bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II trial of vandetanib in children and adolescents with hereditary medullary thyroid carcinoma
Authors: Fox E. , Widemann B. C. , Whitcomb P. O. , Aikin A. , Dombi E. , Lodish M. , Stratakis C. A. , Steinberg S. , Wells S. A. , Balis F. M.
Published: August 2020

10014

Background: Mutations in the RET protooncogenecause hereditary medullary thyroid carcinoma (MTC) including Multiple Endocrine Neoplasia (MEN) Type 2A, Type 2B and familial MTC. Vandetanib inhibits VEGFR, EGFR, and RET tyrosine kinases and is active in adults with hereditary MTC. Methods: We are conducting a trial of vandetanib in children and adolescents with RET mutations and MTC. Safety is evaluated at each dose level in adolescents (13–18 years) prior to enrolling children (5–12 years). In the absence of dose limiting toxicity (DLT), intrapatient dose escalation is permitted after cycle 2. To assess bone toxicity, growth plate volume is measured using MRI. Response is monitored using tumor measurements (RECIST), serum biomarkers, calcitonin (CTN), and carcinoembryonic antigen (CEA). Results: Five adolescents and 2 children were enrolled at the 100 mg/m2 dose level, 3 adolescents were dose escalated to 150 mg/m2. Six have MEN2B (M918T RET mutation). Median (range) baseline CTN was 12,200 pg/mL (2,300–67,000) and CEA was 104 mcg/L (5–325). Dose limiting diarrhea was observed in 1/5 adolescents at the 100 mg/m2 and 1/3 adolescents escalated to 150 mg/m2. No DLTs were observed in children receiving 100 mg/m2. Non-DLT included elevated TSH (n = 6), rash (n = 5), anorexia (n = 3), diarrhea (n = 2), hypertension (n = 1), and fatigue (n = 1). Median (range) percent change in growth plate volume during therapy was -18% (-44% to + 50%). All patients had linear growth during therapy. Serum CTN and CEA decreased by ≥ 50% in 6/7 and 2/7 patients, respectively. Tumor size decreased in 6/6 patients with M918T RET mutations; 2 achieved RECIST partial response after 6 and 12 cycles. Conclusions: Preliminary results suggest that vandetanib has activity in children and adolescents with MEN2B associated MTC. Vandetanib 100 mg/m2 was well tolerated. Linear growth was not impaired.

[Table: see text]
Pediatric Preclinical Testing Program (PPTP) testing of the CENP-E inhibitor GSK923295A
Authors: Smith M. A. , Morton C. L. , Carol H. , Gorlick R. G. , Kang M. H. , Keir S. T. , Kolb E. A. , Lock R. B. , Maris J. M. , Houghton P. J.
Published: August 2020

10015

Background: GSK923295A is a small molecule inhibitor of centromere-associated protein E (CENP-E), a mitotic kinesin that is required for metaphase chromosome alignment and integration of mitotic spindle mechanics with mitotic checkpoint signaling. An initial phase I clinical trial in adults is ongoing. Methods: The PPTP includes a molecularly characterized in vitro panel of cell lines (n = 27) and in vivo panel of xenografts (n = 60) representing most of the common types of childhood solid tumors and childhood acute lymphoblastic leukemia (ALL). GSK923295A was tested in vitro at concentrations from 1.0 nM to 10.0 μM (96 hour exposure) and was tested in vivo using a daily × 3 for 2 weeks schedule, repeated at day 21. GSK923295A was administered IP at a dose of 125 mg/kg. Three measures of antitumor activity were used: 1) an objective response measure modeled after the clinical setting; 2) a time to event measure based on the median event-free survival (EFS); and 3) a treated to control (T/C) tumor volume measure. Results: GSK923295A demonstrated potent in vitro activity against the PPTP cell line panel with a median IC50 of 27 nM (range 12 nM to > 10 μM). 35 of 37 solid tumor xenograft models were evaluable. GSK923295A induced significant differences in EFS distribution compared to controls in 32 of 35 evaluable models. Objective responses were noted in 13 of 35 xenografts, including 9 with maintained complete responses (MCR), 3 with complete response (CR), and 1 with partial response (PR). Three of 5 Ewing sarcoma xenografts achieved MCR or CR, as did 2 of 3 rhabdoid tumor, and 2 of 5 rhabdomyosarcoma models. For the neuroblastoma panel, the best response was progressive disease (PD) with growth delay compared to controls (PD2 response), which was observed in 5 of 6 xenografts. GSK923295A showed activity against the ALL panel, but unexplained toxicity (generally on or after day 21) precluded formal analysis. Conclusions: GSK923295A has substantial in vitro and in vivo activity against the PPTP's preclinical models. The observed high level of preclinical activity for GSK923295A will need to be evaluated in the context of systemic exposures achieved in the xenograft models and those achievable in humans at tolerable doses. (Supported by NCI NO1CM42216)

[Table: see text]
Pharmacokinetic and biological study of erlotinib in children as monotherapy for refractory brain tumors or with radiation for newly diagnosed brain stem gliomas
Authors: Geoerger B. , Hargrave D. , Thomas F. , Andreiuolo F. , Varlet P. , Frappaz D. , Doz F. , Riccardi R. , Jaspan T. , Vassal G.
Published: August 2020

10019

Background: This multicenter phase I study was designed to determine the recommended dose (RD) of erlotinib, a small-molecule EGFR TKI, in patients ≤ 21 years as monotherapy or in combination with radiation therapy (RT). Methods: Group 1 included patients with brain tumors refractory to or relapsing after conventional therapy; receiving erlotinib alone. Group 2 included newly diagnosed patients with brain stem gliomas, who received RT (54Gy) and erlotinib. Conventional 3+3 dose escalation was used for Group 1; a continual reassessment method for Group 2. Four dose levels were planned: 75, 100, 125 and 150 mg/m2/day. Results: A total of 51 patients were enrolled (30 in Group 1; 21 in Group 2); 50 received treatment. Median age was 10 and 6 years, respectively. The RD of erlotinib was 125 mg/m2/day as monotherapy or in combination with RT. 203 adverse events in 44 patients were possibly treatment-related; 188 were G1/2; 9 G3, 2 G4, and 4 G5. Dermatologic and neurologic symptoms were most common; intratumoral hemorrhage was noted in 4 patients. In Group 1, 8 patients (27.6%) had stable disease, 2 with 45% tumor regression. In Group 2, 3 patients (14%) had partial response and 8 (38%) were stabilized; median OS was 12 months. Pharmacokinetic data of 46 patients were analyzed; patients’ weight and erlotinib clearance (CL) were significantly correlated. Mean (± SD) apparent CL and volume of distribution for erlotinib were 143.7 mL/h/kg (± 66.3) and 3.5 L/kg (± 3.0), respectively, and were independent of dose level. Mean half-life for erlotinib was 20.4 hours. Biomarker analyses on archived tumor or biopsy tissue prior to study entry for newly diagnosed brain stem glioma found 18/37 tumors tested were EGFR IHC+; 16/37 and 23/36 were pAKT+ and pMAPK+, respectively. High EGFR expression was more common in supratentorial gliomas; PTEN loss was most common in brain stem glioma (15/19) and was not observed in ependymomas. Conclusions: Erlotinib 125 mg/m2/day has an acceptable tolerability profile in pediatric patients with brain tumors, and can be safely combined with RT. Further studies are required to define the efficacy of this treatment approach and to establish the impact of biomarkers on outcomes in pediatric glial tumors.

No significant financial relationships to disclose.
DNA methylation pattern of brain stem pilocytic astrocytomas in children
Authors: Witt H. , Korshunov A. , Remke M. , Janzarik W. G. , Gnekow A. , Scheurlen W. , Kulozik A. E. , Lichter P. , Pfister S.
Published: August 2020

10021

Background: Pilocytic astrocytoma (WHO grade I) comprises the most frequent brain tumor in childhood. We were recently able to identify BRAF as a centrally important oncogene in these tumors showing duplication or activation in a majority of cases. Although histologically indistinguishable, tumors with brain stem location have a particularly poor prognosis. It is not well established, whether this is due to their close proximity to pivotal anatomic sites or due to distinct biological characteristics. Methods: To identify novel genes involved in astrocytoma pathogenesis, we performed a genome-wide DNA methylation analysis of 78 pilocytic astrocytoma samples from different tumor locations (diencephalic, cerebral, cerebellar, brain stem). BeadChip methylation technology was used to identify genes showing differential promoter methylation among tumors. Two CpG sites were analyzed for each of a total of 14.000 promoters per sample. Clinical and molecular subgroups were compared using Significance Analysis of Microarrays (SAM). Results: In this genome-wide approach, we identified an 11-gene signature that was able to correctly separate all brain stem tumors (n = 8) from the majority of tumors from other locations (56/70). Moreover, from 14 tumors clustering together with the brain stem tumors, 5 patients experienced disease recurrence (38%) as opposed to 20% in the remaining group. Genes contained in the signature most interestingly included three homeobox family genes (HOXB1, HOXD3, and HOXD4), and NES, a tumor stem cell marker. Conclusions: These data suggest that brain stem pilocytic astrocytomas display biologic features different from most tumors of other locations and share a methylation signature with tumors prone to disease recurrence from other locations. We provide first evidence for a role of differentially methylated homeobox family genes in the pathogenesis of pilocytic astrocytoma.

No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) study of lenalidomide (LEN) in pediatric patients with relapsed/refractory solid tumors or myelodysplastic syndrome (MDS): A Children's Oncology Group Phase I Consortium study
Authors: Berg S. L. , Russell H. , Cairo M. , Ingle A. M. , Adamson P. C. , Blaney S. M.
Published: August 2020

10023

Background: LEN, which has immunomodulatory, antiangiogenic, and antiproliferative effects, is indicated for the treatment of adults with MDS and multiple myeloma. We report the final results of a phase 1 and PK study of LEN in children with recurrent or refractory solid tumors (ST) or MDS. Methods: LEN was administered by mouth once daily for 21 of 28 days. Cohorts of 3 to 12 children with ST were enrolled at 15, 25, 40, 55 and 70 mg/m2/d dose levels. Children with MDS received a fixed dose of 5 mg/m2/d. PK and correlative biology studies were performed in cycle 1. Results: 49 patients (23 female), median age 16 years (range, 1–21) were enrolled and received a median of 1 cycle (range 1–11). 39/46 ST patients and 3/3 MDS patients were fully evaluable for toxicity. 0/3 patients with MDS had DLT. At 15 mg/m2/d, 1/6 ST patients developed DLT (Gr 3 hypercalcemia). At 25 mg/m2/d 1 patient had a cerebrovascular ischemic event of uncertain relationship to LEN; future subjects were screened for thromboembolic risk factors prior to enrollment. At 40 mg/m2/d 3/12 patients developed DLTs (Gr 3 hypophosphatemia/hypokalemia; Gr 4 neutropenia delaying the start of the next cycle for > 7 days; Gr 3 somnolence); at 55 mg/m2/d 1/6 patients developed DLT (Gr 3 urticaria). At 70 mg/m2/d 0/6 patients had DLT. No further dose escalation was attempted. No objective responses were observed. LEN enhanced IL-2 and IL-15 concentrations; NK expansion and activation; and NK and LAK cytotoxicity (Ayello, ASH, 2008). The median apparent LEN clearance and half-life were 135 ± 45 ml/min/m2 and 2.3 ± 1.1 hr. Conclusions: LEN is well tolerated at doses up to 70 mg/m2/d x 21d of 28 days in children with recurrent or refractory ST. Enhancement of immune function is significant. PK parameters in children are similar to those in adults.

No significant financial relationships to disclose.
Advanced stage, elevated LDH, primary sites, but not adolescent (A) age (≥ 15 years) as risk factors for disease progression in childhood (C) and adolescent (A) mature B-NHL: Report of the FAB/LMB 96 international trial
Authors: Cairo M. S. , Sposto R. , Gerrard M. , Waxman I. , Goldman S. , Auperin A. , Pinkerton R. , Raphael M. , McCarthy K. , Perkins S. L. , Patte C.
Published: August 2020

10032

Background: We recently reported the results in C & A with low risk (group A), intermediate risk (group B) and high risk (group C) mature B-NHL treated on FAB/LMB 96 (Gerrard et al, Br J Haematol, 2008; Patte et al, Blood, 2007; Cairo et al, Blood, 2007, respectively). Adolescent age (15–21 yrs) has historically been considered to be an independent risk factor for poor outcome in subsets of mature B-NHL (Hochberg/Cairo et al, Br J Haematol, 2008; Burkhardt et al, Br J Haematol 2005; Cairo et al, Br J Haematol, 2003). Methods: We analyzed the EFS of all pts treated on FAB/LMB 96 and the following risk factors were significant in a univariate and Cox multivariate analysis: age (<15 vs ≥15 yrs), stage I/II vs III/IV, primary sites, LDH <2 vs ≥2 NL and histology (DLBCL vs BL/BLL). Results: 1111 pts (15%, 15–21 years) were treated with group A (N = 132), group B (N = 744), and group C (N = 235) therapy. Five year EFS (CI95) for all, A, B, C pts was 86% (84%,88%), 98% (93%, 100%), 87%% (84%, 89%), and 79%% (73%,84%), respectively. Age (≥15 yrs), LDH ≥2NL, stage III/IV, and BM+/CNS+ and histology were significant univariate risk factors for decreased EFS (P<0.045, <0.0001, <0.0001, <0.0001, and <0.0001 respectively). Multivariate analysis demonstrated age ≥15 yrs and DLBCL histology were no longer independent significant risk factors (p = .82 and 0.08, respectively), but LDH (RR 2.0, p = .001), stage III/IV (RR 3.8, p<0.001), and primary sites including PMBL (RR 4.0, p<.001) and BM+/CNS+ (RR 2.8, p<0.001) were independent significant risk factors for poorer outcome. Conclusions: With the use of modern short but intense FAB-LMB 96 therapy, adolescent age is no longer a poor risk factor in children with mature B-NHL. The independent risk factors identified in this study (stage, LDH, primary site) for decreased EFS in C & A mature B-NHL will form the basis of the next risk adapted international pediatric mature B-NHL trial.

No significant financial relationships to disclose.
Pilot study of haploidentical natural killer cell transplantation in childhood acute myeloid leukemia
Authors: Rubnitz J. , Inaba H. , Ribeiro R. , Pounds S. , Pui C. , Leung W.
Published: August 2020

10034

Background: In the setting of hematopoietic stem cell transplantation (HSCT), donor natural killer (NK) cells exhibit potent anti-leukemic effects without causing graft-versus-host disease. We hypothesized that the transplantation of purified haploidentical NK cells may be a safe and effective form of consolidation therapy that will reduce the risk of relapse among children with acute myeloid leukemia (AML) who are not treated with HSCT. In this pilot study, we assessed the safety, feasibility, and engraftment of NK cell infusions in 10 patients with AML in first remission.Methods: Patients received cyclophosphamide, 60 mg/kg on day -7; fludarabine, 25 mg/m2/day on days -6 through -2; and IL-2, 1 million units/m2, every other day for 6 doses starting on day -1. On day -1, the donor underwent apheresis and the product was purified for CD56+ cells by a two-step procedure. The entire purified product was infused on day 0.Results: The 10 patients had a median age of 2.5 years (range, 8 months to 21 years) and a median leukocyte count of 62 x 109/L (range, 4 to 487) at diagnosis. Leukemic cell genetic abnormalities included CBFβ-MYH11in 4 cases, RBM15-MKL1in 2 cases, MLL-ENL and MLL-AF9 in 1 case each; 2 cases had no detectable abnormalities. Patients received a median of 29 × 106/kg NK cells (range, 5 to 81 × 106/kg). All patients had detectable donor NK cells at one or more time points: donor NK cell chimerism ranged from 0% to 30% during the first 4 weeks after the infusions and was greater than 1% in 9 cases at week 1, 4 cases at week 2, 5 cases at week 3, and 3 cases at week 4. One patient had prolonged NK engraftment (189 days), but no non-hematological toxicity. Grade 3–4 non-hematological toxicity was limited to one respiratory viral infection and one episode of febrile neutropenia. Median length of hospitalization was 2 days (range, 0–3) and median time to neutrophil recovery was 12 days (range, 9–56). With a median follow-up time of 637 days, all patients remain in remission. Conclusions: Haploidentical NK cells can be safely administered to AML patients who are in remission. All patients demonstrated temporary engraftment, which may have antileukemic effects. We have recently opened a new trial to evaluate the efficacy of NK cell therapy in children in first remission of AML.

No significant financial relationships to disclose.
Overall survival trends in pediatric osteosarcoma patients over the past three decades
Authors: van Schie R. , Hagleitner M. , Hoogerbrugge P. , Flucke U. , Schreuder H. , te Loo M.
Published: August 2020

10041

Background: In the late seventies, the combination of chemotherapy and surgery, significantly improved survival of osteosarcoma patients. However, the chemotherapeutic drugs used for treatment of osteosarcoma patients has not significantly changed since then although surgery clearly improved further and adjuvant chemotherapy have been added. In this study, we retrospectively evaluated, whether after the introduction of neoadjuvant chemotherapy in the late seventies, further improvement in outcome of pediatric osteosarcoma patients was achieved. Methods: Since 1978 and 2008, 54 previously untreated pediatric patients with osteosarcoma were enrolled in six consecutive regimens of different agents and intensity. The main difference between the treatment protocols is the addition of either methothrexate or ifosfamide. Overall survival (OS) and event free survival (EFS) in relationship to the different treatment regimens was calculated using the Kaplan-Meier method. Significance of difference in outcome were calculated using the log rank test. Results: The 5-year EFS and OS of the whole group was 54.7% and 61.1%, respectively. There was no significant difference in outcome in patients treated between 1978 and 1993 (n = 18), as compared to patients treated after 1993 (n = 36, OS 47.1% vs 69.4%, p = 0.34). Of all treatment regimens used, OS was the highest in patients treated with cisplatin, doxorubicin, and methotrexate (OS after 5 year 70%). Multivariate analysis showed that EFS and OS significantly correlated with the histological response but not with one of the treatment regimens used. Conclusions: No significant improvement in overall survival has been accomplished in pediatric osteosarcoma patients during the past thirty years. Histological response after neoadjuvant chemotherapy was the most important prognostic factor.

No significant financial relationships to disclose.
Association of time to leukemia (TTL) in NOD/SCID mice with expression of apoptosis regulators in pediatric ALL
Authors: Meyer L. H. , Zangrando A. , Eckhoff S. M. , Queudeville M. , Vendramini E. , Basso G. , te Kronnie G. , Debatin K.
Published: August 2020

10042

Background: Acute lymphoblastic leukemia (ALL) is the most frequent malignant disease in childhood. Although advances in therapy have led to improved long term survival, relapse remains a major challenge. In a recent study we transplanted pediatric leukemia samples from newly diagnosed BCP-ALL patients into NOD/SCID mice. Time to leukemia (TTL) was analyzed for each patient sample as time from transplant to overt leukemia in the recipients. Patients whose leukemia cells engrafted rapidly showed a clearly inferior relapse free survival in contrast to patient samples with prolonged in vivo growth. Multivariate analysis showed an almost 45- fold increased risk for relapse in patients with short TTL. Methods: Gene expression profiles of ALL samples (N = 14) with short versus long TTL in the xenograft model were analyzed using a human whole genome array (Affymetrix U133 Plus 2.0) correlating gene expression values (relative expression) to the time from transplant to manifestation of leukemia in the NOD/SCID mice (TTL, in weeks) by quantitative traits analysis (QTA). Results: Among 5 genes significantly correlated (Spearman correlation, P < .0001) XIAP-associated factor 1 (XAF1) was found to be up-regulated in patients with long TTL. XAF1 abrogates the inhibitory effect of XIAP on caspase-3 thereby sensitizing for apoptosis. In accordance to this caspase-3 activation was also found to be up-regulated in patients with long TTL. Patient samples exhibiting a short time to overt leukemia in the xenotransplant model associated with poor relapse free survival showed down-regulated XAF1 and impaired caspase-3 activation leading to decreased apoptosis of the leukemia cells. Conclusions: Taken together, we used a novel approach directly correlating gene expression values to time from transplant to overt leukemia (TTL) identifying the apoptosis regulator XAF1 to be associated with poor outcome of patients. Small XIAP-inhibiting molecules can be used to substitute the lacking inhibitory effect of down-regulated XAF1 in these poor responding pediatric ALL patients.

No significant financial relationships to disclose.
Promoter DNA methylation of CD10 in infant acute lymphoblastic leukemia with MLL/AF4 fusion gene
Authors: Ikawa Y. , Sugimoto N. , Koizumi S. , Yachie A. , Saikawa Y.
Published: August 2020

10045

Background: Infant ALL displays distinct biologic and clinical features with a poor prognosis. The CD10-negative immunophenotype of infant ALL is a hallmark and provides a predictable signature of MLL rearrangements. While CD10 negativity reflects an earlier stage of B-cell development, complete IgH gene rearrangements (VDJH) show more mature IgH status. Discordance between immunophenotype and genotype of infant ALL suggests an aberrant process in immunophenotypic steps of differentiation or a secondary down-regulation of CD 10 expression associated with MLL rearrangements. We performed methylation analysis of full promoter regions of the CD10 gene to investigate epigenetic mechanisms responsible for CD10 negativity. Methods: CD10-negative infant ALL with MLL/AF4, CD10-positive infant ALL with germ-line MLL, CD10-positive pre-B ALL cell line, infant AML (M5) with MLL/AF9 and pediatric AML (M2) with AML1/ETO were analyzed for VDJH status and methylation of CD10 gene promoters. Results: Three of 4 cases with infant ALL revealed complete rearrangements of VDJH gene with productive joints. Bisulfite sequencing of CD 10 type 1 and 2 promoters identified more than 84% of methylated CpG dinucleotides in all three CD10-negative infant ALL cases with MLL/AF4. The CpG dinucleotides distributed in the clusters of putative Sp 1 binding sites and functionally active regulatory regions of the promoters were fully methylated. In contrast, none or a few of the CpG dinucleotides were methylated in the CD10-positive ALL, AML (M5) with MLL/AF9 or AML (M2) with AML1/ETO. Conclusions: Structural evidence of dense methylation in the CD 10 gene promoter suggested that methylated transcription factor binding sites contribute to CD10 silencing as an epigenetic mechanism. [Table: see text]

No significant financial relationships to disclose.
How could improvement in the management of T-cell acute lymphoblastic leukemia be achieved? Experience of Princess Nourah Oncology Center, National Guard Hospital, Jeddah, Saudi Arabia
Authors: Khattab T. M. , Jastaniah W. A. , Felimban S. K. , Elemam N. , Abdullah K. , Ahmed B.
Published: August 2020

10048

Background: T-cell acute lymphoblastic leukemia (T-ALL) is representing 10–15% of pediatric ALL. The use of more intensive treatments and risk adapted therapy have significantly improved the outcome of patients with T-ALL and event-free survival rate of 60–70% are now reported in children. Our published data showed that T-ALL phenotype patients fared poorly with 5 year survival of 27% versus 83% for precursor B-ALL (Recent Advances Research Update: 2006, 7; 1, P 51–56). Objectives: We reviewed all patients diagnosed with T-ALL to assess risk classification according to NCI criteria, type of therapy received, overall survival and causes of mortality. Methods: Retrospective review of all patients files diagnosed with T-ALL from 1989 until now with data collection including; sex, age, white cell count (WBCs), CNS disease, type of protocol used, length of survival, overall survival, cause of death (toxic, disease). Results: Over the last 20 years, T-ALL cases registered were 52/460 (11%) of all ALL cases, Male:Female ratio 42:10 (4.2:1), median age 7 year (range: 1.5–12 yrs). Median WBCs 50,000/Cmm (range: 1.500–619,000/Cmm) and positive CNS at diagnosis 10/52 (20%). NCI risk classification criteria showed SR 24/52 (46%) and HR 28/52 (54%). Protocols used were UKALL ( n = 21; 3 UKALL X-B, 4 UKALL X-D, 10 UKALL XI and 4 MRC-97 ). BFM (n = 8); and CCG 1961 (n = 23). Overall survival 27/52 (52%) and 25 pts. died (48%); 15 secondary to disease recurrence (9 on UKALL, 4 BFM, 2 CCG 1961); 4 during induction, 1 fulminant hepatic failure, 1 tumor lysis syndrome, and 4 due to toxicities (mucormycosis, staphylococcal toxic shock syndrome, CMV pneumonia, pseudomonas sepsis). Survival for different regimen; UKALL: 5/21=31%, BFM: 4/8=50%, CCG: 18/23=78%, while overall cohort survival 52%. Mean length of survivors 4 year (range 4–140 month) and mean length for non-survivors 1 year (range 0.1–40 months). Conclusions: This review showed the improvement of T-ALL survival from 27% to 56%. Using augmented therapy based on CCG1961 was associated with better outcome. Further risk and response stratification in addition to intensification of therapy for T-cell ALL in our center may prove to be beneficial. Therapy remains an important prognostic factor.

No significant financial relationships to disclose.
Effect of selenium on anthracycline induced cardiotoxicity in children that treated for cancer: Correlation with pro-brain natriuretic peptide levels
Authors: Tacyildiz N. , Ucar T. , Ozyoruk D. , Yavuz G. , Unal E. , Atalay S. , Ozelci Kavas G. , Aribal P. , Dincaslan H. , Cavdar A.
Published: August 2020

10061

Background: High cumulative doses of an anthracyclin (300–500 mg/m2) are used in the several treatment protocols of children with Cancer. Probrain natriuretic peptit (Pro-BNP), is relased by cardiac cells and elevated even before overt cardiac distress symptoms. Selenium, is an antioxidant which its’ absence cause cardiomyopathy in people living in the poor selenium soil area. Aim 1: Assesment of anthracycline-induced cardiotoxicity with Pro-BNP levels, correlated with echo-cardiographic (ECHO) findings. Aim 2: Determine possible effects of selenium levels and supplemantation on cardiac toxicity. Methods: Plasma levels of Pro-BNP have been measured in 58 pediatric cancer patients (leukemias, lymphomas,solid tumors; 38 boys, 20 girls; between 2–18 years, median:12) after completed their anthracycline containing regimens. Serum selenium levels examined in 12 patients (six patients were with high and other six with normal pro-BNP levels). Three of four Patients with low level of selenium showed cardiac failure according to ECHO and supplemanted with selenium besides digoxine, ACE inhibitors. Results: Eleven patients have found with high pro-BNP levels (120–8022 pg/ml; normal: lower than 120 pg/ml).Six of these patients (with 170–8022 pg/ml, median:798pg/ml pro-BNP) and other six patients with normal levels of pro-BNP (10–74pg/ml, median: 67pg/ml) examined for their serum selenium levels. All patients with normal pro-BNP levels have found in normal levels of selenium levels (71–150 μg/L,median:125 μg/L). Four patients in high pro-BNP group showed low levels of selenium (52–129 μg/L; median:67.5 μg/L). Since three of that four patients have cardiac failure, treated accordingly and supplemented with 100 μg/day selenium to maintain normal levels. During follow-up periods of 27; 8 and 2 months, all 3 patients are doing well with normal ECHO finding. Two patients reached normal Pro-BNP levels while one of them has 80 % decrease. Conclusions: Serum Pro-BNP levels can be used as a marker for anthracycline toxicity and as follow-up marker for protective agents. Selenium suplemantation may have a potential role to protect and/or overcome the difficulties related anthracyclin-induced toxicities.

No significant financial relationships to disclose.
Endocrine complications in children treated for medulloblastoma or ependymoma using radiation therapy. Outcomes in the CT-planning era
Authors: Bahl G. , Urbach S. , Bartels U. , Hodgson D. C. , Millar B. , Parent A. , Le L. , Awrey S. , Laperriere N.
Published: August 2020

10064

Background: The purpose of this study is to determine the frequency of late endocrine complications following radiation therapy (RT) in children treated for medulloblastomas or ependymomas. Methods: Seventy children with medulloblastoma or ependymoma were treated using RT from June 2000 to June 2005 at our institute. Median age at diagnosis was 6 years (range 1–17), and 52 (74%) were boys. Forty-eight patients (69%) had medulloblastomas and 22 (31%) had ependymomas. Twenty-two received highly conformal RT to the tumor bed alone (focal RT: median dose 54 Gy, range 54–59.4), 24 received low dose cranio-spinal RT (CSI: median dose 23.4 Gy) followed by a boost to the post fossa/tumor bed (median 30.6 Gy), and 24 patients received high dose CSI (median 36 Gy) followed by a boost (median 18 Gy). Only two of the 22 children with ependymomas received CSI. All patients underwent CT-based planning and were treated using conventional fractionation; 58 (83%) also received chemotherapy. None of the children had documented endocrinopathy prior to diagnosis. Results: After a median follow-up of 65.3 months, the 5-yr PFS and OS was 70% and 75% for children with medulloblastomas, and 54% and 84% for patients with ependymomas, respectively. Thirty-five children developed evidence of endocrinopathy (Growth hormone deficiency (GHD): 31, hypothyroidism (HPT): 23, precocious puberty (PP): 6, gonadotropin deficiency: 3, ACTH deficiency: 2, and diabetes insipidus: 2). The 5-yr cumulative incidence (CI) of endocrinopathy was 71% for the children treated with CSI vs. 18% for those treated with focal RT (Gray's test p-value = 0.004). The median time to development of endocrinopathy was 38 months for the patients who had CSI. For these children the 5-yr CI was 68% for GHD, 52% for HPT, and 16% for PP. There was no significant difference in the incidence of endocrinopathy for patients treated with low dose vs. high dose CSI. Conclusions: The 5-yr CI of endocrine toxicity in children treated with cranio-spinal RT is 71% (median time to development: 38 months), which is significantly higher than in children treated with focal RT. All children treated for medulloblastomas or ependymomas require long-term surveillance and close monitoring for the development of endocrinopathies.

No significant financial relationships to disclose.
Safety and antitumor activity of 3-weekly anti-EpCAM antibody adecatumumab (MT201) in combination with docetaxel for patients with metastatic breast cancer: Results of a multicenter phase Ib trial
Authors: Sebastian M. , Hanusch C. , Schmidt M. , Marschner N. , Oruzio D. , Wolf C. , Reinhardt C. , Eiermann W. , Rüttinger D. , Schuler M.
Published: August 2020

1009

Background: The fully human IgG1 antibody adecatumumab (MT201) binds to the epithelial cell adhesion molecule (EpCAM), which is expressed in over 90% of breast cancers and has been associated with poor prognosis. Data from a previous phase II study in metastatic breast cancer (MBC) indicated that single agent MT201 could prolong progression-free survival in a subset of patients with high EpCAM expression. This study tested safety and tolerability of MT201 treatment in combination with standard docetaxel. Methods: Relapsed or primary refractory, EpCAM-positive MBC patients were treated with docetaxel (100 mg/m2 q21d) in combination with MT201 (dose levels 180 mg/m2, and 550 mg/m2 q21d). A loading dose of 100 mg/m2 and 300 mg/m2, respectively, was administered on day 1 and 7. Patients were grouped into high- and low-level EpCAM expression. Primary objectives were safety and tolerability; anti-tumor activity according to RECIST was a secondary objective. Results: A total of 22 patients with a median of 3 prior chemotherapy lines were enrolled. Most frequent grade 3/4 adverse events (AE) in all patients were leucopenia (90%), neutropenia (77%), lymphopenia (68%), and diarrhea (23%). No evidence for aggravation of grade 3/4 toxicities typically associated with docetaxel was found. The dose level 550 mg/m2 q21d has been determined as MTD in combination with 100 mg/m2 q21d docetaxel. The overall response rate (CR/PR; RECIST) and clinical benefit rate (CR/PR and SD>24wks) in all evaluable patients was 24% and 41%, respectively. Patients with high EpCAM expression showed a response rate of 43%, whereas patients with low EpCAM expression had a response rate of 10%. Median time-to-progression (TTP) in all evaluable patients was 165 days. Conclusions: Combining MT201 with docetaxel for the treatment of MBC appears to be safe and feasible. The DLT of this combination were short and manageable episodes of grade 3 diarrhea. The response rate and TTP observed in this heavily pre-treated population is encouraging and warrant further development of MT201/chemotherapy combinations in patients with tumors of high EpCAM target level.

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Gemcitabine plus docetaxel versus docetaxel in patients (pts) with HER2-negative locally advanced or metastatic breast cancer (MBC): A randomized phase III study
Authors: Nielsen D. L. , Langkjer S. T. , Bjerre K. , Cold S. , Stenbygaard L. , Soerensen P. G. , Kamby C.
Published: August 2020

1015

Background: Gemcitabine (G), either as a single agent or in combination with taxanes, has demonstrated efficacy in MBC in phase II and III studies. We conducted a phase III study to compare time to progression (TTP) of G plus docetaxel (T) versus (vs.) T alone. The secondary endpoints included overall survival (OS), overall response rate (ORR), and toxicity. Methods: Females with HER-2-negative locally advanced or MBC and a WHO performance status ≤ 2 were randomized to GT (G 1,000mg/m2 day 1 + 8; T 75mg/m2 day 1) or T (100mg/m2 day 1) every 21 days. Pts were previously untreated, had prior anthracycline-based (neo)adjuvant chemotherapy or had received a single prior anthracycline-bsed chemotherapy regimen for MBC. Time-to-event endpoints were estimated using the Kaplan-Meier method, and the log-rank test was applied for comparisons between regimens. The planned sample size was 254 evaluable pts with α I and β of 0.05 and 0.90, respectively. Results: A total of 336 pts were randomized (170 GT; 166 T), data from one centre are yet missing and the present evaluation is based on data from 306 pts (155 GT; 151 T). The pts had a median age of 58 years in both regimens; range 36–73 years and 30–74 years, respectively. The median TTP was 7.5 months for the GT regimen vs. 6.5 months for the T regimen. The GT arm demonstrated an ORR of 44% vs. 38% in the T arm with 4 and 3 % complete responses, respectively. The OS was 13.4 vs. 13.2 months in the GT and T arm, respectively. Hematologic toxicity was common, especially grade 3–4 neutropenia (GT = 69%; T = 61%); infection was reported in 22 and 20% of the pts, respectively (none of the pts received G-CSF). The most commonly reported non-hematologic toxicities of grade 3–4 included mucositis (GT = 2%; T = 5%), diarrhea (GT = 4%; T = 7 %), fatigue (GT = 6%; T = 11%), oedema (GT = 10%; T = 3%), and peripheral neuropathy (GT = 9%; T = 28%). Conclusions: Preliminary data of GT as first- or second-line chemotherapy demonstrates a TTP advantage among HER-2-negative pts with advanced breast cancer. Updated results and proper statistical analyses will be presented.

No significant financial relationships to disclose.
Relevance of serum HER2 extracellular domain (sECD) in EGF30008, a study of letrozole ± lapatinib in patients (pts) with hormone-receptor positive (HR+) metastatic breast cancer (MBC)
Authors: Platek G. T. , Koehler M. , Gagnon R. , O'Rourke L. , Maltzman J. D. , Press M. , Johnston S. , Pegram M.
Published: August 2020

1019

Background: Elevated baseline sECD (BsECD) correlates weakly with HER2 overexpression (HER2+). HR+ MBC. Lapatinib benefit was reported in pts with HER2+ tumors irrespective of BsECD status; BsECD status did not predict benefit for HER2- negative (HER2-ve) tumors. sECD levels and their predictive and prognostic value for progression-free survival (PFS) were further examined in a randomized, phase III trial of letrozole ± lapatinib. Methods: Pts (n=1286) with HR+ MBC were randomized to letrozole with placebo (P) or lapatinib (L). HER2 status was evaluated by FISH or IHC in archived tissue. sECD was measured by ELISA at baseline (n=1102 available samples), and every 4 wk. Pts were considered sECD+ if serum sECD was >15 ng/ml. Results: BsECD was positive in 14% (125/894) and 42% (87/208) of pts with HER2-ve and HER2+ tumors, respectively. Correlation between BsECD and FISH was weak but significant in HER2+ pts (R=0.35, p<0.0001) but not in HER2-ve pts (R=0.03, p=0.362). Unlike for HER2+ tumors, BsECD+ did not predict benefit in PFS from L in pts with HER2-ve tumors. HR: Hazard Ratio In pts with HER2- ve tumors, median ECD levels were stable in the P arm but increased slightly (4 ng/mL) in the L arm. In the HER2+ group, median levels in the P arm declined (3.5 ng/mL) but increased at 4 wk in L arm (3.4 ng/mL) and were stable thereafter. Conversion from sECD-ve to sECD+ was observed in both arms but did not correlate with outcome or provide predictive value. Data related to ECD status conversion will be reported. Conclusions: BsECD+ status correlates with HER2+ tumor status and may predict L benefit but BsECD+ status did not predict benefit in pts with HER2-ve tumors. On therapy changes in median sECD were small. Conversion from BsECD-ve to sECD+ did not predict L benefit and we could not confirm that evaluation of on treatment ECD status may help treatment decision.

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Pertuzumab monotherapy following trastuzumab-based treatment: Activity and tolerability in patients with advanced HER2- positive breast cancer
Authors: Cortés J. , Baselga J. , Petrella T. , Gelmon K. , Fumoleau P. , Verma S. , Pivot X. , Ross G. , Szado T. , Gianni L.
Published: August 2020

1022

Background: Pertuzumab binds to the dimerization epitope of the HER2 receptor, inhibits HER dimerization and signal transduction, and induces ADCC. In 2 cohorts of pts (n = 66) with HER2-positive metastatic breast cancer which had progressed during trastuzumab therapy after ≤3 lines of chemotherapy with or without trastuzumab, pertuzumab plus trastuzumab has been shown to be active (CR 7.6%, PR 16.7%, SD ≥6/12 25.8%) (Gelmon et al. ASCO 2008, Abs 1026). To assess the activity of pertuzumab monotherapy in this clinical setting, the protocol was amended to include a 3rd cohort of pts. Methods: Pt selection was not changed except that ≥1 month between the last dose of trastuzumab and study start was required. Pts received pertuzumab monotherapy. If the tumor failed to respond or responded and then progressed, trastuzumab could be added to pertuzumab. 27 pts were to be recruited to ensure that ≥24 were fully evaluable for objective response and stabilization of disease ≥6 months. Standard 21-day schedules of the antibodies were given. Results: 29 pts were recruited. Tolerability was good: the major adverse events were mild diarrhea and rash with no clinical cardiac events. To date, 2 responses have been reported, and several pts have ongoing stabilization of disease. 14 pts have received trastuzumab plus pertuzumab following inadequate response (or response then relapse) on pertuzumab monotherapy. Of these 14, 2, having progressed during trastuzumab, failed to respond to pertuzumab monotherapy but underwent confirmed response when trastuzumab was added to the pertuzumab –possibly the first report of such a phenomenon and providing good evidence of an enhanced effect when the antibodies are combined. Updated results will be presented. Conclusions: Pertuzumab monotherapy is active against HER2-positive breast cancer which has progressed during trastuzumab-based therapy. The combination of the two antibodies appears to be more active than either antibody alone. The combination is also active in patients that had failed both antibodies given separately. In clinical studies, the use of the two antibodies combined is justified.

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Tumor phenotype and characteristics of metastatic brain involvement in breast cancer patients: Potential clinical consequences
Authors: Palacova M. , Svoboda M. , Fabian P. , Ondrova B. , Grell P. , Jana G. , Princ D. , Radova L. , Slampa P. , Vyzula R.
Published: August 2020

1026

Background: Central nervous system metastases (CNS) occur in about 20% of patients with breast cancer. Despite the fact that most of these patients die within a few months, substantial subgroup may survive a year or more. Methods: We performed this study on cohort of 187 breast cancer patients who developed CNS metastases to identify relations between the tumor phenotype and the incidence and characteristics of CNS dissemination, response to the local therapy and overall survival since the development of metastases in brain (OScns). Results: The incidence of monitored phenotypes and other data are included in the table. An unambiguous dependence between the tumor's phenotype and the following attributes has been proven: a) interval between the disease diagnosis and the 1st metastatic event (DFS); b) interval between the 1st metastatic event and the metastases in the CNS (TTPcns); c) characteristics of CNS dissemination. The CNS dissemination was the most extensive in patients with HER-2+ tumors in comparison with HER-2 negat. carcinomas. Surprisingly, patients with triple-negative tumors had the minimal metastatic involvement of CNS defined by size and number of lesions. Phenotype did not correlate with local response to therapy and OScns. The OScns has been significantly prolonged by neurosurgery (median 13,8 vs 2,4 months, p<0.0001) and when the effective local treatment was followed by system treatment (6,1 vs 1,9 months, p<0.0001). Conclusions: Our study has confirmed the dependence between primary tumor phenotype and the time of incidence of metastatic brain affection and character of their spread. Our results encourage the inclusion of CNS imaging examination (CT or MRI) into the regular restaging of patients with HER2 positive and triple-negative primary breast cancer, who are at high risk for early development of CNS dissemination. Especially in case of triple-negative tumors, there is higher probability for early detection of limited CNS metastatic involvement.

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No significant financial relationships to disclose.
Complications associated with erythropoietin stimulating agents (ESAs) in patients with metastatic breast cancer: A surveillance, epidemiology, and end results (SEER)–Medicare study
Authors: Chavez-Macgregor M. , Fang S. , Srokowski T. P. , Hortobagyi G. N. , Giordano S. H.
Published: August 2020

1034

Background: Results of recent clinical trials suggest that the use of ESAs is associated with adverse outcomes. ESAs increase the risk for thrombotic events and have the potential of decreasing survival. Guidelines recommend the use of ESAs in patients with chemotherapy-induced anemia being treated with non curative intent. In this population-based study, we sought to evaluate the thromboembolic effects associated with the use of ESAs in patients receiving chemotherapy for metastatic breast cancer. Methods: Retrospective cohort study using the SEER-Medicare linked database. Patients with stage IV breast cancer diagnosed from 1995–2002, who were 66 and older, were treated with chemotherapy, and had full coverage of Medicare A and B were identified. Patients with end stage renal disease were excluded. ICD-9 and HCPCS codes were used to identify the use of ESAs, chemotherapy, comorbidities, and complications of therapy. Analyses were conduced using descriptive statistics, logistic regression, and Cox proportional hazard models. Results: 1411 women were included, 519 (36.8%) received ESAs and 892 (63.2%) did not; median age was 73 and 74 years old respectively. Median time from diagnosis to first ESA dose was 6 months, median number of ESAs doses was 8.5. In univariate analysis, patients receiving ESAs had higher rates of MI/CAD (38% vs 32.9% p = 0.051), thrombosis (32.4% vs 23.2% p = 0.0002), phlebitis (21.4% vs 12.6% p < 0.0001), and transfusion (37.76% vs 19.4% p < 0.0001), with no difference in the rate of stroke or pulmonary embolism. Multivariate analysis showed HR for MI/CAD 1.29 (1.01–1.66); thrombosis 1.5 (1.116–1.93), phlebitis 1.79 (1.32–2.43), and transfusion 2.65 (2.05–3.43). Significant dose effect was evident for the thrombosis and phlebitis outcomes for patients receiving more than 5 ESAs doses. Conclusions: The use of ESAs in patients with metastatic breast cancer increases the risk of thrombosis and phlebitis, with evidence of a dose-dependent effect. Patients receiving ESAs were more likely to have blood transfusions. These data support current practice of using ESAs for minimum necessary time to reduce risk of complications.

No significant financial relationships to disclose.
In vitro activity of sorafenib against imatinib- and sunitinib-resistant kinase mutations associated with drug-resistant GI stromal tumors
Authors: Heinrich M. C. , Carden R. , Griffith D. , Liang C. , Marino-Enriquez A. , McKinley A. , Presnell A. , Fletcher J. A.
Published: August 2020

10500

Background: Most gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor alpha (PDGFRA) kinases, which are targets of imatinib (front-line therapy) or sunitinib (second-line therapy). Resistance to imatinib (IM) or sunitinib (SU) is commonly associated with the acquisition of secondary kinase mutations. In phase II studies, sorafenib (SOR), which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in GIST patients after failure of IM and SU. We evaluated the in vitro activity of SOR against IM and/or SU resistant kinases. Methods: Kinase mutants were biochemically profiled for SOR, SU, and IM sensitivity by measuring inhibition of kinase phosphorylation after drug treatment in mutant-expressing CHO cells. We also tested the biochemical and cellular activity of SOR and IM against GIST cells derived from IM-resistant tumor clones. Results: SOR had superior potency to IM against IM-resistant KIT secondary mutations involving the ATP binding pocket (V654A, T670I) and the activation loop (D816H, D820A/G, N822K, Y823D). SOR and SU had similar potency against IM-resistant KIT secondary mutations involving the ATP binding pocket. In contrast, SOR had markedly increased potency, compared to SU, against IM-resistant KIT activation loop mutations. Both SOR and SU were more potent than IM against the isolated KIT exon 9 mutation. To confirm these observations in a GIST cellular context, we tested the relative potency of IM and SU against two previously described IM-resistant GIST cell lines (GIST430: exon 11 + V654A, GIST48: exon 11 + D820A). SOR was significantly more potent than IM against KIT in these cell lines. This also correlated with enhanced inhibition of downstream signaling pathways and cellular proliferation. Conclusions: SOR has superior in vitro potency compared with IM or SU against a panel of GIST-relevant mutant kinases. Notably, SOR, unlike SU, is active against most IM-resistant secondary mutations involving the KIT activation loop. Based on these results, we hypothesize that SOR might have superior clinical activity to SU in the setting of imatinib-resistant GIST and should be further evaluated for clinical efficacy in the second-line setting.

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