plasma and CSF samples were obtained at specified intervals, and the thalidomide or lenalidomide concentrations were determined by high-performance liquid chromatography with tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods. CSF penetration was calculated as area under the concentration-time curve (AUC) CSF/AUC plasma.

Results: For thalidomide, the median apparent clearance (Cl/F) was 2.9 mL/min/kg, the median plasma AUC was 80 μM h, and the median terminal half-life (t(½)) was 13.3 h. For lenalidomide, the median Cl/F was 8.7 mL/min/kg, the median AUC was 9 μM h, and the median t(½) was 5.6 h. Thalidomide was detected in the CSF of all animals, with a median penetration of 42%. Lenalidomide was detected in the CSF of 2 of 3 animals, with a CSF penetration of 11% in each.

Conclusion: Thalidomide and lenalidomide penetrate into the CSF after oral administration of clinically relevant doses. Plasma exposure to lenalidomide was similar in our model to that observed in studies involving children who have brain tumors. These results support further development of lenalidomide for the treatment of central nervous system malignancies.
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http://dx.doi.org/10.1007/s00280-011-1781-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3685292PMC
April 2012

Plasma and cerebrospinal fluid pharmacokinetics of ABT-888 after oral administration in non-human primates.

Cancer Chemother Pharmacol 2010 Feb 13;65(3):419-25. Epub 2009 Jun 13.

Texas Children's Cancer Center, Baylor College of Medicine, and Texas Children's Hospital, 6621 Fannin Street, MC3-3320, Houston, TX 77030, USA.

Purpose: ABT-888 inhibits poly(ADP-ribose) polymerase (PARP) and may enhance the efficacy of chemotherapy and radiation in CNS tumors. We studied the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of ABT-888 in a non-human primate (NHP) model that is highly predictive of human CSF penetration.

Methods: ABT-888, 5 mg/kg, was administered orally to three NHPs. Serial blood and CSF samples were obtained. Plasma and CSF concentrations of ABT-888 were measured using LC/MS/MS, and the resulting concentration versus time data were evaluated using non-compartmental and compartmental PK methods.

Results: The CSF penetration of ABT-888 was 57+/-7% (mean+/-SD). The peak ABT-888 concentration in the plasma was 0.62+/-0.18 microM. Plasma and CSF AUC0-infinity were 3.7+/-1.7 and 2.1+/-0.8 microM h. PARP inhibition in peripheral blood mononuclear cells was evident 2 h after ABT-888 administration.

Conclusion: The CSF penetration of ABT-888 after oral administration was 57%. Plasma and CSF concentrations were in the range that has been shown to inhibit PARP activity in vivo in humans.
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http://dx.doi.org/10.1007/s00280-009-1044-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953793PMC
February 2010

Changes mimicking new leptomeningeal disease after intensity-modulated radiotherapy for medulloblastoma.

Int J Radiat Oncol Biol Phys 2009 Jan 15;73(1):214-21. Epub 2008 May 15.

Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Purpose: Acute and late changes in magnetic resonance imaging of the pediatric brain have been described after radiotherapy (RT). We report the post-RT neuroimaging changes in the posterior fossa after intensity-modulated RT (IMRT) in children with medulloblastoma and contrast them with those of leptomeningeal disease.

Methods And Materials: We performed a retrospective review of 53 consecutive children with medulloblastoma who were treated with craniospinal RT followed by IMRT to the posterior fossa and chemotherapy between 1997 and 2006.

Results: After IMRT to the posterior fossa, 8 (15%) of 53 patients developed increased fluid-attenuated inversion-recovery signal changes in the brainstem or cerebellum and patchy, multifocal, nodular contrast enhancement at a median of 6 months. The enhancement superficially resembled leptomeningeal disease. However, the enhancement resolved without intervention at a median of 6 months later. The accompanying fluid-attenuated inversion-recovery signal changes occasionally preceded the enhancement, were often parenchymal in location, and resolved or persisted to a lesser degree. All 8 patients with transient magnetic resonance imaging changes in the posterior fossa were alive at last follow-up. In contrast, leptomeningeal disease occurred in 8 (15%) of our 53 patients at a median of 19.5 months after IMRT completion. Of these 8 patients, 7 demonstrated initial nodular enhancement outside the conformal field, and 7 patients died.

Conclusion: Magnetic resonance imaging changes can occur in the posterior fossa of children treated with IMRT for medulloblastoma. In our experience, these transient changes occur at a characteristic time and location after RT, allowing them to be distinguished from leptomeningeal disease.
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http://dx.doi.org/10.1016/j.ijrobp.2008.03.056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2953789PMC
January 2009