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1.
Pediatr Blood Cancer ; 71(3): e30817, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38189770

ABSTRACT

BACKGROUND: Ramucirumab is a monoclonal antibody that binds the extracellular domain of vascular endothelial growth factor receptor (VEGFR-2) and prevents binding of VEGF ligands. Based on population pharmacokinetic (PK) analysis and correlation with efficacy in adults, a target steady state trough concentration (Css,min ) ≥ 50 µg/mL was established. PROCEDURES: This phase 1 trial (ADVL1416) used a rolling six design and a PK primary endpoint to define the recommended phase 2 dose (RP2D) of ramucirumab in children with recurrent/refractory solid tumors. Two dose levels (DL) were planned (DL1: 8 mg/kg, DL2: 12 mg/kg administered intravenously [IV] every 2 weeks). Toxicity during the initial 6 weeks was used to assess maximum tolerated dose (MTD). Cycle 1 Day 42 trough (Cmin ) ≥ 50 µg/mL was the target concentration for the PK endpoint. At the RP2D, cohorts for PK expansion and children with central nervous tumors were planned. RESULTS: Twenty-nine patients were enrolled; 28 were eligible; median age [range] = 13.5 [1-21] years; 22 were evaluable for the PK endpoint. Dose-limiting proteinuria occurred at both DLs; however, the MTD was not exceeded. At DL2 (12 mg/kg), the median Day 42 Cmin (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a Cmin  ≥ 50 µg/mL. CONCLUSION: Ramucirumab was well tolerated in children and adolescents with solid tumors. The RP2D for ramucirumab was 12 mg/kg IV every 2 weeks. This trial demonstrates the feasibility of incorporating a primary PK endpoint to determine dose escalation and the RP2D in children. Studies of ramucirumab in children with selected solid tumors are ongoing.


Subject(s)
Central Nervous System Neoplasms , Neoplasms , Adult , Child , Humans , Adolescent , Ramucirumab , Vascular Endothelial Growth Factor A/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Neoplasms/pathology , Antibodies, Monoclonal/therapeutic use , Central Nervous System Neoplasms/drug therapy , Maximum Tolerated Dose
2.
Pediatr Transplant ; 23(4): e13410, 2019 06.
Article in English | MEDLINE | ID: mdl-31012199

ABSTRACT

Hepatic angiosarcoma is an extremely rare diagnosis in children, with fewer than 50 pediatric cases reported in the literature worldwide. This aggressive vascular sarcoma carries a very dismal prognosis and is known to be resistant to radiation, chemotherapy, and other vascular-targeted agents. Complete surgical resection is felt to provide the best chance for long-term survival. In patients with tumors not amenable to resection, a liver transplant can be considered. However, very few such transplants have been reported, given that they remain controversial due to high cancer recurrence and mortality post-transplant. Herein, we report the unique case of a 2-year-old child with localized hepatic angiosarcoma not amendable to resection who successfully underwent a liver transplant and received chemotherapy with six cycles of doxorubicin, docetaxel, and ifosfamide.


Subject(s)
Antineoplastic Agents/pharmacology , Hemangiosarcoma/surgery , Liver Neoplasms/surgery , Liver Transplantation , Biopsy , Child, Preschool , Docetaxel/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Ifosfamide/administration & dosage , Liver/diagnostic imaging , Neoplasm Recurrence, Local , Treatment Outcome
3.
Oncotarget ; 9(15): 11938-11947, 2018 Feb 23.
Article in English | MEDLINE | ID: mdl-29552283

ABSTRACT

Children with high risk sarcoma have a poor prognosis despite surgical resection, irradiation and chemotherapy. Alternative therapies are urgently needed. Urokinase-type plasminogen activator receptor (uPAR) and epidermal growth factor receptor (EGFR) are surface proteins expressed by some pediatric sarcomas. We show for the first time that a de-immunized bispecific ligand toxin, EGFATFKDEL, directed against EGFR and uPAR, successfully targets pediatric sarcoma. Using flow cytometry, we identified a rhabdomyosarcoma (RMS) cell line, RH30, that expresses both uPAR and EGFR, and a Ewing sarcoma (EWS) cell line, TC-71, that expresses only uPAR. We tested the differential sensitivity of these two sarcoma cell lines to toxin-induced killing, using both in vitro assays and an in vivo murine model. We show that pediatric sarcomas are highly sensitive to EGFATFKDEL (at subnanomolar concentrations) in vitro. In vivo, tumor growth was significantly attenuated after treatment with EGFTFKDEL, compared to untreated controls, in both RH30 and TC-71 tumor bearing mice. In addition, we found that simultaneously targeting both receptors in a dual positive cell line was more effective than targeting a single receptor or antigen, resulting in a greater tumor response, including complete tumor regression in an animal model of bulky disease. Our findings provide support for further exploration of bispecific targeting of pediatric sarcomas with bispecific ligand toxins, such as EGFATFKDEL.

4.
Mol Cancer Ther ; 16(5): 956-965, 2017 05.
Article in English | MEDLINE | ID: mdl-28193671

ABSTRACT

Sarcomas differ from carcinomas in their mesenchymal origin. Therapeutic advancements have come slowly, so alternative drugs and models are urgently needed. These studies report a new drug for sarcomas that simultaneously targets both tumor and tumor neovasculature. eBAT is a bispecific angiotoxin consisting of truncated, deimmunized Pseudomonas exotoxin fused to EGF and the amino terminal fragment of urokinase. Here, we study the drug in an in vivo "ontarget" companion dog trial as eBAT effectively kills canine hemangiosarcoma and human sarcoma cells in vitro We reasoned the model has value due to the common occurrence of spontaneous sarcomas in dogs and a limited lifespan allowing for rapid accrual and data collection. Splenectomized dogs with minimal residual disease were given one cycle of eBAT followed by adjuvant doxorubicin in an adaptive dose-finding, phase I-II study of 23 dogs with spontaneous, stage I-II, splenic hemangiosarcoma. eBAT improved 6-month survival from <40% in a comparison population to approximately 70% in dogs treated at a biologically active dose (50 µg/kg). Six dogs were long-term survivors, living >450 days. eBAT abated expected toxicity associated with EGFR targeting, a finding supported by mouse studies. Urokinase plasminogen activator receptor and EGFR are targets for human sarcomas, so thorough evaluation is crucial for validation of the dog model. Thus, we validated these markers for human sarcoma targeting in the study of 212 human and 97 canine sarcoma samples. Our results support further translation of eBAT for human patients with sarcomas and perhaps other EGFR-expressing malignancies. Mol Cancer Ther; 16(5); 956-65. ©2017 AACR.


Subject(s)
ErbB Receptors/genetics , Hemangiosarcoma/drug therapy , Molecular Targeted Therapy , Receptors, Urokinase Plasminogen Activator/genetics , ADP Ribose Transferases/administration & dosage , ADP Ribose Transferases/chemistry , ADP Ribose Transferases/genetics , Animals , Bacterial Toxins/administration & dosage , Bacterial Toxins/chemistry , Bacterial Toxins/genetics , Cell Line, Tumor , Disease Models, Animal , Dogs , Doxorubicin/administration & dosage , Epidermal Growth Factor/chemistry , Epidermal Growth Factor/genetics , ErbB Receptors/antagonists & inhibitors , Exotoxins/administration & dosage , Exotoxins/chemistry , Exotoxins/genetics , Hemangiosarcoma/genetics , Hemangiosarcoma/pathology , Humans , Mice , Neoplasm Staging , Receptors, Urokinase Plasminogen Activator/antagonists & inhibitors , Urokinase-Type Plasminogen Activator/chemistry , Urokinase-Type Plasminogen Activator/genetics , Virulence Factors/administration & dosage , Virulence Factors/chemistry , Virulence Factors/genetics , Pseudomonas aeruginosa Exotoxin A
5.
J Immunol ; 180(3): 1432-41, 2008 Feb 01.
Article in English | MEDLINE | ID: mdl-18209038

ABSTRACT

A subset of NK cells bears incomplete V(D)J rearrangements, but neither the consequence to cell activities nor the precise developmental stages in which recombination occurs is known. These are important issues, as recombination errors cause cancers of the B and T lineages. Using transgenic recombination reporter mice to examine NK cell dynamics in vivo, we show that recombination(+) NK cells have distinct developmental patterns in the BM, including reduced homeostatic proliferation and diminished Stat5 phosphorylation. In the periphery, both recombination(+) and recombination(-) NK cells mediate robust functional responses including IFN-gamma production, cytolysis, and tumor homing, suggesting that NK cells with distinct developmental histories can be found together in the periphery. We also show that V(D)J rearrangement marks both human cytolytic (CD56(dim)) and immunoregulatory (CD56(bright)) populations, demonstrating the distribution of permanent DNA rearrangements across major NK cell subsets in man. Finally, direct quantification of rag transcripts throughout NK cell differentiation in both mouse and man establishes the specific developmental stages that are susceptible to V(D)J rearrangement. Together, these data demonstrate that multipotent progenitors rather than lineage-specified NK progenitors are targets of V(D)J recombination and that NK cells bearing the relics of earlier V(D)J rearrangements have different developmental dynamics but robust biological capabilities in vivo.


Subject(s)
Gene Rearrangement , Killer Cells, Natural/immunology , Animals , CD56 Antigen/analysis , Cell Lineage , DNA-Binding Proteins/genetics , Homeodomain Proteins/genetics , Humans , Killer Cells, Natural/enzymology , Mice , Mice, Transgenic , Multipotent Stem Cells/immunology , Phosphorylation , Recombination, Genetic/genetics , STAT5 Transcription Factor/metabolism , VDJ Recombinases/metabolism
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