294 results on '"Susan M. Blaney"'
Search Results
2. Figure S2 from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
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Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade
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Figure S2 supporting expression and localization of ZRfus in the mouse IUE model.
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- 2023
3. Data from ZFTA–RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
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Stephen C. Mack, Benjamin Deneen, Kelsey C. Bertrand, Claudia L. Kleinman, Nada Jabado, Joanna Yi, Richard J. Gilbertson, Sameer Agnihotri, Kristian W. Pajtler, Donald W. Parsons, Susan M. Blaney, Murali M. Chintagumpala, Thomas F. Westbrook, Irtisha Singh, H. Courtney Hodges, Charles Y. Lin, Stefan M. Pfister, Daisuke Kawauchi, Felix Sahm, Luz A. De León, Peter R. Wang, Madeline Ngo, Sarah G. Injac, Baoli Hu, Robert Kupp, Kathleen Kong, Kristen L. Karlin, Calla Olson, Yuen San Chan, Ann-Catherine J. Stanton, Brian J. Golbourn, Dana Tlais, Alisha Kardian, Minerva Solis, Austin J. Stuckert, Bryan Rivas, Selin Jessa, Hsiao-Chi Chen, Srinidhi Varadharajan, Yanhua Zhao, and Amir Arabzade
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More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks.Significance:Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA–RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing.This article is highlighted in the In This Issue feature, p. 2113
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- 2023
4. Data from A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921)
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Brenda J. Weigel, Susan M. Blaney, Stacey L. Berg, Stephan D. Voss, Mark Krailo, Donald A. Barkauskas, David Hall, Malcolm A. Smith, Peter J. Houghton, Richard B. Lock, Hernan Carol, Stephanie L. Safgren, Joel M. Reid, David T. Teachey, Elizabeth Fox, and Yael P. Mossé
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Purpose:Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816).Patients and Methods:Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle.Results:A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed.Conclusions:Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
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- 2023
5. Supplementary Data from Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity
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Stacey L. Berg, Madhuri Hegde, Shannon L. Delaney, Susan M. Blaney, Alison A. Bertuch, Albert Ribes-Zamora, M. Eileen Dolan, Linna Zhang, Debananda Pati, Gaye Jenkins, and Terzah M. Horton
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Supplementary Data from Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity
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- 2023
6. CCR Translation for This Article from A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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Julie R. Park, Peter C. Adamson, Brenda Weigel, Alice Chen, Darrell J. Yamashiro, Ashish M. Ingle, Charlotte Ahern, Sylvain Baruchel, Joel M. Reid, Scott Borinstein, Susan M. Blaney, and Julia Glade Bender
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CCR Translation for This Article from A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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- 2023
7. Supplemental Figure 1 from A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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Susan M. Blaney, Brenda Weigel, Helen Chen, L. Austin Doyle, Peter J. Houghton, Darcy A. Krueger, Carol A. Mercer, George Thomas, Charlotte Ahern, Joel M. Reid, Alexander A. Vinks, Lars M. Wagner, John P. Perentesis, and Maryam Fouladi
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Supplemental Figure 1. Graph of IMC-A12 trough serum concentrations versus time.
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- 2023
8. Data from Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)
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Yael P. Mossé, Brenda J. Weigel, Susan M. Blaney, Peter C. Adamson, Elizabeth Fox, Stacey L. Berg, Keith Wilner, Frank M. Balis, Charles G. Minard, David C. Hall, Stephan D. Voss, and Jennifer H. Foster
- Abstract
Purpose:Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration.Patients and Methods:Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study.Results:The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count.Conclusions:Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity.See related commentary by Schulte and Eggert, p. 3507
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- 2023
9. Data from A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report
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Susan M. Blaney, Frank M. Balis, Diana Stempak, Brenda Weigel, Michael Burke, Julia Glade Bender, Ashish M. Ingle, Peter C. Adamson, Sylvain Baruchel, Elizabeth Fox, AeRang Kim, and Brigitte C. Widemann
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Purpose: To determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of sorafenib in children with refractory extracranial solid tumors and evaluate the tolerability of the solid tumor MTD in children with refractory leukemias.Experimental Design: Sorafenib was administered orally every 12 hours for consecutive 28-day cycles. Pharmacokinetics (day 1 and steady-state) and pharmacodynamics were conducted during cycle 1.Results: Of 65 patients enrolled, 60 were eligible. In the solid tumor cohort (n = 49), 4 of 6 patients experienced a DLT [hypertension, pain, rash/urticaria, thrombocytopenia, alanine aminotransferase (ALT)/aspartate aminotransferase (AST)] at the starting dose (150 mg/m2/dose) which resulted in de-escalation to 105 mg/m2/dose. After eligibility criteria modification and dose re-escalation, the MTD was 200 mg/m2/dose for solid tumors and 150 mg/m2/dose for leukemias. Sorafenib exposure was highly variable between patients but was within the ranges reported in adults. The apparent sorafenib clearance increased with patient age. Diarrhea, rash, fatigue, and increased ALT/AST were the most common sorafenib-related toxicities. Stable disease for 4 or more cycles was observed in 14 solid tumor patients, and 2 patients with acute myeloid leukemia (AML) and FLT3 internal tandem duplication (FLT3ITD) experienced a decrease in bone marrow blasts to less than 5%.Conclusions: The recommended phase II dose of sorafenib administered every 12 hours continuously for children with solid tumors is 200 mg/m2/dose and 150 mg/m2/dose for children with leukemias. Sorafenib toxicities and distribution in children are similar to adults. The activity of sorafenib in children with AML and FLT3ITD is currently being evaluated, and a phase II study for select solid tumors is ongoing. Clin Cancer Res; 18(21); 6011–22. ©2012 AACR.
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- 2023
10. Data from Poly(ADP-ribose) polymerase inhibitor ABT-888 potentiates the cytotoxic activity of temozolomide in leukemia cells: influence of mismatch repair status and O6-methylguanine-DNA methyltransferase activity
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Stacey L. Berg, Madhuri Hegde, Shannon L. Delaney, Susan M. Blaney, Alison A. Bertuch, Albert Ribes-Zamora, M. Eileen Dolan, Linna Zhang, Debananda Pati, Gaye Jenkins, and Terzah M. Horton
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The poly(ADP-ribose) polymerase (PARP) inhibitor ABT-888 potentiates the antitumor activity of temozolomide (TMZ). TMZ resistance results from increased O6-methylguanine-DNA methyltransferase (MGMT) activity and from mismatch repair (MMR) system mutations. We evaluated the relative importance of MGMT activity, MMR deficiency, nonhomologous end joining (NHEJ), and PARP activity in ABT-888 potentiation of TMZ. MMR-proficient and MMR-deficient leukemia cells with varying MGMT activity, as well as primary leukemia samples, were used to determine TMZ IC50 alone and with ABT-888. ABT-888 effectively inhibited PARP activity and enhanced TMZ growth inhibition in most leukemia cells. ABT-888 potentiation was most effective in MMR-deficient cells with low MGMT activity [potentiation factor (PF) = 21]. ABT-888 also potentiated TMZ activity in MMR-deficient cells with elevated MGMT activity. Unexpectedly, ABT-888 also enhanced TMZ activity in MMR-proficient cells (PF = 3–7). ABT-888 potentiation was unrelated to NHEJ activity. ABT-888 potentiated TMZ (PF = 2–5) in two of four acute myeloid leukemia patient samples but showed little potentiation in primary acute lymphoblastic leukemia. In conclusion, although ABT-888 potentiation of TMZ was most pronounced in MMR-deficient cells with low MGMT activity, neither MMR proficiency nor MGMT overexpression completely abrogated ABT-888 potentiation of TMZ. [Mol Cancer Ther 2009;8(8):2232–42]
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- 2023
11. Data from A Phase I Trial and Pharmacokinetic Study of Aflibercept (VEGF Trap) in Children with Refractory Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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Julie R. Park, Peter C. Adamson, Brenda Weigel, Alice Chen, Darrell J. Yamashiro, Ashish M. Ingle, Charlotte Ahern, Sylvain Baruchel, Joel M. Reid, Scott Borinstein, Susan M. Blaney, and Julia Glade Bender
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Purpose: Aflibercept is a novel decoy receptor that efficiently neutralizes circulating VEGF. A pediatric phase I trial was conducted to define the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of aflibercept.Experimental Design: Cohorts of three to six children with refractory solid tumors received aflibercept intravenously over 60 minutes every 14 days, at 2.0, 2.5, or 3.0 mg/kg/dose. PK sampling and analysis of peripheral blood biomarkers were conducted with the initial dose.Results: Twenty-one eligible patients were enrolled; 18 were fully evaluable for toxicity. One of six patients receiving 2.0 mg/kg/dose developed dose-limiting intratumoral hemorrhage and two of six receiving 3.0 mg/kg/dose developed either dose-limiting tumor pain or tissue necrosis. None of the six patients receiving 2.5 mg/kg/dose developed DLTs, defining this as the MTD. The most common non-DLTs were hypertension and fatigue. Three patients with hepatocellular carcinoma, hepatoblastoma and clear cell sarcoma had stable disease for >13 weeks. At the MTD, the ratio of free-to-bound aflibercept serum concentration was 2.10 on day 8 but only 0.44 by day 15. A rapid decrease in VEGF (P < 0.05) and increase in placental growth factor (PlGF; P < 0.05) from baseline was observed in response to aflibercept by day 2.Conclusions: The aflibercept MTD in children of 2.5 mg/kg/dose every 14 days is lower than the adult recommended dose of 4.0 mg/kg. This dose achieves, but does not sustain, free aflibercept concentrations in excess of bound. Tumor pain and hemorrhage may be evidence of antitumor activity but were dose-limiting. Clin Cancer Res; 18(18); 5081–9. ©2012 AACR.
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- 2023
12. Supplemental Table 1 from A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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Susan M. Blaney, Brenda Weigel, Helen Chen, L. Austin Doyle, Peter J. Houghton, Darcy A. Krueger, Carol A. Mercer, George Thomas, Charlotte Ahern, Joel M. Reid, Alexander A. Vinks, Lars M. Wagner, John P. Perentesis, and Maryam Fouladi
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Supplemental Table 1. IMC-A12 trough serum concentrations during cycle 1 and cycle 2
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- 2023
13. Supplementary Figure 2B from A Phase I Trial and Pharmacokinetic Study of Sorafenib in Children with Refractory Solid Tumors or Leukemias: A Children's Oncology Group Phase I Consortium Report
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Susan M. Blaney, Frank M. Balis, Diana Stempak, Brenda Weigel, Michael Burke, Julia Glade Bender, Ashish M. Ingle, Peter C. Adamson, Sylvain Baruchel, Elizabeth Fox, AeRang Kim, and Brigitte C. Widemann
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PDF file, 39K, Plasma soluble VEGFR2 (A) and Placental Growth Factor (B) concentrations prior to therapy (baseline) and at the end of cycle 1 (steady state).
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- 2023
14. Data from A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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Susan M. Blaney, Brenda Weigel, Helen Chen, L. Austin Doyle, Peter J. Houghton, Darcy A. Krueger, Carol A. Mercer, George Thomas, Charlotte Ahern, Joel M. Reid, Alexander A. Vinks, Lars M. Wagner, John P. Perentesis, and Maryam Fouladi
- Abstract
Purpose: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors.Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle.Results: Thirty-nine patients, median age 11.8 years (range, 1–21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2,946 ng • h/mL (range, 937–5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245–3,675).Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. Clin Cancer Res; 21(7); 1558–65. ©2014 AACR.
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- 2023
15. Supp Table 1 from Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)
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Yael P. Mossé, Brenda J. Weigel, Susan M. Blaney, Peter C. Adamson, Elizabeth Fox, Stacey L. Berg, Keith Wilner, Frank M. Balis, Charles G. Minard, David C. Hall, Stephan D. Voss, and Jennifer H. Foster
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Supp Table 1
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- 2023
16. Supplemental Materials from A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921)
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Brenda J. Weigel, Susan M. Blaney, Stacey L. Berg, Stephan D. Voss, Mark Krailo, Donald A. Barkauskas, David Hall, Malcolm A. Smith, Peter J. Houghton, Richard B. Lock, Hernan Carol, Stephanie L. Safgren, Joel M. Reid, David T. Teachey, Elizabeth Fox, and Yael P. Mossé
- Abstract
Figure S1. Percentage of huCD45+ cells in blood (cardiac bleed) of engrafted mice at treatment initiation, then on Days 7, 21 and 42 for control (light grey), mice treated with Schedule A (7 days, BID, dark grey) or Schedule B (5 days BID X 3, black). The hatched bar corresponds to day 0. Medians and ranges are depicted. Figure S2. Percentage of huCD45+ cells in spleens of engrafted mice at treatment initiation, then on Days 7, 21 and 42 for control (light grey), mice treated with Schedule A (7 days, BID, dark grey) or Schedule B (5 days BID X 3, black). The hatched bar corresponds to day 0. Medians and ranges are depicted. Figure S3. Percentage of huCD45+ cells in bone marrows of engrafted mice at treatment initiation, then on Days 7, 21 and 42 for control (light grey), mice treated with Schedule A (7 days, BID, dark grey) or Schedule B (5 days BID X 3, black). The hatched bar corresponds to day 0. Medians and ranges are depicted. Table S1. Alisertib Pharmacokinetic Parameters Table S2. Summary table of in vivo drug responses
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- 2023
17. Table S2 from Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups
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Ching C. Lau, Murali Chintagumpala, Susan M. Blaney, Robert Dauser, Meenakshi Bhattacharjee, Dawna L. Armstrong, Adekunle Adesina, Jack Su, Laszlo Perlaky, Yvonne T.M. Tsang, Yi-Mieng Chang, and Kwong-Kwok Wong
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Genes differentiate two groups of JPA Hanash data
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- 2023
18. Data from Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups
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Ching C. Lau, Murali Chintagumpala, Susan M. Blaney, Robert Dauser, Meenakshi Bhattacharjee, Dawna L. Armstrong, Adekunle Adesina, Jack Su, Laszlo Perlaky, Yvonne T.M. Tsang, Yi-Mieng Chang, and Kwong-Kwok Wong
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Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expression profiles of 21 JPAs, determined using Affymetrix GeneChip U133A, were compared with subjects with normal cerebella. The genes involved in neurogenesis, cell adhesion, synaptic transmission, central nervous system development, potassium ion transport, protein dephosphorylation, and cell differentiation were found to be significantly deregulated in JPA. These 21 JPAs were further clustered into two major groups by unsupervised hierarchical clustering using a set of 848 genes with high covariance (0.5-10). Supervised analysis with Significance Analysis of Microarrays software between these two potential subgroups identified a list of significant differentially expressed genes involved in cell adhesion, regulation of cell growth, cell motility, nerve ensheathment, and angiogenesis. Immunostaining of myelin basic protein on paraffin sections derived from 18 incompletely resected JPAs suggests that JPA without myelin basic protein–positively stained tumor cells may have a higher tendency to progress.
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- 2023
19. Figure S1 from Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups
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Ching C. Lau, Murali Chintagumpala, Susan M. Blaney, Robert Dauser, Meenakshi Bhattacharjee, Dawna L. Armstrong, Adekunle Adesina, Jack Su, Laszlo Perlaky, Yvonne T.M. Tsang, Yi-Mieng Chang, and Kwong-Kwok Wong
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Figure S1 from Expression Analysis of Juvenile Pilocytic Astrocytomas by Oligonucleotide Microarray Reveals Two Potential Subgroups
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- 2023
20. Activity of Crizotinib in Patients with ALK-Aberrant Relapsed/Refractory Neuroblastoma: A Children's Oncology Group Study (ADVL0912)
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Brenda J. Weigel, Keith D. Wilner, David Hall, Charles G. Minard, Jennifer Foster, Peter C. Adamson, Stacey L. Berg, Elizabeth Fox, Susan M. Blaney, Stephan D. Voss, Yael P. Mosse, and Frank M. Balis
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Lung Neoplasms ,medicine.drug_class ,medicine.disease_cause ,Neuroblastoma ,03 medical and health sciences ,0302 clinical medicine ,Crizotinib ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Child ,Adverse effect ,Protein Kinase Inhibitors ,Mutation ,business.industry ,medicine.disease ,ALK inhibitor ,030104 developmental biology ,030220 oncology & carcinogenesis ,Absolute neutrophil count ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
Purpose: Anaplastic lymphoma kinase (ALK) aberrations are a promising target for patients with neuroblastoma. We assessed the activity of first-generation ALK inhibitor crizotinib in patients with no known curative treatments and whose tumors harbored an activating ALK alteration. Patients and Methods: Twenty patients with relapsed/refractory ALK-positive neuroblastoma received crizotinib at the recommended phase II dose of 280 mg/m2/dose. A Simon two-stage design was used to evaluate the antitumor activity of crizotinib monotherapy. Response evaluation occurred after cycles 1, 3, 5, 7, and then every 3 cycles. Correlation of ALK status and response was a secondary aim of the study. Results: The objective response rate for patients with neuroblastoma was 15% [95% confidence interval (CI): 3.3%–34.3%]: two with partial responses and 1 with a complete response. All three patients had a somatic ALK Arg1275Gln mutation, the most common ALK hotspot mutation observed in neuroblastoma and the only mutation predicted to be sensitive to ALK inhibition with crizotinib. Two patients had prolonged stable disease (10 and 13 cycles, respectively); both harbored an ALK Arg1275Gln mutation. Three patients with ALK Phe1174Leu mutations progressed during cycle 1 of therapy, and one patient with an ALK Phe1174Val received three cycles before disease progression. The two patients with ALK amplification had no response. The most common adverse event was a decrease in neutrophil count. Conclusions: Despite limited activity seen in this trial, we conclude that this is more likely due to an inability to reach the higher concentrations of crizotinib needed to overcome the competing ATP affinity. See related commentary by Schulte and Eggert, p. 3507
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- 2021
21. Phase I/II trial of vorinostat and radiation and maintenance vorinostat in children with diffuse intrinsic pontine glioma: A Children’s Oncology Group report
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David B Mansur, Elizabeth Fox, Amar Gajjar, Maryam Fouladi, Lindsay Kilburn, Allen Buxton, Peter C Adamson, Mark Krailo, Jack Su, Brenda J. Weigel, Adesina Adekunle, and Susan M. Blaney
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Oncology ,Cancer Research ,medicine.medical_specialty ,Historical model ,medicine.medical_treatment ,Phases of clinical research ,Astrocytoma ,Hydroxamic Acids ,Maintenance therapy ,Monday through friday ,Internal medicine ,Suberoylanilide Hydroxamic Acid ,medicine ,Brain Stem Neoplasms ,Humans ,Child ,Vorinostat ,business.industry ,Diffuse Intrinsic Pontine Glioma ,Radiation therapy ,Histone Deacetylase Inhibitors ,Regimen ,Neurology (clinical) ,business ,Pediatric Neuro-Oncology ,medicine.drug - Abstract
Background A phase I/II trial of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor, was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) through the Children’s Oncology Group (COG) to: 1) determine the recommended phase II dose (RP2D) of vorinostat given concurrently with radiation therapy; 2) document the toxicities of continuing vorinostat as maintenance therapy after radiation; and 3) to determine the efficacy of this regimen by comparing the risk of progression or death with a historical model from past COG trials. Methods Vorinostat was given once daily, Monday through Friday, during radiation therapy (54 Gy in 30 fractions), and then continued at 230 mg/m2 daily for a maximum of twelve 28-day cycles. Results Twelve patients enrolled in the phase I study; the RP2D of vorinostat given concurrently with radiation was 230 mg/m2/day, Monday through Friday weekly. The six patients enrolled at the RP2D and an additional 64 patients enrolled in the phase II study contributed to the efficacy assessment. Although vorinostat was well-tolerated, did not interrupt radiation therapy, and was permanently discontinued in only 8.6% of patients due to toxicities, risk for EFS-event was not significantly reduced compared with the target risk derived from historical COG data (P = 0.32; 1-sided). The 1-year EFS was 5.85% (95% CI 1.89–13.1%) and 1-year OS was 39.2% (27.8–50.5%). Conclusions Vorinostat given concurrently with radiation followed by vorinostat monotherapy was well tolerated in children with newly diagnosed DIPG but failed to improve outcome.
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- 2021
22. COVID-19 outcomes in a large pediatric hematology-oncology center in Houston, Texas
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Kala Y. Kamdar, Shawki L Qasim, Thomas M Pfeiffer, Mary Nell Suell, Susan M. Blaney, Amber M Yates, Taylor O Kim, and Erin E Doherty
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Male ,medicine.medical_specialty ,Pediatrics ,Pediatric Hematology/Oncology ,Population ,Disease ,Asymptomatic ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Neoplasms ,medicine ,Humans ,education ,Child ,Pandemics ,Retrospective Studies ,education.field_of_study ,Hematology ,business.industry ,Medical record ,COVID-19 ,Retrospective cohort study ,Hematologic Diseases ,Texas ,Oncology ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,Cohort ,medicine.symptom ,business ,030215 immunology - Abstract
An understanding of the behavior of SARS-CoV-2 in pediatric hematology-oncology patients is essential to the optimal management of these patients during the COVID-19 pandemic. This study describes the characteristics and outcomes of COVID-19 disease in children with cancer or hematologic disorders treated at a large children's hospital. A retrospective cohort study was conducted at Texas Children's Cancer and Hematology Center from January 1, 2020 to September 30, 2020. All patients with a primary hematology-oncology diagnosis and SARS-CoV-2 positivity by reverse transcription polymerase chain reaction were identified. Clinical and laboratory data were obtained from the medical record. Descriptive analyses were performed to evaluate COVID-19-related outcomes and risk factors for severe disease in this population. We identified 109 patients with COVID-19 disease, including 52 hematology, 51 oncology, and 6 HSCT patients; median age was 10.3 years (IQR 4.4-15.9), and 58.7% were male. Seventy-four percent of the patients were managed in the outpatient setting. Patients with sickle cell disease were more likely to require hospitalization. ICU care was needed in 8% (n = 9) of the entire cohort, and mechanical ventilation was required in 6.4% (6 oncology patients, 1 hematology patient). COVID-19 contributed to the deaths of two cancer patients. No deaths occurred in hematology or HSCT patients. In conclusion, the risk of severe COVID-19 complications is slightly higher in pediatric hematology-oncology patients than in the general pediatric population but lower than initially feared. For most asymptomatic patients, primary disease management may continue as planned, but treatment decisions must be individualized.
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- 2021
23. A Phase II Study of Alisertib in Children with Recurrent/Refractory Solid Tumors or Leukemia: Children's Oncology Group Phase I and Pilot Consortium (ADVL0921)
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Peter J. Houghton, Mark Krailo, Stephanie L. Safgren, Malcolm A. Smith, Hernan Carol, Yael P. Mosse, Richard B. Lock, Brenda J. Weigel, Donald A. Barkauskas, David T. Teachey, Joel M. Reid, David Hall, Elizabeth Fox, Stacey L. Berg, Stephan D. Voss, and Susan M. Blaney
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Acute leukemia ,business.industry ,Aurora A kinase ,Phases of clinical research ,medicine.disease ,03 medical and health sciences ,Leukemia ,chemistry.chemical_compound ,030104 developmental biology ,0302 clinical medicine ,Pharmacokinetics ,chemistry ,030220 oncology & carcinogenesis ,Neuroblastoma ,Internal medicine ,Toxicity ,Alisertib ,Medicine ,business - Abstract
Purpose: Aurora A kinase (AAK) plays an integral role in mitotic entry, DNA damage checkpoint recovery, and centrosome and spindle maturation. Alisertib (MLN8237) is a potent and selective AAK inhibitor. In pediatric preclinical models, antitumor activity was observed in neuroblastoma, acute lymphoblastic leukemia, and sarcoma xenografts. We conducted a phase 2 trial of alisertib in pediatric patients with refractory or recurrent solid tumors or acute leukemias (NCT01154816). Patients and Methods: Alisertib (80 mg/m2/dose) was administered orally, daily for 7 days every 21 days. Pharmacogenomic (PG) evaluation for polymorphisms in the AURK gene and drug metabolizing enzymes (UGT1A1*28), and plasma pharmacokinetic studies (PK) were performed. Using a 2-stage design, patients were enrolled to 12 disease strata (10 solid tumor and 2 acute leukemia). Response was assessed after cycle 1, then every other cycle. Results: A total of 139 children and adolescents (median age, 10 years) were enrolled, 137 were evaluable for response. Five objective responses were observed (2 complete responses and 3 partial responses). The most frequent toxicity was myelosuppression. The median alisertib trough concentration on day 4 was 1.3 μmol/L, exceeding the 1 μmol/L target trough concentration in 67% of patients. No correlations between PG or PK and toxicity were observed. Conclusions: Despite alisertib activity in pediatric xenograft models and cogent pharmacokinetic-pharmacodynamic relationships in preclinical models and adults, the objective response rate in children and adolescents receiving single-agent alisertib was less than 5%.
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- 2019
24. Current Activities of the Coalition of Cancer Cooperative Groups
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Monica M. Bertagnolli, Susan M. Blaney, Robert S. Mannel, Walter J. Curran, Janet Dancey, Charles D. Blanke, Peter J. O'Dwyer, Norman Wolmark, and Mitchell D. Schnall
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Cancer Research ,Biomedical Research ,MEDLINE ,03 medical and health sciences ,0302 clinical medicine ,Cancer control ,Neoplasms ,medicine ,Humans ,Cooperative group ,Cooperative Behavior ,business.industry ,Cancer ,Public relations ,medicine.disease ,Private sector ,Combined Modality Therapy ,Clinical trial ,ComputingMethodologies_PATTERNRECOGNITION ,Oncology ,Work (electrical) ,030220 oncology & carcinogenesis ,Practice Guidelines as Topic ,Commentary ,Research questions ,Health Planning Councils ,Business - Abstract
The Coalition of Cancer Cooperative Groups is an organization representing the interests of patients and researchers who conduct research through the National Cancer Institute-supported National Clinical Trials Network (NCTN). The NCTN provides a crucial mechanism for executing practice-changing cancer clinical research to achieve both cancer control and development of new therapeutic agents or modality approaches. Public funding, largely through the National Cancer Institute, ensures that the work of the NCTN achieves important research that would not otherwise be accomplished in the private sector. In fall 2017, the Coalition of Cancer Cooperative Groups convened a Scientific Leadership Council to review the current state of the network with regard to research capabilities and to develop a list of research questions to be prioritized by the network. This report presents the results of this meeting, detailing a roadmap for future work by the NCTN.
- Published
- 2018
25. ZFTA-RELA Dictates Oncogenic Transcriptional Programs to Drive Aggressive Supratentorial Ependymoma
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Claudia L. Kleinman, Yanhua Zhao, Austin J. Stuckert, H. Courtney Hodges, Bryan Rivas, Donald W. Parsons, Felix Sahm, Kelsey C. Bertrand, Thomas F. Westbrook, Nada Jabado, Stefan M. Pfister, Murali Chintagumpala, Kathleen Kong, Susan M. Blaney, Daisuke Kawauchi, Charles Y. Lin, Srinidhi Varadharajan, Minerva Solis, Irtisha Singh, Alisha Kardian, Robert Kupp, Stephen C. Mack, Yuen San Chan, Calla M. Olson, Sarah Injac, Hsiao-Chi Chen, Richard J. Gilbertson, Kristian W. Pajtler, Sameer Agnihotri, Selin Jessa, Luz A. De León, Ann Catherine J. Stanton, Amir Arabzade, Benjamin Deneen, Baoli Hu, Dana Tlais, Brian Golbourn, Peter R. Wang, Madeline Ngo, Kristen L. Karlin, and Joanna Yi
- Subjects
0301 basic medicine ,BRD4 ,Gene regulatory network ,Transcription Factor RelA ,Supratentorial Neoplasms ,Biology ,Article ,Chromatin ,Fusion gene ,DNA-Binding Proteins ,03 medical and health sciences ,Disease Models, Animal ,Mice ,030104 developmental biology ,0302 clinical medicine ,Oncology ,Ependymoma ,030220 oncology & carcinogenesis ,Gene expression ,Cancer research ,Animals ,Gene ,Transcription factor ,Epigenomics ,Transcription Factors - Abstract
More than 60% of supratentorial ependymomas harbor a ZFTA–RELA (ZRfus) gene fusion (formerly C11orf95–RELA). To study the biology of ZRfus, we developed an autochthonous mouse tumor model using in utero electroporation (IUE) of the embryonic mouse brain. Integrative epigenomic and transcriptomic mapping was performed on IUE-driven ZRfus tumors by CUT&RUN, chromatin immunoprecipitation sequencing, assay for transposase-accessible chromatin sequencing, and RNA sequencing and compared with human ZRfus-driven ependymoma. In addition to direct canonical NFκB pathway activation, ZRfus dictates a neoplastic transcriptional program and binds to thousands of unique sites across the genome that are enriched with PLAGL family transcription factor (TF) motifs. ZRfus activates gene expression programs through recruitment of transcriptional coactivators (Brd4, Ep300, Cbp, Pol2) that are amenable to pharmacologic inhibition. Downstream ZRfus target genes converge on developmental programs marked by PLAGL TF proteins, and activate neoplastic programs enriched in Mapk, focal adhesion, and gene imprinting networks. Significance: Ependymomas are aggressive brain tumors. Although drivers of supratentorial ependymoma (ZFTA- and YAP1-associated gene fusions) have been discovered, their functions remain unclear. Our study investigates the biology of ZFTA–RELA-driven ependymoma, specifically mechanisms of transcriptional deregulation and direct downstream gene networks that may be leveraged for potential therapeutic testing. This article is highlighted in the In This Issue feature, p. 2113
- Published
- 2020
26. Safety, tolerability and pharmacokinetics of crizotinib in combination with cytotoxic chemotherapy for pediatric patients with refractory solid tumors or anaplastic large cell lymphoma (ALCL): a Children's Oncology Group phase 1 consortium study (ADVL1212)
- Author
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Peter C. Adamson, Emily Greengard, Charles G. Minard, Stephan D. Voss, Elizabeth Fox, Brenda J. Weigel, Keith D. Wilner, Joel M. Reid, Xiaowei Liu, Yael P. Mosse, Susan M. Blaney, and Frank M. Balis
- Subjects
0301 basic medicine ,Oncology ,Male ,Cancer Research ,Vincristine ,medicine.medical_specialty ,Cyclophosphamide ,Adolescent ,Maximum Tolerated Dose ,medicine.medical_treatment ,Administration, Oral ,Biological Availability ,Toxicology ,Drug Administration Schedule ,Article ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Crizotinib ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Pharmacology (medical) ,Doxorubicin ,Child ,Pharmacology ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Infant ,030104 developmental biology ,Tolerability ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Child, Preschool ,Lymphoma, Large-Cell, Anaplastic ,Topotecan ,Female ,Neoplasm Recurrence, Local ,business ,medicine.drug - Abstract
This phase 1 study aimed to determine the safety, tolerability and recommended phase 2 dose (RP2D) of crizotinib in combination with cytotoxic chemotherapy for children with refractory solid tumors and ALCL. Pediatric patients with treatment refractory solid tumors or ALCL were eligible. Using a 3 + 3 design, crizotinib was escalated in three dose levels: 165, 215, or 280 mg/m2/dose BID. In Part A, patients received crizotinib oral solution (OS) in combination with topotecan and cyclophosphamide (topo/cyclo); in Part B, crizotinib OS was administered with vincristine and doxorubicin (vcr/dox). In Parts C and D, patients received topo/cyclo in combination with either crizotinib-formulated capsules (FC) or microspheres (cMS), respectively. Crizotinib pharmacokinetic evaluation was required. Forty-four eligible patients were enrolled, 39 were evaluable for toxicity. Parts A and B were terminated due to concerns regarding palatability and tolerability of the OS. In Part C, crizotinib, FC 215 mg/m2/dose BID, in combination with topo/cyclo was tolerated. In Part D, the maximum tolerated dose (MTD) was exceeded at 165 mg/m2/dose of crizotinib cMS. Pharmacokinetics of crizotinib in combination with chemotherapy was similar to single-agent crizotinib and exposures were not formulation dependent. The RP2D of crizotinib FCs in combination with cyclophosphamide and topotecan was 215 mg/m2/dose BID. The oral solution of crizotinib was not palatable in this patient population. Crizotinib cMS was palatable; however, patients experienced increased toxicity that was not explained by the relative bioavailability or exposure and warrants further investigation. The trial is registered as NCT01606878 at Clinicaltrials.gov.
- Published
- 2020
27. A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study
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Patricia Baxter, Xiao-Nan Li, Adekunle M. Adesina, Lindsey Kilburn, Alberto Broniscer, Ibrahim Quaddoumi, Ira J. Dunkel, P. Ansell, Susan M. Blaney, Arnold C. Paulino, Vincent L. Giranda, Edward R. Smith, Patrick A. Thompson, Jack Su, Maryam Fouladi, Tina Young Poussaint, Arzu Onar-Thomas, and Catherine A. Billups
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Pediatric Brain Tumor Consortium ,Veliparib ,Newly diagnosed ,chemistry.chemical_compound ,Pharmacokinetics ,Glioma ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Maculopapular rash ,Temozolomide ,Brain Stem Neoplasms ,Humans ,Child ,business.industry ,Brain Neoplasms ,medicine.disease ,Interim analysis ,chemistry ,Benzimidazoles ,Neurology (clinical) ,medicine.symptom ,business ,Pediatric Neuro-Oncology ,medicine.drug - Abstract
Background A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series. Methods Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity. Results Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively. Conclusion Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG. Trial Registration NCT01514201
- Published
- 2020
28. A phase 2 study of valproic acid and radiation, followed by maintenance valproic acid and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma or high-grade glioma
- Author
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Jeffrey C. Murray, Shafqat Shah, Rene Y. McNall-Knapp, Susan M. Blaney, Adekunle M. Adesina, Eunji Jo, Daniel C. Bowers, Arnold C. Paulino, Qianxing Mo, Jack Meng Fen Su, and Patricia Baxter
- Subjects
Adult ,Male ,medicine.medical_specialty ,Bevacizumab ,Adolescent ,medicine.medical_treatment ,Phases of clinical research ,Neutropenia ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Glioma ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Brain Stem Neoplasms ,Humans ,Child ,Valproic Acid ,business.industry ,Diffuse Intrinsic Pontine Glioma ,Hematology ,Chemoradiotherapy ,medicine.disease ,Prognosis ,Discontinuation ,Radiation therapy ,Survival Rate ,Oncology ,Tolerability ,030220 oncology & carcinogenesis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,lipids (amino acids, peptides, and proteins) ,Female ,business ,030215 immunology ,medicine.drug ,Follow-Up Studies - Abstract
Purpose To study the efficacy and tolerability of valproic acid (VPA) and radiation, followed by VPA and bevacizumab in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG) or high-grade glioma (HGG). Methods Children 3 to 21 years of age received radiation therapy and VPA at 15 mg/kg/day and dose adjusted to maintain a trough range of 85 to 115 μg/mL. VPA was continued post-radiation, and bevacizumab was started at 10 mg/kg intravenously biweekly, four weeks after completing radiation therapy. Results From September 2009 through August 2015, 20 DIPG and 18 HGG patients were enrolled (NCT00879437). During radiation and VPA, grade 3 or higher toxicities requiring discontinuation or modification of VPA dosing included grade 3 thrombocytopenia (1), grade 3 weight gain (1), and grade 3 pancreatitis (1). During VPA and bevacizumab, the most common grade 3 or higher toxicities were grade 3 neutropenia (3), grade 3 thrombocytopenia (3), grade 3 fatigue (3), and grade 3 hypertension (4). Two patients discontinued protocol therapy prior to disease progression (one grade 4 thrombosis and one grade 1 intratumoral hemorrhage). Median event-free survival (EFS) and overall survival (OS) for DIPG were 7.8 (95% CI 5.6-8.2) and 10.3 (7.4-13.4) months, and estimated one-year EFS was 12% (2%-31%). Median EFS and OS for HGG were 9.1 (6.4-11) and 12.1 (10-22.1) months, and estimated one-year EFS was 24% (7%-45%). Four patients with glioblastoma and mismatch-repair deficiency syndrome had EFS of 28.5, 16.7, 10.4, and 9 months. Conclusion Addition of VPA and bevacizumab to radiation was well tolerated but did not appear to improve EFS or OS in children with DIPG or HGG.
- Published
- 2020
29. Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/recurrent solid tumors including Ewing sarcoma: A Children's Oncology Group Phase 1 Consortium study (ADVL1411)
- Author
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Joel M. Reid, Stacey L. Berg, Rachel E. Rau, M. John Hicks, Charles G. Minard, Stephan D. Voss, Marvin D. Nelson, Alexander J.R. Bishop, Xiaowei Liu, Elizabeth Fox, Eric S. Schafer, Brenda J. Weigel, J. Carolina Romero, and Susan M. Blaney
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,Bone Neoplasms ,Sarcoma, Ewing ,Neutropenia ,Gastroenterology ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Pharmacokinetics ,Glioma ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Temozolomide ,medicine ,Humans ,Tissue Distribution ,Dosing ,Child ,Salvage Therapy ,business.industry ,Infant ,Hematology ,Prognosis ,medicine.disease ,Survival Rate ,Oncology ,Drug Resistance, Neoplasm ,Child, Preschool ,030220 oncology & carcinogenesis ,Concomitant ,Pediatrics, Perinatology and Child Health ,Phthalazines ,Female ,Sarcoma ,Neoplasm Recurrence, Local ,business ,Follow-Up Studies ,030215 immunology ,medicine.drug - Abstract
Purpose We conducted a phase 1/2 trial of the poly(ADP-ribose) polymerase 1/2 inhibitor talazoparib in combination with low-dose temozolomide (TMZ) to determine the dose-limiting toxicities (DLTs), recommended phase 2 dose (RP2D), and pharmacokinetics of this combination in children with recurrent/refractory solid tumors; and to explore clinical activity in Ewing sarcoma (EWS) (NCT02116777). Methods Talazoparib (400-600 µg/m2 /dose, maximum daily dose 800-1000 µg) was administered q.d. or b.i.d. orally on day 1 followed by q.d. dosing concomitant with q.d. dosing of oral TMZ (20-55 mg/m2 /day) on days 2 to 6, every 28 days. Results Forty patients, aged 4 to 25 years, were enrolled. Talazoparib was increased to 600 µg/m2 /dose b.i.d. on day 1, and q.d. thereafter, with 20 mg/m2 /day of TMZ, without DLTs. TMZ was subsequently increased, during which dose-limiting neutropenia and thrombocytopenia occurred in two of three subjects at 55 mg/m2 /day, two of six subjects at 40 mg/m2 /day, and one of six subjects at 30 mg/m2 /day. During dose-finding, two of five EWS and four of 25 non-EWS subjects experienced prolonged stable disease (SD), and one subject with malignant glioma experienced a partial response. In phase 2, 0 of 10 EWS subjects experienced an objective response; two experienced prolonged SD. Conclusions Talazoparib and low-dose TMZ are tolerated in children with recurrent/refractory solid tumors. Reversible neutropenia and thrombocytopenia were dose limiting. The RP2D is talazoparib 600 µg/m2 b.i.d. on day 1 followed by 600 µg/m2 q.d. on days 2 to 6 (daily maximum 1000 µg) in combination with temozolomide 30 mg/m2 /day on days 2 to 6. Antitumor activity was not observed in EWS, and limited antitumor activity was observed in central nervous system tumors.
- Published
- 2019
30. Pizzo & Poplack's Pediatric Oncology
- Author
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Susan M Blaney, Lee J Helman, Peter C Adamson, Susan M Blaney, Lee J Helman, and Peter C Adamson
- Subjects
- Children, Tumors in children, Infants
- Abstract
Comprehensive, authoritative, and up to date, Pizzo and Poplack's Pediatric Oncology, 8th Edition, remains your most trusted source of information on the care and research of children with cancer. This award-winning text is the single most comprehensive reference on the biology and genetics of childhood cancer, its diagnosis and multimodal treatment, and long-term management. In the tradition of excellence established by Drs. Philip A. Pizzo and David G. Poplack, this 8th Edition keeps you fully informed while helping you collaborate more effectively with others on the cancer care team to enhance quality-of-life issues for patients and families.
- Published
- 2021
31. Targeting ALK With Crizotinib in Pediatric Anaplastic Large Cell Lymphoma and Inflammatory Myofibroblastic Tumor: A Children’s Oncology Group Study
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Elizabeth Fox, Yael P. Mosse, Charles G. Minard, Megan S. Lim, Susan M. Blaney, Peter C. Adamson, Brenda J. Weigel, Keith D. Wilner, Stephan D. Voss, and Delphine Rolland
- Subjects
Male ,0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Adolescent ,Pyridines ,medicine.drug_class ,Lesion ,Neoplasms, Muscle Tissue ,03 medical and health sciences ,0302 clinical medicine ,Crizotinib ,Refractory ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,Molecular Targeted Therapy ,Child ,Protein Kinase Inhibitors ,Dose-Response Relationship, Drug ,business.industry ,Large cell ,Receptor Protein-Tyrosine Kinases ,ORIGINAL REPORTS ,medicine.disease ,Lymphoma ,Clinical trial ,ALK inhibitor ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Lymphoma, Large-Cell, Anaplastic ,Pyrazoles ,Female ,Neoplasm Recurrence, Local ,medicine.symptom ,business ,medicine.drug - Abstract
Purpose Fusions involving the ALK gene are the predominant genetic lesion underlying pediatric anaplastic large cell lymphomas (ALCL) and inflammatory myofibroblastic tumors (IMTs). We assessed the activity of the ALK inhibitor crizotinib in patients who had no known curative treatment options at diagnosis or with relapsed/recurrent disease. Methods In this study, 26 patients with relapsed/refractory ALK-positive ALCL and 14 patients with metastatic or inoperable ALK-positive IMT received crizotinib orally twice daily. Study objectives were measurement of efficacy and safety. Correlative studies evaluated the serial detection of NPM-ALK fusion transcripts in patients with ALCL. Results The overall response rates for patients with ALCL treated at doses of 165 (ALCL165) and 280 (ALCL280) mg/m2 were 83% and 90%, respectively. The overall response rate for patients with IMT (treated at 100, 165, and 280 mg/m2/dose) was 86%. A complete response was observed in 83% (five of six) of ALCL165, 80% (16 of 20) of ALCL280, and 36% (five of 14) of patients with IMT. Partial response rates were 0% (none of six), 10% (two of 20), and 50% (seven of 14), respectively. The median duration of therapy was 2.79, 0.4, and 1.63 years, respectively, with 12 patients ceasing protocol therapy to proceed to transplantation. The most common drug-related adverse event was decrease in neutrophil count in 33% and 70% of the ALCL165 and ALCL280 groups, respectively, and in 43% of patients with IMT. Levels of NPM-ALK decreased during therapy in most patients with ALCL. Conclusion The robust and sustained clinical responses to crizotinib therapy in patients with relapsed ALCL and metastatic or unresectable IMT highlight the importance of the ALK pathway in these diseases.
- Published
- 2017
32. A phase 1 trial of temsirolimus and intensive re-induction chemotherapy for 2nd or greater relapse of acute lymphoblastic leukaemia: a Children's Oncology Group study (ADVL1114)
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Charles G. Minard, Brenda J. Weigel, Susan M. Blaney, David T. Teachey, Sarah K. Tasian, Xiaowei Liu, Elizabeth Fox, Michael J. Borowitz, Susan R. Rheingold, and James A. Whitlock
- Subjects
Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Adolescent ,medicine.medical_treatment ,Drug Administration Schedule ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Mucositis ,Humans ,Child ,Protein Kinase Inhibitors ,Phosphoinositide-3 Kinase Inhibitors ,Sirolimus ,Chemotherapy ,Dose-Response Relationship, Drug ,business.industry ,Infant ,Induction chemotherapy ,Induction Chemotherapy ,Hematology ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,medicine.disease ,Minimal residual disease ,Temsirolimus ,Clinical trial ,Regimen ,Treatment Outcome ,030104 developmental biology ,Child, Preschool ,030220 oncology & carcinogenesis ,Toxicity ,Female ,Phosphatidylinositol 3-Kinase ,business ,medicine.drug - Abstract
The phosphatidylinositol 3-kinase (PI3K)/mammalian (or mechanistic) target of rapamycin (mTOR) signalling pathway is commonly dysregulated in acute lymphoblastic leukaemia (ALL). A phase 1 trial of the mTOR inhibitor temsirolimus in combination with UKALL R3 re-induction chemotherapy was conducted in children and adolescents with second or greater relapse of ALL. The initial temsirolimus dose level (DL1) was 10 mg/m2 weekly × three doses. Subsequent patient cohorts received temsirolimus 7.5 mg/m2 weekly × three doses (DL0) or, secondary to toxicity, 7.5 mg/m2 weekly × two doses (DL-1). Sixteen patients were enrolled, 15 were evaluable for toxicity. Dose-limiting toxicity (DLT) occurred at all three dose levels and included hypertriglyceridaemia, mucositis, ulceration, hypertension with reversible posterior leucoencephalopathy, elevated gamma-glutamyltransferase or alkaline phosphatase and sepsis. The addition of temsirolimus to UKALL R3 re-induction therapy resulted in excessive toxicity and was not tolerable in children with relapsed ALL. However, this regimen induced remission in seven of fifteen patients. Three patients had minimal residual disease levels
- Published
- 2017
33. First-dose and steady-state pharmacokinetics of orally administered crizotinib in children with solid tumors: a report on ADVL0912 from the Children’s Oncology Group Phase 1/Pilot Consortium
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Susan M. Blaney, Charles G. Minard, Patrick A. Thompson, Yael P. Mosse, Frank M. Balis, Brenda J. Weigel, and Elizabeth Fox
- Subjects
Adult ,Male ,Cancer Research ,Adolescent ,Pyridines ,Administration, Oral ,Pharmaceutical formulation ,Pharmacology ,Toxicology ,030226 pharmacology & pharmacy ,03 medical and health sciences ,0302 clinical medicine ,Crizotinib ,Pharmacokinetics ,Neoplasms ,medicine ,ROS1 ,Humans ,Pharmacology (medical) ,Child ,Children ,Protein Kinase Inhibitors ,business.industry ,3. Good health ,Peak plasma ,ALK ,Oncology ,Child, Preschool ,030220 oncology & carcinogenesis ,Plasma concentration ,Lymphoma, Large-Cell, Anaplastic ,Pyrazoles ,Time to peak ,Original Article ,Female ,Steady state (chemistry) ,Childhood cancer ,business ,medicine.drug - Abstract
Purpose Characterize the pharmacokinetics of oral crizotinib in children with cancer. Methods Sixty-four children with solid tumors or anaplastic large-cell lymphoma (ALCL) enrolled on a phase 1/2 trial of the ALK, MET and ROS1 inhibitor, crizotinib, had pharmacokinetic sampling after the first dose (n = 15) or at steady state (n = 49). Dose levels studied were 100, 130, 165, 215, 280 and 365 mg/m2/dose administered twice daily. Two capsule and two oral liquid formulations were used over the course of the trial. Crizotinib was quantified with a validated HPLC/tandem mass spectrometry method with a lower limit of detection of 0.2 ng/mL. Pharmacokinetic parameters were derived using non-compartmental analysis. Results Time to peak plasma concentration was 4 h. At 280 mg/m2 (MTD), mean (±SD) steady-state peak plasma concentration was 717 ± 201 ng/mL, and steady-state trough plasma concentration was 480 ± 176 ng/mL. At steady state, AUC0–τ was proportional to dose over the dose range of 215–365 mg/m2/dose. Apparent clearance of crizotinib was 731 ± 241 mL/min/m2. Steady-state AUC0–τ at 280 mg/m2/dose was 2.5-fold higher than the AUC0–∞ in adults receiving 250 mg (~140 mg/m2). Age, sex and drug formulation do not account for the inter-subject variability in AUC0–τ at steady state. The accumulation index was 4.9, and the half-life estimated from the accumulation index was 36 h. Conclusions The pharmacokinetics of oral crizotinib in children is similar to that in adults. Steady-state trough-free crizotinib concentrations in plasma at the MTD exceed inhibitory concentrations of crizotinib in ALCL cell lines. ClinicalTrials.gov identifier NCT00939770.
- Published
- 2016
34. EPEN-30. C11ORF95-RELA FUSION PROTEIN ENGAGES NOVEL GENOMIC LOCI TO DRIVE MURINE EPENDYMOMA GROWTH
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Courtney H. Hodges, Amir Arabzade, Kelsey C. Bertrand, Thomas F. Westbrook, Bryan Rivas, Sameer Agnihotri, Charles Y. Lin, Susan M. Blaney, Joanna Yi, Austin J. Stuckert, Stephen C. Mack, Donald W. Parsons, Benjamin Deneen, Yanhua Zhao, Hsiao-Chi Chen, and Srinidhi Varadharajan
- Subjects
Ependymoma ,Genetics ,Cancer Research ,Oncology ,medicine ,AcademicSubjects/MED00300 ,AcademicSubjects/MED00310 ,Neurology (clinical) ,Biology ,medicine.disease ,C11orf95/RELA Fusion Protein - Abstract
RATIONALE Over 70% of supratentorial (ST) ependymoma are characterized by an oncogenic fusion between C11ORF95 and RELA. C11ORF95-RELA fusion is frequently the sole genetic driver detected in ST ependymoma, thus ranking this genomic event as a lead target for therapeutic investigation. RELA is a transcription factor (TF) central to mediating NF-kB pathway activation in processes such as inflammation, cellular metabolism, and chemotaxis. HYPOTHESIS: We posited that C11ORF95-RELA acts as an oncogenic TF that aberrantly shapes the tumor epigenome to drive aberrant transcription. Approach: To this end we developed an in utero electroporation (IUE) mouse model of ependymoma to express C11ORF95-RELA during embryonic development. Our IUE approach allowed us to develop C11ORF95-RELA driven tumor models and cell lines. We comprehensively characterized the epigenome and transcriptome of C11ORF95-RELA fusion driven mouse cells by H3K27ac ChIP-seq, ATAC-seq, and RNA-seq. RESULTS This data revealed that: 1) C11ORF95-RELA directly engages ‘open’ chromatin and is enriched at regions with known RELA TF binding sites as well as novel genomic loci/motifs, 2) C11ORF95-RELA preferentially binds to both H3K27ac (active) enhancers and promoters, and 3) Bound C11ORF95-RELA promoter loci are associated with increased transcription of genes shared with human ependymoma. CONCLUSION Our findings shed light on the transcriptional mechanisms of C11ORF95-RELA, and reveal downstream targets that may represent cancer dependency genes and molecular targets.
- Published
- 2020
35. Phase II evaluation of sunitinib in the treatment of recurrent or refractory high‐grade glioma or ependymoma in children: a children's Oncology Group Study ACNS1021
- Author
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Rachel Tanos, Sarah Leary, Susan M. Blaney, Kelly C. Goldsmith, Vinay M. Daryani, Clinton F. Stewart, Amar Gajjar, Cynthia Wetmore, James M. Boyett, and Catherine A. Billups
- Subjects
Male ,Oncology ,Ependymoma ,Cancer Research ,Indoles ,recurrent brain tumor ,Phases of clinical research ,Angiogenesis Inhibitors ,urologic and male genital diseases ,Tyrosine-kinase inhibitor ,tyrosine kinase inhibitor ,0302 clinical medicine ,Sunitinib ,Medicine ,Child ,Original Research ,Pediatric ,Glioma ,Combined Modality Therapy ,female genital diseases and pregnancy complications ,3. Good health ,Treatment Outcome ,Tolerability ,Child, Preschool ,030220 oncology & carcinogenesis ,Retreatment ,Female ,Drug Monitoring ,medicine.drug ,medicine.medical_specialty ,Adolescent ,medicine.drug_class ,Antineoplastic Agents ,Young Adult ,03 medical and health sciences ,Internal medicine ,Humans ,Pyrroles ,Radiology, Nuclear Medicine and imaging ,Protein Kinase Inhibitors ,Neoplasm Staging ,business.industry ,Clinical Cancer Research ,Sunitinib malate ,medicine.disease ,Interim analysis ,Drug Resistance, Neoplasm ,Neoplasm Grading ,Neoplasm Recurrence, Local ,business ,030217 neurology & neurosurgery - Abstract
Sunitinib malate is a small multi‐targeted tyrosine kinase inhibitor that inhibits vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor (PDGFR) and stem cell factor receptor (KIT), which are highly expressed by some high‐grade brain tumors. We conducted a phase II study to estimate the efficacy and further characterize the pharmacokinetics of sunitinib in pediatric patients with recurrent or refractory high‐grade glioma (Stratum A) or ependymoma (Stratum B). This was a prospective, multicenter Phase II trial conducted through the Children's Oncology Group (ClinicalTrials.gov Identifier NCT01462695). Sunitinib, 15 mg/m2, was orally administered once daily for 4 weeks every 6 weeks. The safety and tolerability of sunitinib, an estimate of progression‐free survival (PFS), analyses of sunitinib pharmacokinetics (PK) and pharmacodynamics modulation of plasma VEGF and VEGFR2 were also assessed. Thirty eligible patients (17 patients on Stratum A, 13 patients on Stratum B) were enrolled and 29 patients were evaluable for response. Sunitinib was reasonably well tolerated in children with recurrent ependymoma or high‐grade glioma. Most adverse events were of mild‐to‐moderate severity and manageable with supportive treatment. While there was a statistically significant modulation of plasma VEGFR2 with sunitinib exposure, there were no sustained tumor responses. Both strata were closed at time of planned interim analysis as there was not sufficient efficacy associated with sunitinib in children with recurrent brain tumors. Sunitinib was well tolerated in children and young adults with recurrent high‐grade glioma or ependymoma but had no single agent objective antitumor activity in these patients.
- Published
- 2016
36. A phase 1 study of eribulin mesylate (E7389), a novel microtubule targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: a Children’s Oncology Group Phase 1 Consortium study (ADVL1314)
- Author
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D. R. D'Adamo, Charles G. Minard, Rachael Scott, Sandhya Devarajan, Gresel Martinez, Joel M. Reid, Susan M. Blaney, Eric S. Schafer, Stacey L. Berg, Rachel E. Rau, Brenda J. Weigel, Xiaowei Liu, Larisa Reyderman, and Elizabeth Fox
- Subjects
0301 basic medicine ,Eribulin Mesylate ,Oncology ,Male ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,Nausea ,Antineoplastic Agents ,Neutropenia ,Microtubules ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Refractory ,Pharmacokinetics ,Internal medicine ,Neoplasms ,Medicine ,Humans ,Child ,Furans ,Dose-Response Relationship, Drug ,business.industry ,Hematology ,Ketones ,medicine.disease ,Hypokalemia ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Toxicity ,Female ,medicine.symptom ,Neoplasm Recurrence, Local ,business ,Eribulin - Abstract
Background Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose-limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. Methods Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. Results Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2 /dose, respectively. One subject at the 1.4 mg/m2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2 /dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low-grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). Conclusions Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2 /dose on days 1 and 8 of a 21-day cycle.
- Published
- 2018
37. Brentuximab vedotin with gemcitabine for paediatric and young adult patients with relapsed or refractory Hodgkin's lymphoma (AHOD1221): a Children's Oncology Group, multicentre single-arm, phase 1-2 trial
- Author
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Brenda J. Weigel, Terzah M. Horton, Qinglin Pei, Peter D. Cole, Richard A. Drachtman, Monika L. Metzger, Rizvan Bush, Menachem Spira, Kara M. Kelly, Susan M. Blaney, and Kathleen M. McCarten
- Subjects
Oncology ,Male ,medicine.medical_specialty ,Canada ,Immunoconjugates ,Time Factors ,Adolescent ,Neutropenia ,Deoxycytidine ,Drug Administration Schedule ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Adverse effect ,Brentuximab vedotin ,Brentuximab Vedotin ,business.industry ,Age Factors ,medicine.disease ,Rash ,Hodgkin Disease ,Gemcitabine ,United States ,Lymphoma ,Clinical trial ,Treatment Outcome ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Female ,medicine.symptom ,business ,030215 immunology ,medicine.drug - Abstract
Summary Background Patients with primary refractory Hodgkin's lymphoma or early relapse have a poor prognosis. Although many salvage regimens have been developed, there is no standard of care. Brentuximab vedotin and gemcitabine have been shown to be active in patients with relapsed or refractory Hodgkin's lymphoma when used as monotherapy, and each has been successfully used in combination with other agents. Preclinical data suggest that brentuximab vedotin can sensitise lymphoma cells to gemcitabine, supporting the use of the combination. We aimed to define the safety and efficacy of brentuximab vedotin with gemcitabine in children and young adults with primary refractory Hodgkin's lymphoma or early relapse. Methods In this Children's Oncology Group, multicentre, single-arm, phase 1–2 trial, we recruited patients with Hodgkin's lymphoma from hospitals across the USA and Canada. Eligible patients were aged younger than 30 years, had no previous brentuximab vedotin exposure, and had primary refractory disease or relapse of less than 1 year from completion of initial treatment. Each 21-day cycle consisted of 1000 mg/m2 intravenous gemcitabine on days 1 and 8 and intravenous brentuximab vedotin on day 1 at 1·4 mg/kg or 1·8 mg/kg. The primary objectives were to establish the recommended phase 2 dose of brentuximab vedotin in this combination, the safety of the combination, and the proportion of patients who achieved a complete response among those treated at the recommended phase 2 level, within four cycles of treatment. This trial is registered with ClinicalTrials.gov, number NCT01780662. Findings Between Feb 5, 2013, and Aug 19, 2016, 46 patients were enrolled, including one who was found to be ineligible, in the two phases of the study. The recommended phase 2 dose of brentuximab vedotin was 1·8 mg/kg in combination with gemcitabine 1000 mg/m2. 24 (57%) of 42 evaluable patients (95% CI 41–72) given this dose level had a complete response within the first four cycles of treatment. Four (31%) of 13 patients with a partial response or stable disease had all target lesions with Deauville scores of 3 or less after cycle 4. By modern response criteria, these were also complete responses (total number with complete response 28 [67%] of 42 [95% CI 51–80]). The most common grade 3–4 adverse events in all 42 participants treated at the recommended phase 2 dose were neutropenia (15 [36%]), rash (15 [36%]), transaminitis (9 [21%]), and pruritus (4 [10%]). There were no treatment-related deaths. Interpretation Brentuximab vedotin with gemcitabine is a safe combination treatment with a tolerable toxicity profile for patients with primary refractory Hodgkin's lymphoma or high-risk relapse. The preliminary activity of this combination shown in this trial warrants further investigation in randomised controlled trials. Funding National Institutes of Health and the St. Baldrick's Foundation.
- Published
- 2018
38. 3488 A comparison between the Rolling 6 and 3+3 dose escalation study designs for phase 1 clinical trials
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Rachel E. Rau, Brenda J. Weigel, Susan G. Hilsenbeck, Susan M. Blaney, Charles G. Minard, Peter C. Adamson, and Elizabeth Fox
- Subjects
medicine.medical_specialty ,Dose limiting toxicity ,Wilcoxon signed-rank test ,business.industry ,Clinical study design ,Significant difference ,Phases of clinical research ,General Medicine ,Cog ,Clinical Epidemiology/Clinical Trial ,Physical therapy ,medicine ,Dose escalation ,Population study ,business - Abstract
OBJECTIVES/SPECIFIC AIMS: The development of new anti-cancer agents for children requires an inherently longer timeline than in adults. The 3+3 study design for Phase 1 dose escalation trials is commonly used to estimate the maximum tolerated dose and assess safety. The Rolling 6 study design was developed to shorten the study conduct timeline. METHODS/STUDY POPULATION: This study compares twenty Phase 1 COG Pilot and Phase 1 Consortium trials that employed the Rolling 6 design with hypothetical results under the assumption that a 3+3 design had been executed. The number of evaluable patients required to complete the study, number of DLTs, number of inevaluable patients, overall study duration, time suspended to enrollment (i.e., waiting for DLT evaluation), and DLT risk are compared between study designs using Wilcoxon’s signed rank test. RESULTS/ANTICIPATED RESULTS: The Rolling 6 study design required less time to complete the studies compared with 3+3 design (median 273 vs. 297 days, P = 0.01). In general, the Rolling 6 study design required more patients, had more inevaluable patients, and there were more dose limiting toxicity (DLT) events. However, there was no significant difference in DLT risk (median 0.15 vs. 0.17, P = 0.72). DISCUSSION/SIGNIFICANCE OF IMPACT: The Rolling 6 study design effectively shortens the study conduct timeline compared with the traditional 3+3 design for Phase 1 COG Pilot and Phase 1 Consortium trials without increasing the risk of toxicity.
- Published
- 2019
39. Editorial
- Author
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Susan M. Blaney
- Subjects
medicine.medical_specialty ,business.industry ,Pediatrics, Perinatology and Child Health ,MEDLINE ,Pediatric oncology ,Humans ,Medicine ,Medical physics ,Child ,Medical Oncology ,business ,Pediatrics - Published
- 2019
40. A Pediatric Brain Tumor Consortium Phase II Trial of Capecitabine Rapidly Disintegrating Tablets with Concomitant Radiation Therapy in Children with Newly Diagnosed Diffuse Intrinsic Pontine Gliomas
- Author
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Mehmet Kocak, Lindsay Kilburn, Eugene Hwang, Alberto Broniscer, Annabelle Lemenuel-Diot, Arnold C. Paulino, Justin N. Baker, Murali Chintagumpala, Tina Young Poussaint, James M. Boyett, Patricia Baxter, Christine Lopez-Diaz, Christine McIntyre, Jack Su, Larry E. Kun, Maryam Fouladi, and Susan M. Blaney
- Subjects
Male ,medicine.medical_specialty ,Pediatric Brain Tumor Consortium ,Adolescent ,medicine.medical_treatment ,Phases of clinical research ,Administration, Oral ,Gastroenterology ,Article ,Capecitabine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Brain Stem Neoplasms ,Humans ,Prospective Studies ,Child ,business.industry ,Hematology ,Chemoradiotherapy ,Glioma ,Surgery ,Clinical trial ,Radiation therapy ,Oncology ,030220 oncology & carcinogenesis ,Concomitant ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Vomiting ,Female ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug ,Follow-Up Studies ,Tablets - Abstract
Background We conducted a phase II study of oral capecitabine rapidly disintegrating tablets given concurrently with radiation therapy (RT) to assess progression-free survival (PFS) in children with newly diagnosed diffuse intrinsic pontine gliomas (DIPG). Patients and methods Children 3-17 years with newly diagnosed DIPG were eligible. Capecitabine, 650 mg/m2 /dose BID (maximum tolerated dose [MTD] in children with concurrent radiation), was administered for 9 weeks starting the first day of RT. Following a 2-week break, three courses of capecitabine, 1,250 mg/m2 /dose BID for 14 days followed by a 7-day rest, were administered. As prospectively designed, 10 evaluable patients treated at the MTD on the phase I trial were included in the phase II analyses. The design was based on comparison of the PFS distribution to a contemporary historical control (n = 140) with 90% power to detect a 15% absolute improvement in the 1-year PFS with a type-1 error rate, α = 0.10. Results Forty-four patients were evaluable for the phase II objectives. Capecitabine and RT was well tolerated with low-grade palmar plantar erythrodyesthesia, increased alanine aminotransferase, cytopenias, and vomiting the most commonly reported toxicities. Findings were significant for earlier progression with 1-year PFS of 7.21% (SE = 3.47%) in the capecitabine-treated cohort versus 15.59% (SE = 3.05%) in the historical control (P = 0.007), but there was no difference for overall survival (OS) distributions (P = 0.30). Tumor enhancement at diagnosis was associated with shorter PFS and OS. Capecitabine was rapidly absorbed and converted to its metabolites. Conclusion Capecitabine did not improve the outcome for children with newly diagnosed DIPG.
- Published
- 2017
41. Rudolph's Pediatrics, 23rd Edition
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Mark W. Kline, Susan M. Blaney, Angelo P. Giardino, Jordan S. Orange, Daniel J. Penny, Gordon E. Schutze, Lara S. Shekerdemian, Abraham M. Rudolph, Colin D. Rudolph, Mark W. Kline, Susan M. Blaney, Angelo P. Giardino, Jordan S. Orange, Daniel J. Penny, Gordon E. Schutze, Lara S. Shekerdemian, Abraham M. Rudolph, and Colin D. Rudolph
- Abstract
Publisher's Note: Products purchased from Third Party sellers are not guaranteed by the publisher for quality, authenticity, or access to any online entitlements included with the product. The landmark pediatrics reference – completely reinvented by an all new team of editors Rudolph's Pediatrics has virtually defined the pediatric field for over a century, becoming one of the most important and well-respected pediatrics texts ever published. Renowned for its balance of clinical features and treatment of disease with underlying biological principles, this classic sourcebook has helped generations of pediatricians optimize their care of infants, children, and adolescents. The Twenty-Third Edition of Rudolph's has been completely restructured and streamlined thanks to an all new team of editors whose goal was to reinvent this classic with today's busy practitioner in mind. Presented in full color, the Twenty-Third Edition provides an up-to-date, in-depth survey of pediatric medicine unmatched by any other text. With its algorithmic approach to pediatric systems, the book facilitates the diagnosis and treatment of both common and uncommon pediatric illnesses; and it reflects new technologies and advances in molecular medicine that continue to evolve with current thinking about normal childhood development and pediatric disease processes. • New team of editors achieves consistency in both tone and depth of content • Contributions from section editors and authors from leading academic pediatrics programs give expert coverage of general pediatrics and all of the pediatric sub-specialties • Streamlined and consistent format for most chapters outlining Pathogenesis and Epidemiology, Clinical Manifestations, Diagnosis, Treatment, and Prevention • New 2-Volume presentation improves portability • Hundreds of full-color illustrations and tables • The acclaimed balance between clinical applicability and underlying biological principles offers pediatricians a depth of coverage not found anywhere else • Brand new or significantly revised chapters include: Complementary and Integrative Pediatrics, Childhood Adversity and Toxic Stress, Autism Spectrum Disorder, Pediatric Depression and Bipolar Spectrum Disorders, Extracorporeal Membrane Oxygenation (ECMO), Palliative Care for Children with Chronic Diseases, Arboviruses (with new coverage of Zika virus and chikungunya virus), Physiologic Basis of Pulmonary Function; Acute Lymphoblastic Leukemia; Neuroblastoma “You'd be hard pressed to find a resource that matches up to the comprehensive scope of Rudolph's. It's no wonder it's a staple in most offices and hospitals.” -Doody's Review Service
- Published
- 2018
42. A phase 1 dosing study of ruxolitinib in children with relapsed or refractory solid tumors, leukemias, or myeloproliferative neoplasms: A Children's Oncology Group phase 1 consortium study (ADVL1011)
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Mignon L. Loh, Charlotte H. Ahern, Patrick Brown, Karen R. Rabin, Susan M. Blaney, Sarah K. Tasian, Brenda J. Weigel, Daniel Magoon, Joel M. Reid, and Xuejun Chen
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Oncology ,medicine.medical_specialty ,Ruxolitinib ,business.industry ,Hematology ,Neutropenia ,medicine.disease ,Polycythemia vera ,Pharmacokinetics ,Refractory ,Oral administration ,Pharmacodynamics ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Dosing ,business ,medicine.drug - Abstract
Background Ruxolitinib, an orally bioavailable JAK1/JAK2 inhibitor, may treat cancers with CRLF2 and/or JAK pathway mutations. Procedure A phase 1 trial of ruxolitinib was performed to determine the maximum tolerated or recommended phase 2 dose, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and pharmacodynamics (PD) in children with recurrent/refractory solid tumors (STs). Ruxolitinib was administered twice daily (BID) in 28-day cycles at five dose levels (15, 21, 29, 39, and 50 mg/m2/dose). PK and PD studies were performed during cycle 1. Toxicity, preliminary efficacy, and PK/PD were also assessed in children with relapsed/refractory hematologic malignancies (HMs). Results Forty-nine patients were enrolled, 28 with STs (dose escalation cohort) and 21 with HMs. Ruxolitinib was well-tolerated with one DLT per cohort of six patients at dose levels (DLs) 2–5. One patient with an ST had grade 5 multi-organ failure at DL2. One patient each at DL3 and DL4 had a grade 4 neutropenia, and one patient at DL5 had a grade 4 creatinine phosphokinase elevation. No objective responses were observed in patients with STs. One patient with polycythemia vera achieved a partial response and received 18 cycles of ruxolitinib. The PK of ruxolitinib were similar to that in adults. Partial inhibition of phosphorylated JAK2, STAT5, and S6 was observed in in vitro plasma inhibitory activity PD assay. Conclusion Ruxolitinib was well tolerated in children with refractory cancer. The recommended phase 2 dose for continuous BID oral administration is 50 mg/m2/dose. Subsequent evaluation of ruxolitinib in combination with cytotoxic chemotherapy in children, adolescents, and young adults with JAK-mutant leukemias is planned. Pediatr Blood Cancer 2015;62:1717–1724. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
43. Phase 2 trial of sorafenib in children and young adults with refractory solid tumors: A report from the Children's Oncology Group
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AeRang Kim, Elizabeth Fox, Nalini Jayaprakash, Brigitte C. Widemann, Mark Krailo, Brenda J. Weigel, and Susan M. Blaney
- Subjects
Sorafenib ,Oncology ,medicine.medical_specialty ,business.industry ,Salvage therapy ,Phases of clinical research ,Wilms' tumor ,Hematology ,medicine.disease ,female genital diseases and pregnancy complications ,digestive system diseases ,Regimen ,Pharmacodynamics ,Hepatocellular carcinoma ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,business ,Rhabdomyosarcoma ,neoplasms ,medicine.drug - Abstract
Background Sorafenib is an oral small molecule inhibitor of multiple kinases controlling tumor growth and angiogenesis. The purpose of the phase 2 study was to determine the response rate of sorafenib and gain further information on the associated toxicities, pharmacokinetics, and pharmacodynamics of sorafenib in children and young adults with relapsed or refractory tumors including rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma (HCC), and papillary thyroid carcinoma (PTC). Procedure Sorafenib, 200 mg/m2/dose, was administered every 12 hr continuously for 28 day cycles using a two-stage design in two primary strata (rhabdomyosarcoma and Wilms tumor) and two secondary strata (HCC and PTC). Correlative studies in consenting patients included determination of sorafenib steady state trough concentrations and assessments of VEGF and sVEGFR2. Results Twenty patients (median age of 11 years; range, 5–21) enrolled. No objective responses (RECIST) were observed in the 10 evaluable patients enrolled in each of the two primary disease strata of rhabdomyosarcoma and Wilms tumor. No patients with HCC or PTC were enrolled. Sorafenib was not associated with an excessive rate of dose-limiting toxicity (DLT). The mean ± SD steady state concentration during cycle 1 day 15 was 6.5 ± 3.9 μg/ml (n = 10). Conclusions Sorafenib was well tolerated in children at 200 mg/m2/dose twice daily on a continuous regimen with toxicity profile and steady state drug concentrations similar to those previously reported. Single agent sorafenib was inactive in children with recurrent or refractory rhabdomyosarcoma or Wilms tumor. Pediatr Blood Cancer 2015;62:1562–1566. © 2015 Wiley Periodicals, Inc.
- Published
- 2015
44. A Phase I Study of Cixutumumab (IMC-A12) in Combination with Temsirolimus (CCI-779) in Children with Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Report
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Carol A. Mercer, Helen X. Chen, Peter J. Houghton, L. Austin Doyle, Charlotte H. Ahern, Brenda J. Weigel, Darcy A. Krueger, Joel M. Reid, Susan M. Blaney, George Thomas, Maryam Fouladi, Lars M. Wagner, Alexander A. Vinks, and John P. Perentesis
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Cixutumumab ,Pharmacology ,medicine.disease ,Peripheral blood mononuclear cell ,Gastroenterology ,Temsirolimus ,chemistry.chemical_compound ,Oncology ,Refractory ,chemistry ,Pharmacokinetics ,Internal medicine ,Sirolimus ,Toxicity ,Mucositis ,Medicine ,business ,medicine.drug - Abstract
Purpose: To determine the MTD, dose-limiting toxicities (DLT), pharmacokinetics, and biologic effects of cixutumumab administered in combination with temsirolimus to children with refractory solid tumors. Experimental Design: Cixutumumab and temsirolimus were administered intravenously once every 7 days in 28-day cycles. Pharmacokinetic and biology studies, including assessment of mTOR downstream targets in peripheral blood mononuclear cells, were performed during the first cycle. Results: Thirty-nine patients, median age 11.8 years (range, 1–21.5), with recurrent solid or central nervous system tumors were enrolled, of whom 33 were fully assessable for toxicity. There were four dose levels, which included two dose reductions and a subsequent intermediated dose escalation: (i) IMC-A12 6 mg/kg, temsirolimus 15 mg/m2; (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m2; (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m2; and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m2. Mucositis was the predominant DLT. Other DLTs included hypercholesterolemia, fatigue, thrombocytopenia, and increased alanine aminotransferase. Target inhibition (decreased S6K1 and PAkt) in peripheral blood mononuclear cells was noted at all dose levels. Marked interpatient variability in temsirolimus pharmacokinetic parameters was noted. At 8 mg/m2, the median temsirolimus AUC was 2,946 ng • h/mL (range, 937–5,536) with a median sirolimus AUC of 767 ng • h/mL (range, 245–3,675). Conclusions: The recommended pediatric phase II doses for the combination of cixutumumab and temsirolimus are 6 mg/kg and 8 mg/m2, respectively. Clin Cancer Res; 21(7); 1558–65. ©2014 AACR.
- Published
- 2015
45. A phase I trial and viral clearance study of reovirus (Reolysin) in children with relapsed or refractory extra-cranial solid tumors: A Children's Oncology Group Phase I Consortium report
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Timothy P. Cripe, Deborah L. Stabley, Valerie B. Sampson, Susan M. Blaney, Charlotte H. Ahern, James A. Zwiebel, E. Anders Kolb, Katia Sol-Church, Pooja Hingorani, Alexa Walter, and Brenda J. Weigel
- Subjects
Oncology ,medicine.medical_specialty ,Cyclophosphamide ,business.industry ,viruses ,Hematology ,Pediatric cancer ,Pharmacokinetics ,Refractory ,Internal medicine ,Pediatrics, Perinatology and Child Health ,Reolysin ,Medicine ,Malignant cells ,Single agent ,business ,medicine.drug - Abstract
Purpose Reovirus is a naturally occurring human virus that is cytopathic to malignant cells possessing an activated Ras signaling pathway. We conducted a phase I trial of Reolysin, a manufactured, proprietary isolate of purified reovirus, in children with relapsed/refractory extracranial solid tumors to define the recommended phase 2 dose (RP2D), toxicities and pharmacokinetic properties when administered as a single agent or in combination with cyclophosphamide.
- Published
- 2015
46. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: A report from the children's oncology group
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Atif A. Ahmed, Steven G. DuBois, L. Austin Doyle, Susan M. Blaney, Brenda J. Weigel, Helen X. Chen, Mark Krailo, Lars M. Wagner, and Maryam Fouladi
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Soft tissue sarcoma ,Phases of clinical research ,Cixutumumab ,Hematology ,medicine.disease ,Temsirolimus ,chemistry.chemical_compound ,chemistry ,Sirolimus ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Osteosarcoma ,Sarcoma ,Rhabdomyosarcoma ,business ,medicine.drug - Abstract
Background The combined inhibition of insulin-growth factor type 1 receptor (IGF-1R) and the mammalian target of rapamycin (mTOR) has shown activity in preclinical models of pediatric sarcoma and in adult sarcoma patients. We evaluated the activity of the anti-IGF-1R antibody cixutumumab with the mTOR inhibitor temsirolimus in patients with relapsed or refractory Ewing sarcoma, osteosarcoma, rhabdomyosarcoma, and other soft tissue sarcoma, using the recommended dosages from a pediatric phase I trial.
- Published
- 2014
47. A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study
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Mehmet Kocak, Maryam Fouladi, Larry E. Kun, Richard J. Gilbertson, Susan M. Blaney, Anuradha Banerjee, Lindsay Kilburn, Stewart Goldman, James M. Boyett, Cynthia Wetmore, Jack Su, Murali Chintagumpala, and Rodney Decker
- Subjects
Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Indoles ,Pediatric Brain Tumor Consortium ,Adolescent ,Nausea ,Central nervous system ,Brain tumor ,Administration, Oral ,Antineoplastic Agents ,Pharmacology ,Central Nervous System Neoplasms ,Young Adult ,chemistry.chemical_compound ,Enzastaurin ,Refractory ,Pharmacokinetics ,Internal medicine ,Glioma ,Protein Kinase C beta ,medicine ,Humans ,Phosphorylation ,Child ,Dose-Response Relationship, Drug ,business.industry ,medicine.disease ,Treatment Outcome ,medicine.anatomical_structure ,chemistry ,Child, Preschool ,Female ,Neurology (clinical) ,medicine.symptom ,business ,Proto-Oncogene Proteins c-akt ,Pediatric Neuro-Oncology - Abstract
We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cβ, in children with recurrent central nervous system malignancies.Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples.Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma.Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily.
- Published
- 2014
48. A Phase 1 Study of the c-Met Inhibitor, Tivantinib (ARQ197) in Children with Relapsed or Refractory Solid Tumors: A Children’s Oncology Group Study Phase 1 and Pilot Consortium Trial (ADVL1111)
- Author
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Susan M. Blaney, Joel M. Reid, Elizabeth Fox, Charles G. Minard, John P. Perentesis, Rachel A. Kudgus, Xiaowei Liu, James I. Geller, and Brenda J. Weigel
- Subjects
0301 basic medicine ,Oncology ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Maximum Tolerated Dose ,Brain tumor ,Cmax ,Pilot Projects ,CYP2C19 ,Article ,c-Met inhibitor ,03 medical and health sciences ,chemistry.chemical_compound ,Young Adult ,0302 clinical medicine ,Pharmacokinetics ,Refractory ,Internal medicine ,Neoplasms ,medicine ,Humans ,Tissue Distribution ,Tivantinib ,Child ,Neoplasm Staging ,Salvage Therapy ,business.industry ,Infant ,Hematology ,Proto-Oncogene Proteins c-met ,medicine.disease ,Prognosis ,Pyrrolidinones ,030104 developmental biology ,chemistry ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Child, Preschool ,Pediatrics, Perinatology and Child Health ,Cohort ,Quinolines ,Female ,Neoplasm Recurrence, Local ,business - Abstract
Background The c-Met receptor tyrosine kinase is dysregulated in many pediatric cancers. Tivantinib is an oral small molecule that inhibits the c-Met receptor tyrosine kinase. A phase 1 and pharmacokinetic (PK) trial evaluating tivantinib was conducted in children with relapsed/refractory solid tumors. Methods Oral tivantinib capsules were administered twice daily with food, continuously in 28-day cycles. Dose levels 170, 200, and 240 mg/m2/dose were evaluated using a rolling-six design (Part A). In Part B, subjects received tivantinib powder sprinkled on food at the recommended phase 2 dose (RP2D) from Part A. PK, CYP2C19 genotyping, and baseline tumor tissue c-Met expression were analyzed. Results Thirty-six patients were enrolled: 20 in Part A, 6 in a PK expansion cohort, and 10 in Part B. Fifteen patients had primary central nervous system tumors and 21 had solid tumors. In Part A, there were no dose-limiting toxicities. One grade 4 intracranial hemorrhage occurred in a patient with a progressive brain tumor in the expanded PK cohort (240 mg/m2). PK analysis showed marked interpatient variability (20-fold) in the Cmax and AUC0-8h across all dose levels. Sprinkling tivantinib powder over food did not alter exposure. Membranous and total c-Met expression was moderate (2), low (4), or not detected (26). Two patients had stable disease as the best response. Conclusions The RP2D of tivantinib given with food in children with refractory solid tumors is 240 mg/m2/dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial.
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- 2017
49. 50 Years Ago in The Journal of Pediatrics: Diencephalic Syndromes of Infancy: Report of 3 Children with Emaciation Syndrome and Disproportionately Large Hands and Feet
- Author
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Emily B, Heikamp and Susan M, Blaney
- Subjects
Emaciation ,Brain Neoplasms ,Foot ,Humans ,Glioma ,Syndrome ,Diencephalon ,History, 20th Century ,Hand - Published
- 2017
50. Phase I trial of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors: A report of the Children's Oncology Group
- Author
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Charles M. Rudin, Susan M. Blaney, Brenda J. Weigel, M. Brooke Bernhardt, John T. Poirier, Timothy P. Cripe, Michael J. Burke, Yingbei Chen, and Charlotte H. Ahern
- Subjects
medicine.medical_specialty ,Leukopenia ,Cyclophosphamide ,business.industry ,Anemia ,Nausea ,Salvage therapy ,Wilms' tumor ,Hematology ,Neutropenia ,medicine.disease ,Gastroenterology ,Surgery ,Oncology ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,medicine.symptom ,business ,Rhabdomyosarcoma ,medicine.drug - Abstract
Background To determine the MTD of Seneca Valley Virus (NTX-010) in children with relapsed/refractory solid tumors. Patients (≥3–≤21 years) with neuroblastoma, rhabdomyosarcoma, or rare tumors with neuroendocrine features were eligible. Procedure Part A (single dose of NTX-010) enrolled 13 patients at three dose levels (1 × 109 viral particles (vp)/kg [n = 6], 1 × 1010 vp/kg [n = 3], 1 × 1011 vp/kg [n = 4]). Diagnoses included neuroblastoma (n = 9), rhabdomyosarcoma (n = 2), carcinoid tumor (n = 1), and adrenocorticocarcinoma (n = 1). Part B added cyclophosphamide (CTX) (oral CTX (25 mg/m2/day) days 1–14 and IV CTX (750 mg/m2) days 8 and 29) to two doses of NTX-010 (1 × 1011 vp/kg, days 8 and 29). Nine patients enrolled to Part B. Diagnoses included neuroblastoma (n = 3), rhabdomyosarcoma (n = 1), Wilms tumor (n = 3), and adrenocorticocarcinoma (n = 2). Results Twelve patients on Part A were evaluable for toxicity. There was a single DLT (grade 3 pain) at dose level 1. Additional grade ≥3 related adverse events (AEs) included leukopenia (n = 1), neutropenia (n = 3), lymphopenia (n = 3), and tumor pain (n = 1). No DLTs occurred on part B. Other grade ≥3 related AEs on Part B included: Leukopenia (n = 3), nausea (n = 1), emesis (n = 1), anemia (n = 1), neutropenia (n = 4), platelets (n = 1), alanine aminotransferase (n = 1), and lymphopenia (n = 2). All patients cleared NTX-010 from blood and stool by 3 weeks with 17/18 patients developing neutralizing antibodies. Conclusion NTX-010 is feasible and tolerable at the dose levels tested in pediatric patients with relapsed/refractory solid tumors either alone or in combination with cyclophosphamide. However, despite the addition of cyclophosphamide, neutralizing antibodies appeared to limit applicability. Pediatr Blood Cancer 2015;62:743–750. © 2014 Wiley Periodicals, Inc.
- Published
- 2014
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