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Purpose: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice trial assigned patients age 1-21 years with relapsed or refractory solid tumors, lymphomas, and histiocytic disorders to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with tumors that harbored prespecified genomic alterations in the cyclinD-CDK4/6-INK4a-Rb pathway with intact Rb expression were assigned and treated with the cdk4/6 inhibitor palbociclib., Methods: Patients received palbociclib orally once daily for 21 days of 28-day cycles until disease progression, intolerable toxicity, or up to 2 years. The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival., Results: Twenty-three patients (median age, 15 years; range, 8-21) were enrolled; 20 received protocol therapy and were evaluable for toxicity and response. Of the evaluable patients, the most common diagnoses were osteosarcoma (n = 9) and rhabdomyosarcoma (n = 6). A single actionable gene amplification was found in 19 tumors ( CDK4 , n = 11, CDK6 , n = 2, CCND3 , n = 6), with one tumor harboring two amplifications ( CDK4 and CCND2 ). Hematologic toxicities were the most common treatment-related events. No objective responses were seen. Two patients with tumors harboring CDK4 amplifications (neuroblastoma and sarcoma) had best response of stable disease for six and three cycles. Six-month progression was 10% (95% CI, 1.7 to 27.2)., Conclusion: The CDK4/6 inhibitor palbociclib at 75 mg/m 2 orally daily was tolerable in this heavily pretreated cohort. No objective responses were observed in this histology-agnostic biomarker-selected population with treatment-refractory solid tumors, demonstrating that pathway alteration alone is insufficient in pediatric cancers to generate a response to palbociclib monotherapy.

Purpose: The objective of this study was to determine the recommended Phase 2 dose (RP2D) of pevonedistat, a first in class inhibitor of NEDD8 activating enzyme, in combination with irinotecan (IRN) and temozolomide (TMZ) in children with cancer., Methods: This Phase 1 study used a rolling 6 design to evaluate escalating doses of pevonedistat in combination with standard doses of IRN and TMZ in pediatric patients with recurrent/refractory solid or CNS tumors. During cycle 1, pevonedistat was administered intravenously on days 1, 8, 10, and 12, with IRN (IV, 50 mg/m 2 ) and TMZ (orally, 100 mg/m 2 ), on days 8-12 of a 28-day cycle. In subsequent cycles, pevonedistat was administered on days 1, 3, and 5, with IRN/TMZ on days 1-5 of a 21-day cycle., Results: Thirty patients enrolled; all were eligible and evaluable for toxicity. Six patients each enrolled on pevonedistat dose levels (DL) 1 (15 mg/m 2 ), 2 (20 mg/m 2 ), 3 (25 mg/m 2 ) and 4 (35 mg/m 2 ) as well as an expanded pharmacokinetic (PK) cohort at DL4. The maximum tolerated dose (MTD) was not exceeded. 2/12 (17 %) patients treated at the RP2D (35 mg/m 2 ) experienced a cycle 1 dose limiting toxicity (DLT). IRN is unlikely to affect the pharmacokinetics of pevonedistat. Two patients had a partial response and 6 patients had prolonged stable disease (> 6 cycles)., Conclusions: Pevonedistat in combination with IRN/TMZ is well tolerated in children with solid or CNS tumors. The RP2D of pevonedistat is 35 mg/m 2 on days 1, 3, 5 in combination with IRN/TMZ., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib., Methods: Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response., Results: Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed., Conclusion: Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual., Clinicaltrials.gov Identifier: NCT03233204. IRB approved: initial July 24, 2017., (© The Author(s) 2024. Published by Oxford University Press.)

Purpose: Pepinemab, a humanized IgG4 monoclonal antibody, targets the SEMA4D (CD100) antigen to inhibit binding to its high-affinity receptors (plexin B1/PLXNB1, plexin B2/PLXNB2) and low-affinity receptor (CD72). SEMA4D blockade leads to increased cytotoxic T-cell infiltration, delayed tumor growth, and durable tumor rejection in murine tumor models. Pepinemab was well tolerated and improved T cell infiltration in clinical studies in adults with refractory tumors. SEMA4D was identified as a strong candidate proto-oncogene in a model of osteosarcoma. Based on these preclinical and clinical data, we conducted a phase 1/2 study to determine the recommended phase 2 dose (RP2D), pharmacokinetics, pharmacodynamics, and immunogenicity, of pepinemab in pediatric patients with recurrent/refractory solid tumors, and activity in osteosarcoma., Experimental Design: Pepinemab was administered intravenously on Days 1 and 15 of a 28-day cycle at 20 mg/kg, the adult RP2D. Part A (phase 1) used a Rolling 6 design; Part B (phase 2) used a Simon 2-stage design in patients with osteosarcoma. Pharmacokinetics and target saturation were evaluated in peripheral blood., Results: Pepinemab (20 mg/kg) was well tolerated and no dose-limiting toxicities were observed during Part A. There were no objective responses. Two patients with osteosarcoma achieved disease control and prolonged stable disease. Pepinemab pharmacokinetics were similar to adults., Conclusions: Pepinemab (20 mg/kg) is safe, well tolerated and resulted in adequate and sustained target saturation in pediatric patients. Encouraging disease control in two patients with osteosarcoma warrants further investigation with novel combination strategies to modulate the tumor microenvironment and antitumor immune response., Clinical Trial Registry: This trial is registered as NCT03320330 at Clinicaltrials.gov., Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health., (© 2024 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Purpose: The National Cancer Institute-Children's Oncology Group (NCI-COG) Pediatric MATCH trial assigns patients age 1-21 years with refractory malignancies to phase II treatment arms of molecularly targeted therapies on the basis of genetic alterations detected in their tumor. Patients with activating alterations in the mitogen-activated protein kinase pathway were treated with ulixertinib, an extracellular signal-regulated kinase (ERK)1/2 inhibitor., Methods: As there were no previous pediatric data, ulixertinib was initially tested in a dose escalation cohort to establish the recommended phase II dose (RP2D) before proceeding to the phase II cohort. Ulixertinib was administered at 260 mg/m 2 /dose orally twice a day (dose level 1 [DL1], n = 15) or 350 mg/m 2 /dose orally twice a day (DL2, n = 5). The primary end point was objective response rate; secondary end points included safety/tolerability and progression-free survival (PFS)., Results: Twenty patients (median 12 years; range, 5-20) were treated, all evaluable for response. CNS tumors comprised 55% (11/20) of diagnoses, with high-grade glioma and low-grade glioma most common (n = 5 each). All CNS tumors except one harbored BRAF fusions or V600E mutations. Rhabdomyosarcoma (n = 5) was the most frequent non-CNS diagnosis. DL1 was declared the RP2D in the dose escalation cohort after dose-limiting toxicities in Cycle 1 occurred in 1/6 patients at DL1 and 2/5 patients at DL2, including fatigue, anorexia, rash, nausea, vomiting, diarrhea, dehydration, hypoalbuminemia, and hypernatremia. No objective responses were observed. Six-month PFS was 37% (95% CI, 17 to 58). Three patients with BRAF -altered CNS tumors achieved stable disease >6 months., Conclusion: Ulixertinib, a novel targeted agent with no previous pediatric data, was successfully evaluated in a national precision medicine basket trial. The pediatric RP2D of ulixertinib is 260 mg/m 2 /dose orally twice a day. Limited single-agent efficacy was observed in a biomarker-selected cohort of refractory pediatric tumors.

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 (C ss,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 (C min ) ≥ 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 C min (n = 16) was 87.8 µg/mL; 15 of 16 patients achieved a C min  ≥ 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., (© 2024 Wiley Periodicals LLC.)

Copanlisib is an intravenously administered phosphatidylinositol 3-kinase (PI3K) inhibitor which was investigated in pediatric patients with relapsed/refractory solid tumors. A model-informed approach was undertaken to support and confirm an empirically selected starting dose of 28 mg/m 2 for pediatric patients ≥1 year old, corresponding to 80% of the adult recommended dose adjusted for body surface area. An adult physiologically based pharmacokinetic (PBPK) model was initially established using copanlisib physicochemical and disposition properties and clinical pharmacokinetics (PK) data and was shown to adequately capture clinical PK across a range of copanlisib doses in adult cancer patients. The adult PBPK model was then extended to the pediatric population through incorporation of age-dependent anatomical and physiological changes and used to simulate copanlisib exposures in pediatric cancer patient age groups. The pediatric PBPK model predicted that the copanlisib 28 mg/m 2 dose would achieve similar copanlisib exposures across pediatric ages when compared with historical adult exposures following the approved copanlisib 60 mg dose administered on Days 1, 8, and 15 of a 28-day cycle. Clinical PK were collected from a phase I study in pediatric patients with relapsed/refractory solid tumors (aged ≥4 years). An established adult population PK model was extended to incorporate an allometrically-scaled effect of body surface area and confirmed that the copanlisib maximum tolerated dose of 28 mg/m 2 was appropriate to achieve uniform copanlisib exposures across the investigated pediatric age range and consistent exposures to historical data in adult cancer patients. The model-informed approach successfully supported and confirmed the copanlisib pediatric dose recommendation., (© 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The purpose of this study was to develop and validate a population pharmacokinetic model for Z-endoxifen in patients with advanced solid tumors and to identify clinical variables that influence pharmacokinetic parameters. Z-endoxifen-HCl was administered orally once a day on a 28-day cycle (±3 days) over 11 dose levels ranging from 20 to 360 mg. A total of 1256 Z-endoxifen plasma concentration samples from 80 patients were analyzed using nonlinear mixed-effects modeling to develop a population pharmacokinetic model for Z-endoxifen. A 2-compartment model with oral depot and linear elimination adequately described the data. The estimated apparent total clearance, apparent central volume of distribution, and apparent peripheral volume of distribution were 4.89 L/h, 323 L, and 39.7 L, respectively, with weight-effect exponents of 0.75, 1, and 1, respectively. This model was used to explore the effects of clinical and demographic variables on Z-endoxifen pharmacokinetics. Weight, race on clearance, and aspartate aminotransferase on the absorption rate constant were identified as significant covariates in the final model. This novel population pharmacokinetic model provides insight regarding factors that may affect the pharmacokinetics of Z-endoxifen and may assist in the design of future clinical trials., (© 2022, The American College of Clinical Pharmacology.)

Purpose: Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response., Methods: Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length., Results: Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients., Conclusions: Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Prexasertib (LY2606368) is a novel, second-generation, selective dual inhibitor of checkpoint kinase proteins 1 (CHK1) and 2 (CHK2). We conducted a phase 1 trial of prexasertib to estimate the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), to define and describe the toxicities, and to characterize the pharmacokinetics (PK) of prexasertib in pediatric patients with recurrent or refractory solid and central nervous system (CNS) tumors., Methods: Prexasertib was administered intravenously (i.v.) on days 1 and 15 of a 28-day cycle. Four dose levels, 80, 100, 125, and 150 mg/m 2 , were evaluated using a rolling-six design. PK analysis was performed during cycle 1. Tumor tissue was examined for biomarkers (CHK1 and TP53) of prexasertib activity., Results: Thirty patients were enrolled; 25 were evaluable. The median age was 9.5 years (range: 2-20) and 21 (70%) were male. Twelve patients (40%) had solid tumors and 18 patients (60%) had CNS tumors. There were no cycle 1 or later dose-limiting toxicities. Common cycle 1, drug-related grade 3/4 toxicities (> 10% of patients) included neutropenia (100%), leukopenia (68%), thrombocytopenia (24%), lymphopenia (24%), and anemia (12%). There were no objective responses; best overall response was stable disease in three patients for five cycles (hepatocellular carcinoma), three cycles (ependymoma), and five cycles (undifferentiated sarcoma). The PK appeared dose proportional across the 80-150 mg/m 2 dose range., Conclusions: Although the MTD of prexasertib was not defined by this study, 150 mg/m 2 administered i.v. on days 1 and 15 of a 28-day cycle was determined to be the RP2D., (© 2021 Wiley Periodicals LLC.)

Background: Entinostat is an oral small molecule inhibitor of class I histone deacetylases (HDAC), which has not previously been evaluated in pediatrics. We conducted a phase I trial to determine the maximum tolerated dose/recommended phase 2 dose (MTD/RP2D), toxicity profile, pharmacokinetics (PK), and pharmacodynamics (PD) of entinostat in children with relapsed or refractory solid tumors including central nervous system (CNS) malignancies., Methods: A rolling six dose escalation design evaluated two dose levels. Entinostat oral tablet formulation was administered once per week, four doses per 28-day cycle. PK and PD studies were performed., Results: Twenty-one eligible patients' median (range) age was 14 years (6-20). Six subjects were treated at 3 mg/m 2 dose level and 15 were treated in 4 mg/m 2 dose level. The study included patients with CNS tumors (n = 12), sarcomas (n = 6), or other solid tumors (n = 3). Eight patients were not fully evaluable for toxicity due to progression of disease prior to receiving the required percentage of protocol therapy. No cycle one dose-limiting toxicity (DLT) was observed at either dose level. A three-fold higher area under the curve (AUC) was achieved in our cohort compared to adults using a similar dosing schedule. The PD studies showed increase in acetylated lysine in peripheral blood leukocytes at both doses., Conclusions: Entinostat was well tolerated with no DLT observed. All patients experienced progression within the first two cycles, except one patient with ependymoma with stable disease. Based on PK and PD, the R2PD in pediatric patients with solid tumors is 4 mg/m 2 orally administered once weekly., (© 2021 Wiley Periodicals LLC.)

Background: Immune checkpoint inhibitors targeting PD-1 have shown clinical benefit in adults with cancer, but data on these drugs in children are scarce. We did a phase 1-2 study of nivolumab, a PD-1 blocking monoclonal antibody, to determine its safety, pharmacokinetics, and antitumour activity in children and young adults with recurrent or refractory non-CNS solid tumours or lymphoma., Methods: We did a multicentre, open-label, single-arm, dose-confirmation and dose-expansion, phase 1-2 trial in 23 hospitals in the USA. Eligible patients for part A (dose-confirmation phase) of the study were aged 1-18 years with solid tumours with measurable or evaluable disease (by Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) regardless of histology. Eligible patients for part B (dose-expansion phase) were aged 1-30 years with measurable disease (by RECIST criteria) in the following disease cohorts: rhabdomyosarcoma, Ewing sarcoma, osteosarcoma, neuroblastoma, Hodgkin lymphoma, non-Hodgkin lymphoma, and melanoma. Patients in part A and were given nivolumab 3 mg/kg intravenously over 60 min on days 1 and 15 of a 28-day cycle in a rolling 6 study design with de-escalation upon dose-limiting toxicities to establish the recommended phase 2 dose. Patients in part B were given the recommended phase 2 dose. The primary outcomes were the tolerability, systemic exposure, maximum tolerated dose, and the antitumour activity of nivolumab at the adult recommended dose in children and young adults. This trial is registered with ClinicalTrials.gov, NCT02304458, with follow-up ongoing and is closed to new participants., Findings: 85 patients were enrolled between Feb 22, 2015, and Dec 31, 2018, and 75 patients were fully evaluable for toxicity. Median follow-up was 30 days (IQR 27-83). In part A, 13 patients were enrolled and 12 were evaluable for toxicity. There were no dose de-escalations or dose-limiting toxicities and nivolumab 3 mg/kg was confirmed as the paediatric recommended phase 2. 72 patients were enrolled in part B and 63 were evaluable for toxicity. Five (7%) patients in part B had dose-limiting toxicities. The most common overall toxicity was anaemia (35 [47%] of 75 patients; five patients had grade 3 or grade 4) and non-haematological toxicity was fatigue (28 [37%] patients; none had grade 3 or grade 4). Responses were observed in patients with lymphoma (three [30%] of ten with Hodgkin lymphoma and one [10%] of ten with non-Hodgkin lymphoma; all responders had PD-L1 expression). Objective responses were not observed in other tumour types., Interpretation: Nivolumab was safe and well tolerated in children and young adults and showed clinical activity in lymphoma. Nivolumab showed no significant single-agent activity in the common paediatric solid tumours. This study defines the recommended phase 2 dose and establishes a favourable safety profile for nivolumab in children and young adults, which can serve as the basis for its potential study in combinatorial regimens for childhood cancer., Funding: Bristol-Myers Squibb, Children's Oncology Group, National Institutes of Health, Cookies for Kids Cancer Foundation., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors., Patients and Methods: Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m 2 /day) delivered on days 1-5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed., Results: Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2-20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m 2 ) in combination with irinotecan (90 mg/m 2 ) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients., Conclusions: Adavosertib (85 mg/m 2 ) in combination with irinotecan (90 mg/m 2 ) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors., (©2019 American Association for Cancer Research.)

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/m 2 /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%., (©2019 American Association for Cancer Research.)

Background: Axitinib is an oral small molecule that inhibits receptor tyrosine kinases vascular endothelial growth factor receptors 1 to 3. A phase 1 and pharmacokinetic (PK) trial evaluating axitinib was conducted in children with refractory solid tumors., Methods: Axitinib was administered orally twice daily in continuous 28-day cycles. Dose levels (2.4 mg/m 2 /dose and 3.2 mg/m 2 /dose) were evaluated using a rolling 6 design. Serial PKs (cycle 1, days 1 and 8) and exploratory biomarkers were analyzed., Results: A total of 19 patients were enrolled; 1 patient was ineligible due to inadequate time having elapsed from prior therapy. The median age of the patients was 13.5 years (range, 5-17 years). Two of 5 patients who were treated at dose level 2 experienced dose-limiting toxicities (palmar-plantar erythryodysesthesia syndrome in 1 patient and intratumoral hemorrhage in 1 patient). Frequent (>20%) grade 1 to 2 toxicities during cycle 1 included anemia, anorexia, fatigue, diarrhea, nausea, and hypertension. Nonhematological toxicities of grade ≥3 in subsequent cycles included hypertension and elevated serum lipase. PK analysis demonstrated variability in axitinib exposure, the median time to peak plasma concentration was 2 hours, and the half-life ranged from 0.7 to 5.2 hours. Exposure and dose were not found to be significantly associated with hypertension. Five patients achieved stable disease for ≤6 cycles as their best response, including patients with malignant peripheral nerve sheath tumor (1 patient), Ewing sarcoma (1 patient), hepatocellular carcinoma (1 patient), and osteosarcoma (2 patients). One patient with alveolar soft part sarcoma achieved a partial response. Kidney injury biomarkers were found to be elevated at baseline; no trends were identified., Conclusions: In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib appears to be 2.4 mg/m 2 /dose, which provides PK exposures similar to those of adults., (© 2018 American Cancer Society.)

Background: We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors., Methods: Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed., Results: Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m 2 /day. At 40 mg/m 2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m 2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma)., Conclusions: A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m 2 /day. A phase 2 study of cabozantinib is being conducted., (© 2018 Wiley Periodicals, Inc.)

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/m 2 /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/m 2 /dose, respectively. One subject at the 1.4 mg/m 2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m 2 /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/m 2 /dose on days 1 and 8 of a 21-day cycle., (© 2018 Wiley Periodicals, Inc.)

Background: Ontuxizumab is a humanized IgG monoclonal antibody that targets the cell-surface glycoprotein endosialin (tumor endothelial marker-1[TEM-1]/CD248) found on activated mesenchymal cells and certain tumors. Ontuxizumab binding to endosialin may interfere with platelet-derived growth factor signaling, prevent tumor stroma organization, and prevent new vessel formation., Methods: Ontuxizumab was administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle at three dose levels (4, 8, and 12 mg/kg). Further dose escalation to 16 mg/kg was planned if the maximum tolerated dose (MTD) was not reached and the ontuxizumab systemic clearance was ≥30% higher in children compared to adults. Following determination of the MTD/recommended phase 2 dose, an additional cohort of six patients (<12 years) was enrolled for further pharmacokinetics (PK) evaluation., Results: Twenty-seven eligible patients (17 male, median age 15 years, range 3-21 years) were enrolled. Twenty-two patients (neuroblastoma [5], Ewing sarcoma [4], rhabdomyosarcoma [4], and other tumors [9]) were fully evaluable for toxicity. Five patients did not complete cycle 1 due to tumor progression. Two of 10 patients experienced dose-limiting toxicity of bacteremia (n = 1) and hyponatremia (n = 1) at 12 mg/kg. Grade ≤2 fever or infusion-related reactions occurred in 10 patients. Clearance was dose dependent and within 30% of adult value at 12 mg/kg., Conclusion: Ontuxizumab administered weekly at 12 mg/kg appears to be well tolerated in children with relapsed or refractory solid tumors. The PK of ontuxizumab does not appear to be significantly different in children compared to adults., (© 2018 Wiley Periodicals, Inc.)

Purpose: To determine the dose limiting toxicities (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of veliparib in combination with weekly topotecan in patients with solid tumors. Correlative studies were included to assess the impact of topotecan and veliparib on poly(ADP-ribose) levels in peripheral blood mononuclear cells, serum pharmacokinetics of both agents, and potential association of germline repair gene mutations with outcome. Experimental Design: Eligible patients had metastatic nonhematologic malignancies with measurable disease. Using a 3 + 3 design, patients were treated with veliparib orally twice daily on days 1-3, 8-10, and 15-17 and topotecan intravenously on days 2, 9, and 16 every 28 days. Tumor responses were assessed by RECIST. Results: Of 58 patients enrolled, 51 were evaluable for the primary endpoint. The MTD and RP2D was veliparib 300 mg twice daily on days 1-3, 8-10, and 15-17 along with topotecan 3 mg/m 2 on days 2, 9, and 16 of a 28-day cycle. DLTs were grade 4 neutropenia lasting >5 days. The median number of cycles was 2 (1-26). The objective response rate was 10%, with 1 complete and 4 partial responses. Twenty-two patients (42%) had stable disease ranging from 4 to 26 cycles. Patients with germline BRCA1, BRCA2 , or RAD51D mutations remained on study longer than those without homologous recombination repair (HRR) gene mutations (median 4 vs. 2 cycles). Conclusions: Weekly topotecan in combination with veliparib has a manageable safety profile and appears to warrant further investigation. Clin Cancer Res; 24(4); 744-52. ©2017 AACR ., (©2017 American Association for Cancer Research.)

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/m 2 /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/m 2 ). PK analysis showed marked interpatient variability (20-fold) in the C max and AUC 0-8h 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/m 2 /dose. PK of tivantinib in children demonstrated high variability. Objective responses were not observed in this phase 1 trial., (© 2017 Wiley Periodicals, Inc.)

Purpose: Trebananib is a first-in-class antiangiogenic peptibody (peptide-Fc fusion protein) that inhibits Angiopoietin 1 and 2. A pediatric phase 1 trial was performed to define trebananib dose-limiting toxicities (DLT), recommended phase 2 dose (RP2D), and pharmacokinetics (PK). Experimental Design: Trebananib was administered by weekly infusion. Three dose levels (10, 15, or 30 mg/kg/dose) were evaluated using a rolling-six design. Part 2 evaluated a cohort of subjects with primary central nervous system (CNS) tumors. Pharmacokinetic sampling and analysis of peripheral blood biomarkers was performed during the first 4 weeks. Response was evaluated after 8 weeks. Correlative studies included angiogenic protein expression and DCE-MRI. Results: Thirty-seven subjects were enrolled (31 evaluable for toxicity) with median age 12 years (range, 2 to 21). Two of 19 evaluable non-CNS subjects developed DLT at the 30 mg/kg dose level, including venous thrombosis and pleural effusion. In the CNS cohort, 3/12 subjects developed DLT, including decreased platelet count, transient ischemic attack, and cerebral edema with headache and hydrocephalus. Other grade 3 or 4 toxicities included lymphopenia ( n = 4), anemia, thrombocytopenia, neutropenia, vomiting, and hypertension ( n = 1 each). Response included stable disease in 7 subjects, no partial or complete responses. Two subjects continued study treatment with prolonged stable disease for 18 cycles (neuroblastoma) and 26 cycles (anaplastic astrocytoma). Pharmacokinetics appeared linear over 3 dose levels. Correlative studies demonstrated increased PlGF and sVCAM-1, but no change in endoglin or perfusion by DCE-MRI. Conclusions: Trebananib was well tolerated in pediatric patients with recurrent or refractory solid or CNS tumors. RP2D is 30 mg/kg. Clin Cancer Res; 23(20); 6062-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

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/m(2); (ii) IMC-A12 6 mg/kg, temsirolimus 10 mg/m(2); (iii) IMC-A12 4 mg/kg, temsirolimus 8 mg/m(2); and (iv) IMC-A12 6 mg/kg, temsirolimus 8 mg/m(2). 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/m(2), 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/m(2), respectively., (©2014 American Association for Cancer Research.)

Background: We report results of a phase I trial designed to estimate the maximum tolerated dose (MTD), describe dose-limiting toxicities (DLT), and characterize the pharmacokinetic profile of MK-2206, an AKT inhibitor, in children with refractory or recurrent malignancies., Procedure: MK-2206 was administered either every other day (Schedule 1), or once a week (Schedule 2) in a 28-day cycle. Dose escalations in increments of ∼30% were independently made in each part using the rolling-six design. Serial pharmacokinetic (PK) studies were obtained. Biological studies include analysis of PI3K/PTEN/AKT-cell signaling pathway in pre and post-therapy in PBMC and in tumors at diagnosis or recurrence., Results: Fifty patients (26 males, median age 12.6 years [range, 3.1-21.9]) with malignant glioma (16), ependymoma (4), hepatocellular carcinoma (3), gliomatosis cereberi (2), or other tumors (22) were enrolled; 40 were fully evaluable for toxicity (Schedule 1, n = 23; Schedule 2, n = 17). Schedule 1 DLTs included: grade 3 dehydration in 1/6 patients at 28 mg/m(2) ; grade 4 hyperglycemia and neutropenia in 1/6 patients at 45 mg/m(2) ; and grade 3 rash in 3/6 patients at dose level 4 (58 mg/m(2) ). Schedule 2 DLTs included: grade 3 alkaline phosphatase in 1/6 patients at 90 mg/m(2) ; grade 3 rash in 1/6 patients at 120 mg/m(2) ; and grade 3 rash in 2/6 patients at 155 mg/m(2) ., Conclusions: The recommended pediatric phase 2 dose of MK-2206 is 45 mg/m(2) /dose every other day or 120 mg/m(2) /dose weekly. PK appeared linear over the dose range studied., (© 2014 Wiley Periodicals, Inc.)

Background: Accumulating evidence shows evidence of efficacy with the combination of vorinostat and bortezomib in solid tumors. We previously examined a once-daily continuous dosing schedule of vorinostat in combination with bortezomib which was well tolerated in cycles 1 and 2; however, there was concern regarding the tolerability through multiple cycles. This study was conducted to evaluate an intermittent dosing schedule of vorinostat with bortezomib., Methods: Vorinostat was initially administered orally twice daily on days 1-14 with bortezomib IV on days 1, 4, 8, and 11 of a 21 day cycle. Two DLTs (elevated ALT and fatigue) were observed at dose level 1, thus the protocol was amended to administer vorinostat intermittently twice daily on days 1-4 and 8-11., Results: 29 patients were enrolled; 13 men and 16 women. Common cancer types included sarcoma, pancreatic, colorectal, GIST, and breast. The most common Grade 3-4 toxicities at any dose level included thrombocytopenia, fatigue, increased ALT, elevated INR, and diarrhea. DLTs in the intermittent dosing scheduled included thrombocytopenia and fatigue. The Cmax and AUC for the intermittent dosing regimen were similar to those observed in the daily dosing. In this heavily pretreated population, stable disease was observed in patients with sarcoma, colorectal adenocarcinoma and GIST., Conclusions: The MTD was established at vorinostat 300 mg BID on days 1-4 and 8-11 and bortezomib 1.3 mg/m(2) IV on days 1, 4, 8, and 11 of a 21 day cycle. Tolerability was not improved with the intermittent dosing schedule of vorinostat when compared to continuous dosing.

Purpose: This phase 2 study was designed to assess the efficacy of single agent cixutumumab (IMC-A12) and gain further information about associated toxicities and pharmacodynamics in children, adolescents, and young adults with recurrent or refractory solid tumors., Patients and Methods: Patients with relapsed or refractory solid tumors were treated with 9 mg/kg of cixutumumab as a 1-hour IV infusion once weekly. Strata included: osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, neuroblastoma (evaluable disease), neuroblastoma (measurable disease), Wilms tumor, adrenocortical carcinoma, synovial sarcoma, hepatoblastoma, and retinoblastoma. Correlative studies in consenting patients included an assessment of c-peptide, IGFBP-3, IGF-1, IGF-2, hGH, and insulin in consenting patients., Results: One hundred sixteen patients with 114 eligible having a median age of 12 years (range, 2-30) were enrolled. Five patients achieved a partial response: 4/20 with neuroblastoma (evaluable only) and 1/20 with rhabdomyosarcoma. Fourteen patients had stable disease for a median of 10 cycles. Hematologic and non-hematologic toxicities were generally mild and infrequent. Serum IGF-1 and IGFBP-3 increased in response to therapy with cixutumumab., Conclusion: Cixutumumab is well tolerated in children with refractory solid tumors. Limited objective single-agent activity of cixutumumab was observed; however, prolonged stable disease was observed in 15% of patients. Ongoing studies are evaluating the toxicity and benefit of cixutumumab in combination with other agents that inhibit the IGF pathway., (© 2013 Wiley Periodicals, Inc.)

Background: A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors., Methods: Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m(2)). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1., Results: Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m(2) to 1.5 mg/m(2). The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m(2). DLTs consisted of grade 3 fatigue in three patients (1 mg/m(2),1.3 mg/m(2) and 1.5 mg/m(2)) and grade 3 hyponatremia in one patient (1.5 mg/m(2)). The most common grade 1/2 toxicities included nausea (60.9%), fatigue (34.8%), diaphoresis (34.8%), anorexia (30.4%) and constipation (26.1%). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1., Conclusions: This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day cycle.

Purpose: We performed a UGT1A1 genotype-guided study to determine the maximum tolerated dose (MTD) and evaluate the toxicities and pharmacokinetics of the combination of capecitabine (CAP), oxaliplatin (OX), and irinotecan (IRIN)., Experimental Design: Patients were screened for UGT1A1 *28 genotype prior to treatment. The starting dose (mg/m(2)) was IRIN (150), OX (85) and CAP (400), days 2-15. Doses were escalated or de-escalated within each genotype group (*28/*28, *1/*28 and *1/*1). IRIN pharmacokinetics was performed at the MTD., Results: 50 patients were evaluable for toxicity [11 (*28/*28); 18 (*1/*28); 21 (*1/*1)]. UGT1A1 *28/*28 patients experienced hematologic dose limiting toxicity (DLT), requiring dose-de-escalation. The UGT1A1 *28/*28 recommended phase 2 dose (RP2D) was IRIN (75), OX (85), and CAP (400). In contrast, both UGT1A1 *1/*28 and *1/*1 tolerated higher doses of IRIN and non-hematologic toxicity was dose limiting for UGT1A1 *1/*1. The RP2D was IRIN (150), OX (85), and CAP (400) for UGT1A1*1/*28 and IRIN (150), OX (100), and CAP (1600) for UGT1A1 *1/*1. UGT1A1 *1/*28 and *1/*1 patients treated with IRIN (150) had similar AUCs for the active irinotecan metabolite, SN38 (366 +/- 278 and 350 +/- 159 ng/ml*hr, respectively). UGT1A1 *28/*28 patients (n = 3) treated with a lower IRIN dose (100) had non-significantly higher mean SN38 exposures (604 +/- 289 ng/ml*hr, p = 0.14). Antitumor activity was observed in all genotype groups., Conclusions: UGT1A1 genotype affects the dose and pharmacokinetics of the CAPIRINOX regimen and UGT1A1 genotype-guided dosing of CAPIRINOX is ongoing in a phase II study of small bowel cancer (NCT00433550).

Purpose: Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors., Patients and Methods: Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD., Results: Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41)., Conclusion: Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Background: A pediatric Phase I trial was performed to determine the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetics (PK) of vorinostat and bortezomib, in patients with solid tumors., Procedure: Oral vorinostat was administered on days 1-5 and 8-12 of a 21-day cycle (starting dose 180 mg/m(2) /day with dose escalations to 230 and 300 mg/m(2) /day). Bortezomib (1.3 mg/m(2) i.v.) was administered on days 1, 4, 8, and 11 of the same cycle. PK and correlative biology studies were performed during Cycle 1., Results: Twenty-three eligible patients [17 male, median age 12 years (range: 1-20)] were enrolled of whom 17 were fully evaluable for toxicity. Cycle 1 DLTs that occurred in 2/6 patients at dose level 3 (vorinostat 300 mg/m(2) /day) were Grade 2 sensory neuropathy that progressed to Grade 4 (n = 1) and Grade 3 nausea and anorexia (n = 1). No objective responses were observed. There was wide interpatient variability in vorinostat PK parameters. Bortezomib disposition was best described by a three-compartment model that demonstrated rapid distribution followed by prolonged elimination. We did not observe a decrease in nuclear factor-κB activity or Grp78 induction after bortezomib treatment in peripheral blood mononuclear cells from solid tumor patients., Conclusion: The recommended Phase 2 dose and schedule is vorinostat (230 mg/m(2) /day PO on days 1-5 and 8-12) in combination with bortezomib (1.3 mg/m(2) /day i.v. on days 1, 4, 8, and 11 of a 21-day cycle) in children with recurrent or refractory solid tumors., (Copyright © 2012 Wiley Periodicals, Inc.)

Purpose Activation of EGFR can stimulate proliferative and survival signaling through mTOR. Preclinical data demonstrates synergistic activity of combined EGFR and mTOR inhibition. We undertook a phase I trial of temsirolimus (T, an mTOR inhibitor) and EKB-569 (E, an EGFR inhibitor) to determine the safety and tolerability. Methods The primary aim was to determine the maximally tolerated dose (MTD) of this combination in adults with solid tumors. Following the dose-escalation phase, (Cohort A), two subsequent cohorts were used to assess any pharmacokinetic (PK) interaction between the agents. Results Forty eight patients were enrolled. The MTD of this combination was E, 35 mg daily and T, 30 mg on days 1-3 and 15-17 using a 28-day cycle. The most common toxicities were nausea, diarrhea, fatigue, anorexia, stomatitis, rash, anemia, neutropenia, thrombocytopenia, and hypertriglyceridemia. Sixteen patients (36%) had at least one grade 3 toxicity. The most frequent grade 3/4 toxicities were diarrhea, dehydration, and nausea and vomiting (19% each). No grade 5 events were seen. Four patients had a partial response and 15 had stable disease. Clinical benefit was seen across a range of tumor types and in all cohorts. PK analysis revealed no significant interaction between E and T. Conclusions This combination of agents is associated with tolerable toxicities at doses that induced responses. PK studies revealed no interaction between the drugs. Further investigations of this targeting strategy may be attractive in renal cell carcinoma, non-small cell lung cancer, alveolar sarcoma, and carcinoid tumor.

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., (©2012 AACR.)

Purpose: Sunitinib is an oral tyrosine kinase inhibitor of VEGF, PDGF, c-KIT, and flt-3 receptors. A pediatric phase I study of sunitinib capsules identified the maximum tolerated dose as 15 mg/m(2)/day. This study was conducted to evaluate sunitinib given as a powder formulation., Methods: Sunitinib 15 mg/m(2) was administered orally daily for 4 weeks on/2 weeks off to patients <21 years old with refractory solid tumors. Sunitinib capsules were opened, and the powder sprinkled onto applesauce or yogurt. Plasma levels of sunitinib and an active metabolite, SU12662, were measured, and pharmacokinetic parameters were estimated., Results: 12 patients, median age 13 (range 4-21) years, were treated. The most common first-cycle toxicities were leucopenia (n = 6), fatigue (n = 5), neutropenia (n = 4), and hypertension (n = 4). Three patients had dose-limiting toxicities (DLTs) in cycle 1 (dizziness/back pain, hand-foot syndrome, and intratumoral hemorrhage/hypoxia). A median peak plasma sunitinib concentration of 21 (range 6-36) ng/ml was reached at a median of 4 (range 4-8) h after the first dose. The median exposure (AUC(0-48)) was 585 (range 196-1,059) h ng/l. The median half-life was 23 (range 13-36) h. The median trough concentration measured before day 14 dosing was 32 (range 12-58) ng/ml., Conclusions: The pharmacokinetic profile of sunitinib appears similar between a powder formulation and published data using capsules. The powder formulation allows patients unable to swallow capsules to receive sunitinib.

Purpose: Vorinostat (V) at levels >2.5 µM enhances chemotherapy in vitro. Yet the approved oral dose of 400 mg inconsistently achieves this level in patients. We developed an intermittent oral pulse-dose schedule of V to increase serum levels. We combined V with the cyclin dependent kinase inhibitor flavopiridol (F) which increases V-induced apoptosis., Experimental Design: One week before combination treatment, V alone was given daily for 3d (cycle -1). Then V was given on d1-3 and d8-10, and F on d2 and d9, every 21-d. Due to neutropenia, this was modified to V on d1-3 and d15-17, and F on d2 and d16, every 28-d. Bolus and split-dose F schedules were studied., Results: 34 patients were treated. On the 21-d schedule, the maximum tolerated dose (MTD) was V 600 mg/d and F 60 mg/m(2) bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m(2) over 30 min and 30 mg/m(2) over 4 h. V C(max) at the 800 mg dose was 4.8 µM (± 2.8). V C(max) ≥ 2.5 µM was achieved in 86% of patients at the MTD. F increased the C(max) of V by 27% (95% CI 11%-43%). F C(max) of ≥ 2 µM was achieved in 90% of patients. 8 patients had stable disease for on average 5.5 m (range 1.6-13.2 m)., Conclusions: Intermittent high dose oral V in combination with F is feasible and achieves target serum levels >2.5 µM. V concentrations higher than previously reported with oral dosing were achieved.

A phase I trial of ABT-888 (veliparib), a PARP inhibitor, in combination with topotecan, a topoisomerase I-targeted agent, was carried out to determine maximum tolerated dose (MTD), safety, pharmacokinetics, and pharmacodynamics of the combination in patients with refractory solid tumors and lymphomas. Varying schedules and doses of intravenous topotecan in combination with ABT-888 (10 mg) administered orally twice a day (BID) were evaluated. Plasma and urine pharmacokinetics were assessed and levels of poly(ADP-ribose) (PAR) and the DNA damage marker γH2AX were measured in tumor and peripheral blood mononuclear cells (PBMC). Twenty-four patients were enrolled. Significant myelosuppression limited the ability to coadminister ABT-888 with standard doses of topotecan, necessitating dose reductions. Preclinical studies using athymic mice carrying human tumor xenografts also informed schedule changes. The MTD was established as topotecan 0.6 mg/m²/d and ABT-888 10 mg BID on days one to five of 21-day cycles. Topotecan did not alter the pharmacokinetics of ABT-888. A more than 75% reduction in PAR levels was observed in 3 paired tumor biopsy samples; a greater than 50% reduction was observed in PBMCs from 19 of 23 patients with measurable levels. Increases in γH2AX response in circulating tumor cells (CTC) and PBMCs were observed in patients receiving ABT-888 with topotecan. We show a mechanistic interaction of a PARP inhibitor, ABT-888, with a topoisomerase I inhibitor, topotecan, in PBMCs, tumor, and CTCs. Results of this trial reveal that PARP inhibition can modulate the capacity to repair topoisomerase I-mediated DNA damage in the clinic., (©2011 AACR.)

Purpose: Sunitinib is an oral multitargeted receptor tyrosine kinase inhibitor. The purpose of this study was to determine the recommended phase 2 dose, pharmacokinetics, pharmacodynamic effects, and preliminary antitumor activity of sunitinib in a pediatric population., Experimental Design: Patients who were 2 to 21 years of age with refractory solid tumors were eligible if they had measurable or evaluable disease and met baseline organ function requirements. Patients received sunitinib once daily for 28 days followed by a 14-day break between each cycle. Dose levels of 15 and 20 mg/m(2)/d were evaluated, with dose escalation based on a 3 + 3 design. Sunitinib pharmacokinetics and biomarkers of angiogenesis were also evaluated during the first cycle., Results: Twenty-three patients were treated (median age 13.9 years; range, 3.9-20.6 years). The most common toxicities were neutropenia, thrombocytopenia, elevated liver transaminases, gastrointestinal symptoms, and fatigue. Two patients developed dose-limiting reductions in cardiac ejection fraction prompting a protocol amendment to exclude patients with previous exposure to anthracyclines or cardiac radiation. In patients without these cardiac risk factors, the maximum tolerated dose (MTD) was 15 mg/m(2)/d. Steady-state plasma concentrations were reached by day 7. No objective responses were observed. Four patients with sarcoma and glioma had stable disease for 2 to 9 cycles., Conclusions: Cardiac toxicity precluded determination of a recommended dose for pediatric patients with previous anthracycline or cardiac radiation exposure. The MTD of sunitinib for patients without risk factors for cardiac toxicity is 15 mg/m(2)/d for 28 days followed by a 14-day break., (©2011 AACR.)

Background: Inorganic nanoparticles provide promising tools for biomedical applications including detection, diagnosis and therapy. While surface properties such as charge are expected to play an important role in their in vivo behavior, very little is known how the surface chemistry of nanoparticles influences their pharmacokinetics, tumor uptake, and biodistribution., Method/principal Findings: Using a family of structurally homologous nanoparticles we have investigated how pharmacological properties including tumor uptake and biodistribution are influenced by surface charge using neutral (TEGOH), zwitterionic (Tzwit), negative (TCOOH) and positive (TTMA) nanoparticles. Nanoparticles were injected into mice (normal and athymic) either in the tail vein or into the peritoneum., Conclusion: Neutral and zwitterionic nanoparticles demonstrated longer circulation time via both i.p. and i.v. administration, whereas negatively and positively charged nanoparticles possessed relatively short half-lives. These pharmacological characteristics were reflected on the tumor uptake and biodistribution of the respective nanoparticles, with enhanced tumor uptake by neutral and zwitterionic nanoparticles via passive targeting.

Background: Demethylating agents may alter the expression of genes involved in chemotherapy resistance. We conducted a phase I trial to determine the toxicity and molecular effects of the demethylating agent, decitabine, followed by doxorubicin and cyclophosphamide in children with refractory solid tumors., Procedure: Stratum A included children with any solid tumor; Stratum B included neuroblastoma patients only. Patients received a 1-hr decitabine infusion for 7 days, followed by doxorubicin (45 mg/m(2)) and cyclophosphamide (1 g/m(2)) on day 7. Pharmacokinetic studies were performed after the first dose of decitabine. Biological studies included methylation and gene expression analyses of caspase-8, MAGE-1 and fetal hemoglobin (HbF), and expression profiling of pre- and post-treatment peripheral blood and bone marrow cells., Results: The maximum-tolerated dose of decitabine was 5 mg/m(2)/day for 7 days. Dose-limiting toxicities at 10 mg/m(2)/day were neutropenia and thrombocytopenia. Decitabine exhibited rapid clearance from plasma. Three of 9 patients in Stratum A and 4/12 patients in Stratum B had stable disease for > or = 4 months. Sustained MAGE-1 demethylation and increased HbF expression were observed in the majority of patients post-treatment (12/20 and 14/16, respectively). Caspase-8 promoter demethylation and gene expression were seen in 2/7 bone marrow samples. Differentially expressed genes were identified by microarray analysis., Conclusion: Low-dose decitabine when combined with doxorubicin/cyclophosphamide has tolerable toxicity in children. However, doses of decitabine capable of producing clinically relevant biologic effects were not well tolerated with this combination. Alternative strategies of combining demethylating agents with non-cytotoxic, biologically targeted agents such as histone deacetylase inhibitors should be explored., (Copyright 2010 Wiley-Liss, Inc.)

Purpose: The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of vorinostat administered as a single agent and in combination 13-cis retinoic acid (13cRA) in children with refractory solid tumors; to evaluate the tolerability of the solid tumor MTD in children with refractory leukemias; and to characterize the pharmacokinetics of a vorinostat suspension in children., Patients and Methods: Vorinostat was administered orally daily starting at 180 mg/m(2)/d with escalations planned in 30% increments. Pharmacokinetic studies were performed with the initial dose. Acetyl-histone (H3) accumulation was assessed by Western blotting of peripheral blood mononuclear cells (PBMC)., Results: Sixty-four patients were enrolled on this multipart trial. In patients with solid tumors, the MTD was 230 mg/m(2)/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m(2)/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m(2)/d 4 times per week and 13cRA 80 mg/m(2)/dose twice per day, days 1 through 14 every 28 days. Wide interpatient variability was noted in vorinostat disposition, with area under the concentration-time curves at 230 mg/m(2)/d for the capsule (range, 1,415 to 9,291 ng/mL x hr) and oral suspension (range, 1,186 to 4,780 ng/mL x hr). Significant accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat, particularly at higher doses. One patient with neuroblastoma experienced a complete response to the combination., Conclusion: In children with recurrent solid tumors, vorinostat is well-tolerated at 230 mg/m(2)/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.

Background: In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea., Methods: Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m(2) administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses., Results: On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m(2)/day combined with temozolomide 100 mg/m(2)/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m(2)/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m(2)/day, temozolomide 150 mg/m(2)/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m(2)/day, the mean SN-38 AUC(inf) was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received >or=6 courses., Conclusions: The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.

Purpose: Topotecan resistance can result from drug efflux by P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) as well as survival signals initiated by epidermal growth factor receptor family members. The present studies were done to determine the effect of combining topotecan and the dual epidermal growth factor receptor/HER2 inhibitor lapatinib in tissue culture, a murine xenograft model, and a phase I clinical trial., Experimental Design: The effects of lapatinib on topotecan accumulation and cytotoxicity in vitro were examined in paired cell lines lacking or expressing Pgp or BCRP. Antiproliferative effects of the combination were assessed in mice bearing HER2+ BT474 breast cancer xenografts. Based on tolerability in this preclinical model, 37 patients with advanced-stage cancers received escalating doses of lapatinib and topotecan in a phase I trial., Results: Lapatinib increased topotecan accumulation in BCRP- or Pgp-expressing cells in vitro, and the combination showed enhanced efficacy in HER2+ BT474 xenografts. In the phase I study, nausea, vomiting, diarrhea, and fatigue were dose limiting. The maximum tolerated doses were 1,250 mg/d lapatinib by mouth for 21 or 28 days with 3.2 mg/m2 topotecan i.v. on days 1, 8, and 15 of 28-day cycles. Pharmacokinetic analyses showed that combined drug administration resulted in decreased topotecan clearance consistent with transporter-mediated interactions. Seventeen (46%) patients had disease stabilization., Conclusions: The lapatinib/topotecan combination is well tolerated and warrants further study.

Purpose: We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)-neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer., Patients and Methods: BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors., Results: Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data., Conclusion: BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.

Purpose: We report results of a phase I trial and pharmacokinetic study of pemetrexed (LY231514) in children and adolescents with refractory solid tumors. Pemetrexed is a novel antifolate that inhibits multiple enzymes necessary for the biosynthesis of thymidine and purine nucleotides. The purpose of this study was to determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLTs), and pharmacokinetic properties of pemetrexed in children., Patients and Methods: Pemetrexed was administered as a 10-minute intravenous infusion every 21 days. Patients received vitamin B12 and folic acid supplementation as well as dexamethasone prophylaxis. Cohorts of three to six children were enrolled at dose levels of 400, 520, 670, 870, 1,130, 1,470, 1,910, and 2,480 mg/m2. Pharmacokinetic studies were performed during the first course of treatment., Results: Thirty-three patients (31 assessable) with a median age of 12 years were enrolled. DLT occurred in one of six patients at 1,470 mg/m2 and two of four patients at 2,480 mg/m2. The MTD was 1,910 mg/m2. The primary DLTs were neutropenia and rash. No objective antitumor responses were seen. Mean plasma clearance, half-life, and steady-state volume of distribution values were 2.3 L/h/m2, 2.5 hours, and 5.4 L/m2, respectively., Conclusion: Pemetrexed is well-tolerated in children with refractory solid tumors at doses similar to the MTD in adults. The recommended dose for phase II studies is 1,910 mg/m2 administered every 21 days with dexamethasone, folic acid, and vitamin B12 supplementation.

Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG)., Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy., Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C(max) and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m(2) dose level., Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families.

Purpose: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity., Methods: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle., Results: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2, paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC = 6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules., Conclusion: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins., Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one., Results: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells., Conclusions: The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.

Purpose: Intravenous (i.v.) irinotecan is a cytotoxic topoisomerase I inhibitor with broad clinical activity in metastatic colorectal cancer and other tumors. The development of an oral formulation of irinotecan could enhance convenience and lessen the expense of palliative irinotecan delivery. This phase I study evaluated the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of irinotecan given as a powder-filled capsule (PFC) daily for 5 days every 3 weeks., Patients and Methods: Patients with advanced solid tumors received escalating doses of oral irinotecan daily for 5 days every 3 weeks. Plasma samples were collected following the first and fifth doses of irinotecan during Cycle 1 to determine the PK of irinotecan and its major circulating metabolites: SN-38, SN-38G, and APC., Results: 20 patients (median age 61.5 years, range 40-75; M/F 12/8; ECOG PS 0=5, 1=11, 2=4) received oral irinotecan at dose levels of 30 (n=3), 40 (n=3), 50 (n=6), and 60 (n=8) mg/m(2)/day. Of the eight patients enrolled at 60 mg/m(2), three patients experienced DLT (> or = grade 3) consisting of nausea (three patients), vomiting (three patients), diarrhea (two patients), and febrile neutropenia (two patients) for which all the three patients required hospitalization. Treatment of six patients at the 50-mg/m(2) dose level resulted in no DLT. Other toxicities observed include abdominal pain, alopecia, anorexia, and asthenia. After oral administration, irinotecan was rapidly absorbed into systemic circulation and converted to the active metabolite SN-38. Increasing dose levels resulted in a dose-dependent increase in mean exposure parameters (Cmax and AUC) of irinotecan and metabolites. Systemic exposure parameters (Cmax and AUC(0-24)) of irinotecan and SN-38 were comparable between days 1 and 5. The extent of conversion from irinotecan to SN-38 was approximately threefold higher after the oral administration compared to that previously observed after i.v. administration. The exposure parameters of irinotecan or SN-38 are of limited value in predicting severity of Cycle 1 toxicities in the twofold dose range evaluated., Conclusion: Daily oral administration of irinotecan as the PFC formulation for 5 days every 3 weeks can safely deliver protracted exposure to SN-38, with the MTD of 50 mg/m(2)/d.

Purpose: To determine the maximal tolerated dosage (MTD) of oral fenretinide given as intact capsules for 7 days, repeated every 21 days, in children with high-risk solid tumors., Methods: Children 21 years of age or younger received daily doses from 350 mg/m2 to 3,300 mg/m2 (divided into two or three doses), with pharmacokinetics during course one. The MTD was defined as zero to one of six patients with dose-limiting toxicity (DLT), with at least two of three or two of six DLT at next higher dose., Results: Fifty-four patients, age 2 years to 20 years (median, 9 years), were treated: neuroblastoma (n = 39), Ewing sarcoma (n = 5), and other (n = 10). Prior therapy included autologous stem cell transplantation (n = 42), 13-cis-RA (n = 35), and 9-cis-RA (n = 1). One of four patients at 1,050 mg/m2 with prior liver transplant had grade 3 ALT/abdominal pain/nausea/dehydration and grade 4 AST/emesis. At 1,860 mg/m2, one of seven patients had grade 3 hypoalbuminemia/hypophosphatemia. At 2,475 mg/m2, one of eight patients had grade 3 alkaline phosphatase; three of five patients had DLT at 3,300 mg/m2: grade 3 AST/ALT (n = 1), grade 4 bilirubin/grade 3 AST/ALT (n = 1), pseudotumor cerebri (n = 1). Pseudotumor cerebri also occurred at 600 mg/m2 and 800 mg/m2. There was one complete response and 13 patients with stable disease (SD) for 8 or more courses in 30 assessable neuroblastoma patients. SD for 8 or more courses was seen in one of five Ewing sarcoma patients and one melanoma patient. Mean N-4-hydroxyphenyl retinamide plasma level (day 7, steady-state concentration) was 9.9 mumol/L at MTD., Conclusion: The pediatric MTD of oral capsular fenretinide was 2,475 mg/m2 per day, which achieved levels active against neuroblastoma in vitro with minimal toxicity. Response data support a phase II trial in neuroblastoma.

CS-682 (1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-N4-palmitoylcytosine) is a novel orally administered 2'-deoxycytidine-type antimetabolite, which has a wide spectrum of antitumor activity in human tumor xenograft models. We conducted a phase I study to define the toxicity, pharmacokinetics and antitumor activity of CS-682 in patients with advanced solid tumors. Forty patients were enrolled to receive escalating doses of CS-682. CS-682 was given orally, once daily three times a week (Monday, Wednesday and Friday), for four weeks consecutively, followed by a two-week rest period. Twenty-two men and 18 women, median age 63.5 (range 31 to 82) were treated. The most common tumor type was colorectal cancer with 15 patients. Others tumors occurring in 3 or more patients included prostate, breast and lung carcinomas. Sixty percent of the patients had received greater than 2 prior chemotherapy programs. Patients have been treated at each of the following dose levels (mg/m2/day): 1.5, 12, 20, 25, 30, 50, 67, 90, 120, 160 and 220. Non hematologic toxicities grade 3 [NCI Common Toxicity Criteria (version 2.0)] related to treatment included nausea in 2, vomiting in 1, anorexia and asthenia in 2, and dehydration in 1. Severe hematologic toxicities (grade 3-4) were seen more frequently with 10 patients experiencing grade 3-4 neutropenia, 2 with grade 4 thrombocytopenia and 2 with grade 3 anemia. Neutropenia requiring hospitalization occurred in 3 patients. Dose-limiting neutropenia was observed at 220 mg/m2/day. The maximum tolerated dose was determined to be 160 mg/m2/day. No tumor responses were observed in this study. Six patients experienced stable disease, including one who has stable disease after having received 34 courses of CS-682. After oral administration, CS-682 is rapidly absorbed and metabolized to CNDAC, which is further metabolized by cytidine deaminase to the inactive product CNDAU. Peak plasma concentrations of CNDAC were achieved 2.2 +/- 0.9 h after drug administration and the terminal elimination half-life was 1.7 +/- 1.5 h. Measurable concentrations of CNDAU were first seen 0.60 +/- 0.31 h, peak plasma concentrations were achieved 3.1 +/- 0.9 h after the CS-682 dose, and the terminal elimination half-life was 2.3 +/- 1.7 h. The recommended phase 2 starting dose for the 3 days/week regimen of CS-682 is 160 mg/m2/day for 4 weeks repeated after a 2-week rest period.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that degrade the extracellular matrix during the processes of invasion, metastasis and angiogenesis. BAY 12-9566 (BAY) is a selective, non-peptidic biphenyl inhibitor of MMPs, with nanomolar inhibitory activity against MMP-2, -3 and -9, and anti-invasive, anti-metastatic and anti-angiogenic activity in a variety of tumor models. This phase I study of oral BAY was conducted to evaluate the safety and pharmacokinetics of BAY when administered in combination with etoposide (VP-16) or in combination with VP-16 and carboplatin (CBDCA) in subjects with advanced cancer. The first cohort of patients (n=8) received a cycle of VP-16, 60 mg/m, followed 1 week later by a fixed daily oral dose of BAY, 800 mg b.i.d., to which three potential possible doses of VP-16 (low dose: 60 mg/m; mid dose: 90 mg/m; high dose: 120 mg/m) were added every 3 weeks as tolerated. The second cohort (n=5) received VP-16 (120 mg/m) and CBDCA (AUC=5) followed 1 week later by a fixed daily oral dose of BAY (800 mg) b.i.d., to which VP-16 (120 mg/m) and CBDCA (AUC=5) were added. Dose-limiting toxicity (DLT) was defined as toxicity grade 3 or above. Maximum tolerated dose was declared if two or more patients experienced DLT. A performance status of 0-2 and acceptable organ function were required for eligibility. Plasma concentrations of BAY and VP-16 were measured to investigate pharmacokinetic interactions. Eight eligible patients with a variety of tumor types (median age 64 years, range 44-76) were enrolled in the first cohort, six of who whom completed all three levels of VP-16. Progressive disease occurred in five of the eight patients; three patients continued on study with treatment. Drug level and pharmacokinetics analysis of BAY and VP-16 were also determined. The combination of BAY and VP-16 was tolerable in the first cohort, permitting enrollment of the second cohort. In the second cohort (n=5), the combination of BAY, VP-16 and CDBCA was intolerable at the doses used due to excessive hematologic toxicity in the first five patients enrolled. Pharmacokinetics and toxicity analysis was performed for this group of patients. Only Level 1 of treatment was completed for Cohort II. At this point the study was halted due to toxicity and the results of an interim analysis that failed to demonstrate sufficient clinical activity of this compound in other clinical trials. We conclude that the combination of BAY and VP-16 was well tolerated. However, the combination of BAY, VP-16 and CDBCA produces significant hematologic toxicity. Findings from this study may help to direct further studies with other inhibitors of MMPs.

Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, transcription inhibitor, and DNA-interacting agent, was combined with cisplatin or carboplatin to establish toxicities, evaluate pharmacokinetics, and examine its effects on patient cancers and levels of selected polypeptides in patient peripheral blood mononuclear cells (PBMC)., Experimental Design: Therapy was given every 3 weeks. Stage I: cisplatin was fixed at 30 mg/m2 with escalating flavopiridol. Stage II: flavopiridol was fixed at the stage I maximum tolerated dose (MTD) with escalation of cisplatin. Stage III: flavopiridol was fixed at the stage I MTD with escalation of carboplatin., Results: Thirty-nine patients were treated with 136 cycles of chemotherapy. Neutropenia was seen in only 11% of patients. Grade 3 flavopiridol/CDDP toxicities were nausea (30%), vomiting (19%), diarrhea (15%), dehydration (15%), and neutropenia (10%). Flavopiridol combined with carboplatin resulted in unexpectedly high toxicities and one treatment-related death. Stable disease (>3 months) was seen in 34% of treated patients, but there were no objective responses. The stage II MTD was 60 mg/m2 cisplatin and 100 mg/m2/24 hours flavopiridol. As given, CDDP did not alter flavopiridol pharmacokinetics. Flavopiridol induced increased p53 and pSTAT3 levels in patient PBMCs but had no effects on cyclin D1, phosphoRNA polymerase II, or Mcl-1., Conclusions: Flavopiridol and cisplatin can be safely combined in the treatment of cancer patients. Unexpected toxicity in flavopiridol/carboplatin-treated patients attenuates enthusiasm for this alternative combination. Analysis of polypeptide levels in patient PBMCs suggests that flavopiridol may be affecting some, but not all, of its known in vitro molecular targets in vivo.