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1.  E5501 - Phase II Study of Topotecan Sequenced with Etoposide/Cisplatin, and Irinotecan/Cisplatin Sequenced with Etoposide for Extensive Stage Small Cell Lung Cancer 
Purpose
Sequence dependent improved efficacy of topoisomerase I followed by topoisomerase 2 inhibitors was assessed in a randomized phase II study in extensive-stage small cell lung cancer (SCLC).
Methods
Patients with previously untreated extensive stage SCLC with measurable disease, ECOG performance status of 0 to 3 and stable brain metastases were eligible. Arm A consisted of topotecan (0.75 mg/m2) on days 1, 2 and 3, etoposide (70 mg/m2) and cisplatin (20 mg/m2) [PET] on days 8, 9 and 10 in a 3-week cycle. Arm B consisted of irinotecan (50 mg/m2) and cisplatin (20 mg/m2) on days 1 and 8 followed by etoposide (85 mg/m2 PO bid) on days 3 and 10 [PIE] in a 3-week cycle.
Results
We enrolled 140 patients and randomized 66 eligible patients to each arm. Only 54.5% of all patients completed the planned maximum 6 cycles. There were grade ≥3 treatment-related adverse events in approximately 70% of the patients on both arms including 6 treatment-related grade 5 events. The overall response rates (CR+PR) were 69.7% (90% CI: 59.1–78.9%, 95% CI: 57.1–80.4%) for arm A and 57.6% (90% CI: 46.7–67.9%, 95% CI:44.8–69.7%) for arm B. The median PFS and OS were 6.4 months (95% CI: 5.4–7.5 months) and 11.9 months (95% CI: 9.6–13.7 months) for arm A and 6.0 months (95% CI: 5.4–7.0 months) and 11.0 months (95% CI: 8.6–13.1 months) for arm B.
Conclusion
Sequential administration of topoisomerase inhibitors did not improve on the historical efficacy of standard platinum-doublet chemotherapy for extensive stage SCLC.
doi:10.1007/s00280-013-2338-z
PMCID: PMC4705842  PMID: 24288121
small cell; topoisomerase; clinical trial; topotecan; irinotecan; sequential administration; survival
2.  Alliance A091103 a phase II study of the angiopoietin 1 and 2 peptibody trebananib for the treatment of angiosarcoma 
Introduction
Angiosarcomas are rare malignant endothelial cell tumors which have up-regulation of the angiopoietin system [e.g., Tie2 and Angiopoietin 2 (Ang2)]. Trebananib is a novel agent targeting Angiopoietin 1 and Angiopoietin 2.
Methods
Trebananib 30 mg/kg was administered weekly until progressive disease or unacceptable toxicity. The primary endpoint was response rate by RECIST v1.1. Correlatives included: (1) baseline tumor expression of Ang2/Tie2 by immunohistochemistry, (2) serum levels of Ang1 and Ang2, (3) pre- and post-treatment phospho-receptor tyrosine kinase and (4) MYC/FLT-4 amplification status.
Results
Sixteen patients were enrolled [median age 68 years (24–91), 38 % male, median number of prior therapies 2.5 (1–7)]. No responses were observed in 12 evaluable patients. Estimated median and 12-week progression-free survival rate were 7 weeks (95 % 6–8) and 25 % (95 % CI 11–58 %), respectively. Median overall survival was 28 weeks (95 % CI 17–48). There were two (12.5 %) patients who experienced grade 3 adverse event and one (6.3 %) patient who experienced grade 4 adverse event that was considered at least possibly related to treatment.
Conclusions
Trebananib was well tolerated. Lack of response in the first stage of a Simon 2 stage design led to closure of this study. Prolonged PFS was observed in four pts, lasting 3.4–5.5 months.
doi:10.1007/s00280-015-2689-8
PMCID: PMC4699670  PMID: 25672915
Angiosarcoma; Trebananib; Angiopoietin system
3.  TrkB Inhibition by GNF-4256 Slows Growth and Enhances Chemotherapeutic Efficacy in Neuroblastoma Xenografts 
Purpose
Neuroblastoma (NB) is one of the most common and deadly pediatric solid tumors. NB is characterized by clinical heterogeneity, from spontaneous regression to relentless progression despite intensive multimodality therapy. There is compelling evidence that members of the tropomyosin receptor kinase (Trk) family play important roles in these disparate clinical behaviors. Indeed, TrkB and its ligand, brain-derived neurotrophic factor (BDNF), are expressed in 50–60% of high-risk NBs. The BDNF/TrkB autocrine pathway enhances survival, invasion, metastasis, angiogenesis and drug resistance.
Methods
We tested a novel pan-Trk inhibitor, GNF-4256 (Genomics Institute of the Novartis Research Foundation), in vitro and in vivo in a nu/nu athymic xenograft mouse model to determine its efficacy in inhibiting the growth of TrkB-expressing human NB cells (SY5Y-TrkB). Additionally, we assessed the ability of GNF-4256 to enhance NB cell growth inhibition in vitro and in vivo, when combined with conventional chemotherapeutic agents, Irinotecan and Temozolomide (Irino-TMZ).
Results
GNF-4256 inhibits TrkB phosphorylation and the in vitro growth of TrkB-expressing NBs in a dose-dependent manner, with an IC50 around 7 nM and 50 nM, respectively. Furthermore, GNF-4256 inhibits the growth of NB xenografts as a single agent (p<0.0001 for mice treated at 40 mg/kg BID or 100 mg/kg BID, compared to controls), and it significantly enhances the antitumor efficacy of irinotecan plus temozolomide (Irino-TMZ, p<0.0071 compared to Irino-TMZ alone).
Conclusions
Our data suggest that GNF-4256 is a potent and specific Trk inhibitor capable of significantly slowing SY5Y-TrkB growth, both in vitro and in vivo. More importantly, the addition of GNF-4256 significantly enhanced the antitumor efficacy of Irino-TMZ, as measured by in vitro and in vivo growth inhibition and increased event-free survival in a mouse xenograft model, without additional toxicity. These data strongly suggest that inhibition of TrkB with GNF-4256 can enhance the efficacy of current chemotherapeutic treatment for recurrent/refractory high-risk NBs with minimal or no additional toxicity.
doi:10.1007/s00280-014-2627-1
PMCID: PMC4282593  PMID: 25394774
growth inhibition; neuroblastoma; signaling; TrkB
4.  Delayed methotrexate excretion in infants and young children with primary central nervous system tumors and postoperative fluid collections 
Purpose
High-dose methotrexate (HD-MTX) has been used to treat children with central nervous system tumors. Accumulation of MTX within pleural, peritoneal, or cardiac effusions has led to delayed excretion and increased risk of systemic toxicity. This retrospective study analyzed the association of intracranial post-resection fluid collections with MTX plasma disposition in infants and young children with brain tumors.
Methods
Brain MRI findings were analyzed for postoperative intracranial fluid collections in 75 pediatric patients treated with HD-MTX and for whom serial MTX plasma concentrations ([MTX]) were collected. Delayed plasma excretion was defined as [MTX] ≥1μM at 42 hours (h). Leucovorin was administered at 42 h and then every 6 h until [MTX] <0.1μM. Population and individual MTX pharmacokinetic parameters were estimated by nonlinear mixed-effects modeling.
Results
Fifty-eight patients had intracranial fluid collections present. Population average (inter-individual variation) MTX clearance was 96.0 ml/min/m2 (41.1 CV%) and increased with age. Of the patients with intracranial fluid collections, 24 had delayed excretion; only 2 of the 17 without fluid collections (p<0.04) had delayed excretion. Eleven patients had grade 3 or 4 toxicities attributed to HD-MTX. No significant difference was observed in intracranial fluid collection, total leucovorin dosing, or hydration fluids between those with and without toxicity.
Conclusions
Although an intracranial fluid collection is associated with delayed MTX excretion, HD-MTX can be safely administered with monitoring of infants and young children with intracranial fluid collections. Infants younger than one year may need additional monitoring to avoid toxicity.
doi:10.1007/s00280-014-2614-6
PMCID: PMC4282603  PMID: 25342291
Methotrexate; Pharmacokinetics; Pseudocyst; Toxicity; Cerebrospinal Fluid
5.  POPULATION PHARMACOKINETIC/DYNAMIC MODEL OF LYMPHOSUPPRESSION AFTER FLUDARABINE ADMINISTRATION 
Purpose
Quantitative relationships between 9-β-D-arabinofuranosyl-2-fluoroadenine (F-ara-A) concentrations and lymphosuppression have not been reported, but would be useful for regimen design. A population pharmacokinetic/pharmacodynamic model was constructed in this study using data from 41 hematopoietic cell transplant (HCT) recipients conditioned with busulfan in combination with fludarabine (total dose 120 mg/m2, Protocol 1519) or with fludarabine (total dose 250 mg/m2) with rabbit antithymocyte globulin (rATG, Protocol 2041).
Methods
Individual pharmacokinetic parameters were fixed to post-hoc Bayesian estimates, and circulating absolute lymphocyte counts (ALC) were obtained during the three weeks prior to graft infusion. A semi-physiological cell kill model with three lymphocyte transit compartments was applied and aptly characterized the time-course of suppression of circulating ALC by fludarabine administration. Drug and system-specific parameters were estimated using a maximum likelihood expectation maximization algorithm, and the final model was qualified using an internal visual predictive check.
Results
The final model successfully characterized the time-course and variability in ALC. Pharmacodynamic parameters exhibited considerable between subject variability (38.9-211%). The HCT protocol was the only covariate associated with the pharmacodynamic parameters, specifically the lymphocyte kill rate, the transit rate between lymphocyte compartments, and the baseline ALC.
Conclusions
This model can be used to simulate the degree of lymphosuppression for design of future fludarabine-based conditioning regimens.
doi:10.1007/s00280-014-2618-2
PMCID: PMC4282607  PMID: 25374408
fludarabine; nucleoside analogs; lymphocyte; lymphosuppression; population pharmacodynamics; hematopoietic cell transplantation; adoptive immunotherapy
6.  Plasma pharmacokinetics and tissue and brain distribution of cisplatin in musk shrews 
Purpose
Cisplatin induces nausea and emesis, even with antiemetic supportive care. To assess platinum exposure, which could activate nausea and emesis, we quantitated platinum in the brain and various organs, and hindbrain and spinal cord substance P, a key neuropeptide for the neuronal signaling of nausea and emesis.
Methods
Musk shrews, a model species for nausea and emesis research, were dosed intraperitoneally with 20 mg/kg cisplatin and euthanized at up to 72 h after injection. Concentrations of platinum were quantitated in plasma ultrafiltrate, plasma, lung, kidney, combined forebrain and midbrain, hindbrain, and spinal cord by flameless atomic absorption spectrometry. Hindbrains and spinal cords were analyzed for substance P by immunohistochemistry after injection of 20 or 30 mg/kg.
Results
Plasma ultrafilterable platinum concentrations decreased rapidly till 60 min after dosing and then more slowly by 24 h. The concentrations of total platinum in both the fore- and midbrain and the hindbrain were similar at all time points and were at least 20-fold lower than plasma total platinum concentrations. There were no significant changes in substance P immunoreactivity after cisplatin dosing. Histology revealed damage to the renal cortex by 72 h after injection of cisplatin.
Conclusions
This is the first study to examine platinum concentrations in musk shrews after administration of cisplatin, and delineate substance P immunohistochemical staining in the hindbrain and spinal cord of this species. The platinum concentrations detected in the brain could potentially contribute to the neurological side effects of cisplatin, such as nausea and emesis.
doi:10.1007/s00280-014-2623-5
PMCID: PMC4282608  PMID: 25398697
7.  Biological evaluation of a novel sorafenib analogue, t-CUPM 
Sorafenib (Nexavar®) is currently the only FDA-approved small molecule targeted therapy for advanced hepatocellular carcinoma. The use of structural analogues and derivatives of sorafenib has enabled the elucidation of critical targets and mechanism(s) of cell death for human cancer lines. We previously performed a structure-activity relationship study on a series of sorafenib analogues designed to investigate the inhibition overlap between the major targets of sorafenib Raf-1 kinase and VEGFR-2, and an enzyme shown to be a potent off-target of sorafenib, soluble epoxide hydrolase. In the current work, we present the biological data on our lead sorafenib analogue, t-CUPM, demonstrating that this analogue retains cytotoxicity similar to sorafenib in various human cancer cell lines and strongly inhibits growth in the NCI-60 cell line panel. Co-treatment with the pan-caspase inhibitor, Z-VAD-FMK, failed to rescue the cell viability responses of both sorafenib and t-CUPM, and immunofluorescence microscopy shows similar mitochondrial depolarization and apoptosis-inducing factor release for both compounds. These data suggest that both compounds induce a similar mechanism of caspase-independent apoptosis in hepatoma cells. In addition, t-CUPM displays anti-proliferative effects comparable to sorafenib as seen by a halt in G0/G1 in cell cycle progression. The structural difference between sorafenib and t-CUPM significantly reduces inhibitory spectrum of kinases by this analogue, and pharmacokinetic characterization demonstrates a 20-fold better oral bioavailability of t-CUPM than sorafenib in mice. Thus, t-CUPM may have the potential to reduce the adverse events observed from the multikinase inhibitory properties and the large dosing regimens of sorafenib.
doi:10.1007/s00280-014-2626-2
PMCID: PMC4400119  PMID: 25413440
Sorafenib analogue; Hepatoma cells; Kinase selectivity profile; Pharmacokinetics; Caspase-independent cell death; NCI-60 cell lines
8.  Population pharmacokinetic and exposure–response analysis for trastuzumab administered using a subcutaneous “manual syringe” injection or intravenously in women with HER2-positive early breast cancer 
Purpose
To characterize the population pharmacokinetics (PKs) of subcutaneous (SC) and intravenous (IV) trastuzumab in early breast cancer (EBC), assess the impact of covariates on trastuzumab PK, and evaluate fixed (nonweight-based) dosing for the SC regimen administrated via handheld syringe.
Methods
Serum trastuzumab concentrations from 595 patients with HER2-positive EBC in the HannaH study (fixed 600 mg SC trastuzumab or weight-based IV trastuzumab) were analyzed using nonlinear mixed-effects modeling. Multiple logistic regression was used to assess the exposure–response relationships between PK, efficacy [pathologic complete response (pCR)], and safety [grade ≥3 adverse events (AEs)].
Results
Trastuzumab PK was described by a two-compartment model with parallel linear and nonlinear elimination and first-order SC absorption, with a bioavailability of 77 %. Estimated total clearance (CL) values were 0.18–0.22 L/day for steady-state trough/peak concentrations of 75–148 µg/mL; the estimate for central volume of distribution was 2.9 L. Body weight and alanine transaminase, while showing significant effects on PK, only explained 8 % of the variability in CL. Exposure–response analyses showed no relationship between PK, pCR, and grade ≥3 AEs for either regimen.
Conclusion
A fixed 600 mg SC dose of trastuzumab provides the desired exposure, with steady-state trough concentrations (35–123 μg/mL for the 5th–95th percentiles) above the historical target concentration of 20 μg/mL for efficacy. Fixed dosing is further supported by lack of an exposure–response relationship between PK, pCR, and grade ≥3 AEs. No dose adjustment per patient factors is required within the ranges studied.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2922-5) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-015-2922-5
PMCID: PMC4706584  PMID: 26645407
Early breast cancer; Fixed dose; HER2; NONMEM; Population pharmacokinetics modeling; Trastuzumab
9.  Phase I dose-escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors 
Cancer chemotherapy and pharmacology  2014;74(6):1191-1198.
Purpose
This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors.
Methods
Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day).
Results
Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses.
Conclusions
The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.
doi:10.1007/s00280-014-2593-7
PMCID: PMC4562671  PMID: 25257509
Gefitinib; irinotecan; bioavailability; phase I; refractory solid tumors
10.  Risk of hemoptysis in patients with resected squamous cell and other high-risk lung cancers treated with adjuvant bevacizumab 
Purpose
Bevacizumab improves survival in lung adenocarcinomas. The potential anti-tumor benefit of bevacizumab in squamous cell lung cancers (SQCLCs) is unknown because bevacizumab is contraindicated in patients with advanced SQCLC due to an increased risk of hemoptysis. The risk of hemoptysis may be eliminated in patients with resected SQCLCs. We evaluated the safety of adjuvant bevacizumab in patients with resected SQCLCs and other lung cancers at high risk of hemoptysis.
Methods
As part of a prospective, phase II trial, patients with lung cancers at high risk of hemoptysis (defined by SQCLC histology, tumor near the central blood vessels, or history of hemoptysis) were treated with adjuvant bevacizumab following neo-adjuvant chemotherapy and complete surgical resection. Bevacizumab 15 mg/kg was given once every 3 weeks for up to 1 year. Patients were followed for safety and survival.
Results
Thirteen patients with high-risk features were treated: 7 patients had SQCLC, 3 had central tumors, and 3 had previous hemoptysis. No hemoptysis of any grade was seen following treatment with bevacizumab. Five of 13 patients experienced grade 1 bleeding (epistaxis, gum bleeding). Hypertension and lymphopenia were seen.
Conclusions
In a cohort of patients with resected lung cancers at high risk of hemoptysis, including those with SQCLC, treatment with adjuvant bevacizumab did not result in hemoptysis of any grade.
doi:10.1007/s00280-013-2219-5
PMCID: PMC4653739  PMID: 23811982
Non-small cell lung cancers; Squamous cell lung cancers; Bevacizumab; Adjuvant therapy; Hemoptysis; Clinical trial
12.  Antimitotic drugs in the treatment of cancer 
Cancer is a complex disease since it is adaptive in such a way that it can promote proliferation and invasion by means of an overactive cell cycle and in turn cellular division which is targeted by antimitotic drugs that are highly validated chemotherapy agents. However, antimitotic drug cytotoxicity to non-tumorigenic cells and multiple cancer resistance developed in response to drugs such as taxanes and vinca alkaloids are obstacles faced in both the clinical and basic research field to date. In this review, the classes of antimitotic compounds, their mechanisms of action and cancer cell resistance to chemotherapy and other limitations of current antimitotic compounds are highlighted, as well as the potential of novel 17-β estradiol analogs as cancer treatment.
doi:10.1007/s00280-015-2903-8
PMCID: PMC4648954  PMID: 26563258
Taxanes; Epothilones; Vinca alkaloids; Estrogens; 2-Methoxyestradiol
13.  Clinical practice guidelines for the diagnosis and treatment of patients with soft tissue sarcoma by the Spanish group for research in sarcomas (GEIS) 
Soft tissue sarcomas (STS) constitute an uncommon and heterogeneous group of tumours, which require a complex and specialized multidisciplinary management. The diagnostic approach should include imaging studies and core needle biopsy performed prior to undertaking surgery. Wide excision is the mainstay of treatment for localized sarcoma, and associated preoperative or postoperative radiotherapy should be administered in high-risk patients. Adjuvant chemotherapy was associated with a modest improvement in survival in a meta-analysis and constitutes a standard option in selected patients with high-risk STS. In metastatic patients, surgery must be evaluated in selected cases. In the rest of patients, chemotherapy and, in some subtypes, targeted therapy often used in a sequential strategy constitutes the treatment of election. Despite important advances in the understanding of the pathophysiology of the disease, the advances achieved in therapeutic results may be deemed still insufficient. Moreover, due to the rarity and complexity of the disease, the results in clinical practice are not always optimal. For this reason, the Spanish Group for Research on Sarcoma (GEIS) has developed a multidisciplinary clinical practice guidelines document, with the aim of facilitating the diagnosis and treatment of these patients in Spain. In the document, each practical recommendation is accompanied by level of evidence and grade of recommendation on the basis of the available data.
doi:10.1007/s00280-015-2809-5
PMCID: PMC4706580  PMID: 26563256
Soft tissue sarcoma; Clinical practice guidelines; Multidisciplinary management; Treatment
14.  A phase 1 study of lenvatinib, multiple receptor tyrosine kinase inhibitor, in Japanese patients with advanced solid tumors 
Cancer Chemotherapy and Pharmacology  2015;76(6):1153-1161.
Purpose
This phase 1 study aimed to assess the tolerability, safety, pharmacokinetics (PK), pharmacodynamics, and preliminary efficacy of lenvatinib capsules in Japanese patients with solid tumors when administered orally up to 24 mg on a once-daily (QD) continuous schedule.
Methods
Patients were enrolled in one of the two sequential cohorts (20 or 24 mg) of lenvatinib on a 28-day cycle based on the conventional 3 + 3 dose escalation design. Adverse events (AEs) were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Tolerability was judged based on dose-limiting toxicities (DLTs) during Cycle 1. The drug was defined as tolerable when the incidence of DLTs was less than 33 %.
Results
Nine patients received lenvatinib [20 mg (n = 3); 24 mg (n = 6)]. No DLTs were observed. The most common AEs were thrombocytopenia, blood thyroid stimulating hormone increased, and hypertension (89 %), followed by leukopenia, headache, and proteinuria (78 %). The area under the concentration–time curve and maximum observed concentration increased dose proportionally. The PK profiles were similar to those in non-Japanese phase 1 studies. One patient with leiomyosarcoma showed a partial response, and three patients have maintained stable disease for more than 6 months.
Conclusions
The 24-mg QD continuous dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in Japanese patients with solid tumors.
doi:10.1007/s00280-015-2899-0
PMCID: PMC4648947  PMID: 26530955
Lenvatinib; E7080; Phase 1; Angiogenesis; Japanese; Safety
15.  Effect of Age on the Pharmacokinetics of Busulfan in Patients Undergoing Hematopoietic Cell Transplantation; an Alliance study (CALGB 10503, 19808, and 100103) 
Purpose
Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) have often been excluded from myeloablative conditioning regimens containing busulfan because of non-disease related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (>60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability.
Methods
AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS, and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW) or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test.
Results
185 patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients ≥ 60 years old (median 66; range 60–74) had a significantly higher BuCL vs those <60 years old (median 50; range 18–60): BuCL 236 vs 168 mL/min, p=0.0002; BuCL/ABW 3.0 vs 2.1 mL/min/kg, p=0.0001; BuCL/IBW 3.8 vs 2.6 mL/min/kg, p=0.0035; BuCL/CBW 3.4 vs 2.6 mL/min/kg, p=0.0005. Inter-patient variability in clearance (CV%) was up to 48% in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p>0.34).
Conclusions
Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients.
doi:10.1007/s00280-014-2571-0
PMCID: PMC4210372  PMID: 25163570
busulfan; bone marrow transplant; elderly; pharmacokinetics
16.  Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity 
Purpose
Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides (6TGN), the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT.
Methods
Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy.
Results
The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However, since TPMTIA had lower blood counts at initiation of HD-MTX compared to TPMTHA patients (median WBC 2.8 vs. 3.3 ×109/L, P=0.01; median ANC 1.4 vs. 1.7 ×109/L, P=0.02), TPMTIA continued to have lower WBC and ANC levels compared to TPMTHA during all 28 days after HD-MTX (relative difference: 9% (95% CI: 2-17%), P=0.02 and 21% (95% CI: 6-39%), P=0.005). Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMTIA and TPMTHA patients (P=0.47 and P=0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P<0.001 for all analyses).
Conclusion
For both TPMTIA and TPMTHA patients dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.
doi:10.1007/s00280-014-2613-7
PMCID: PMC4446052  PMID: 25347948
17.  Phase II study of temozolomide and veliparib combination therapy for sorafenib-refractory advanced hepatocellular carcinoma 
Cancer Chemotherapy and Pharmacology  2015;76(5):1073-1079.
Purpose
To determine the antitumor efficacy and tolerability of combination temozolomide (TMZ) and veliparib (ABT-888) in patients with advanced, sorafenib-refractory hepatocellular carcinoma (HCC).
Methods
This single-arm phase II trial enrolled patients with pathologically confirmed, sorafenib-refractory HCC. All patients received 40 mg ABT-888 PO daily on days 1–7 and 150 mg/m2 TMZ PO daily on days 1–5 of a 28-day cycle. The primary endpoint was objective response rate (ORR) at 2 months. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and toxicity profile. Tumor response was assessed every 2 cycles using RECIST criteria, and toxicities were assessed using CTCAE v4.03.
Results
We enrolled 16 patients in the first phase of the trial, but the study was discontinued due to a poor ORR; only four patients (25 %) had SD after 2 cycles. Twelve patients (75 %) were taken off study after 2 months of treatment; 10 of these had disease progression. Two patients (13 %) were taken off study due to severe toxicity, and one patient (6 %) died from non-treatment-related liver failure. One patient had SD for 16 months, receiving 11 cycles of therapy before being taken off study. The most common grade 3 treatment-related toxicities included vomiting (n = 2), thrombocytopenia (n = 2), nausea (n = 1), and anemia (n = 1). The median PFS was 1.9 months, and median OS was 13.1 months.
Conclusion
The combination of TMZ and ABT-888 is well tolerated in patients with advanced HCC. However, the regimen failed to show survival benefit.
ClinicalTrials.gov Identifier
NCT01205828.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2852-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-015-2852-2
PMCID: PMC4612326  PMID: 26449224
Refractory; Hepatocellular carcinoma; Temozolomide; Veliparib
18.  Microdialysis Measurement of Intratumoral Temozolomide Concentration after Cediranib, a Pan-VEGF Receptor Tyrosine Kinase Inhibitor, in a U87 Glioma Model 
Background
Combining anti-angiogenesis agents with cytotoxic agents for the treatment of malignant gliomas, may affect the cytotoxic drug distribution by normalizing the blood brain-barrier (BBB). This study examines the intratumoral concentration of temozolomide (TMZ) in the presence and absence of the pan-VEGF receptor tyrosine kinase inhibitor, cediranib.
Methods
Seven nude rats bearing U87 intracerebral gliomas had a microdialysis probe centered within the tumor. Ten-days after tumor implantation TMZ(50mg/kg) was given orally. The extracellular fluid (ECF) concentrations of TMZ within the tumor were assessed via microdialysis for six hours following TMZ administration. Cediranib(6 mg/kg) was then given orally, and 12 hours later, TMZ was re-administered with subsequent microdialysis collection. A subset of animals also underwent functional MRI to assess angiogenesis in vivo at post-inoculation days 12 and 21, before and after the cediranib treatment.
Results
After dosing of oral TMZ only, ECF-TMZ mean-Cmax and area under the concentration curve(AUC0-∞) within the tumor were 0.59μg/mL and 1.82μg·hr/mL, respectively. Post-cediranib, ECF-TMZ mean-Cmax and AUC0-∞ were 0.83μg/mL and 3.72±0.61μg·hr/mL within the tumor, respectively. This represented a 1.4-fold (p=0.3) and 2.0-fold (p=0.06) increase in the ECF-TMZCmax and AUC0-∞, respectively, after cediranib administration. In vivo MRI measurements of the various vascular parameters were consistent with a BBB ‘normalization’ profile following cediranib treatment.
Conclusions
In the U87 intracerebral glioma model, within the first day of administration of cediranib, the intratumoral concentrations of TMZ in tumor ECF were slightly, but not statistically significantly, increased when compared to treatment of TMZ alone with radiographic evidence of a normalized BBB.
doi:10.1007/s00280-013-2172-3
PMCID: PMC4596243  PMID: 23649683
microdialysis; glioma; angiogenesis; temozolomide; cediranib; vascular normalization
19.  Pharmacokinetics of eribulin mesylate in cancer patients with normal and impaired renal function 
Cancer Chemotherapy and Pharmacology  2015;76(5):1051-1061.
Purpose
To evaluate the effect of renal impairment on eribulin mesylate pharmacokinetics following a single dose in adults with advanced solid tumors.
Methods
Patients were grouped by renal function: moderate impairment (creatinine clearance [CrCl] 30–50 mL/min), severe impairment (CrCl 15–29 mL/min), or normal (CrCl ≥80 mL/min). During each 21-day cycle, eribulin mesylate doses (days 1 and 8) were administered intravenously: moderate, 1.1 mg/m2 (except cycle 1 day 1, 1.4 mg/m2); severe, 0.7 mg/m2; normal, 1.4 mg/m2.
Results
Nineteen patients were enrolled (normal, n = 6; moderate, n = 7; severe, n = 6). Renal impairment was associated with an increased mean dose-normalized area under the concentration–time curve (ratios for moderate/normal and severe/normal: 1.49; 90 % confidence interval [CI] 0.9, 2.45). CrCl and renal function correlated positively, with a numerically small slope (0.0184; 90 % CI −0.00254, 0.0394). A simulated dose reduction to eribulin 1.1 mg/m2 in patients with moderate or severe renal impairment achieved the same exposure as 1.4 mg/m2 in those with normal renal function. All groups had similar toxicity profiles, with no unexpected adverse events.
Conclusions
Renal impairment decreased eribulin clearance and increased exposure. Pharmacokinetic evaluation supports an eribulin dose reduction to 1.1 mg/m2 in patients with moderate or severe renal impairment.
ClinicalTrials.gov Identifier
NCT01418677.
doi:10.1007/s00280-015-2878-5
PMCID: PMC4612322  PMID: 26433580
Renal function; Renal impairment; Cancer patients; Eribulin; Pharmacokinetics
20.  A phase 1 study evaluating the pharmacokinetics and preliminary efficacy of veliparib (ABT-888) in combination with carboplatin/paclitaxel in Japanese subjects with non-small cell lung cancer (NSCLC) 
Cancer Chemotherapy and Pharmacology  2015;76(5):1063-1072.
Abstact
Introduction
Veliparib is a potent, orally bioavailable PARP inhibitor that enhances efficacy of DNA-damaging chemotherapeutic agents. The study objectives were to determine the recommended phase 2 dose (RPTD) of veliparib plus carboplatin and paclitaxel, and assess pharmacokinetics (PK), tolerability, and preliminary efficacy in Japanese patients with solid tumors.
Methods
Carboplatin (AUC 6 mg/mL min) and paclitaxel (200 mg/m2) were administered on day 3 of a 21-day cycle. Oral veliparib (40, 80, or 120 mg BID) was administered on days 1–7. Patients received ≤6 cycles. Adverse events (AEs) were reported using NCI-CTCAE version 4.03, PK parameters were analyzed using noncompartmental methods, and responses were measured by RECIST version 1.1.
Results
Twelve patients with non-small cell lung cancer (NSCLC) were treated. Common treatment-emergent AEs, consistent with toxicities associated with carboplatin and paclitaxel, included leukopenia (100 %), neutropenia (100 %), anemia (83 %), thrombocytopenia (75 %), increased alanine aminotransferase (67 %), and increased aspartate aminotransferase (67 %). Grade 3/4 AEs (in ≥2 patients) included neutropenia (100 %), leukopenia (33 %), anemia (25 %), and hyponatremia (17 %). No AEs led to veliparib, carboplatin, or paclitaxel interruption; no DLTs were observed. The RPTD was determined to be 120 mg BID. Veliparib Cmax and AUC were approximately dose proportional. Six partial responses were observed.
Conclusions
Veliparib PK was not impacted by carboplatin and paclitaxel. The safety profile was manageable. The 120 mg BID RPTD confirmed in Japanese patients is the dose being evaluated in global studies of veliparib. Preliminary efficacy suggests veliparib may enhance carboplatin and paclitaxel activity, providing benefit to patients with NSCLC.
doi:10.1007/s00280-015-2876-7
PMCID: PMC4612330  PMID: 26433581
Veliparib (ABT-888); NSCLC; PARP; Carboplatin; Paclitaxel
21.  Anticancer Activity of VDR-Coregulator Inhibitor PS121912 
Purpose
PS121912 has been developed as selective vitamin D receptor (VDR)–coregulator inhibitor starting from a high throughput screening campaign to identify new agents that modulate VDR without causing hypercalcemia. Initial antiproliferative effects of PS121912 were observed that are characterized herein to enable future in vivo investigation with this molecule.
Methods
Antiproliferation and apoptosis was determined using four different cancer cell lines (DU145, Caco2, HL-60, and SKOV3) in the presence of PS121912, 1,25-(OH)2D3, or a combination of 1,25-(OH)2D3 and PS121912. VDR si-RNA was used to identify the role of VDR during this process. The application of ChIP enabled us to determine the involvement of coregulator recruitment during transcription, which was investigated by rt-PCR with VDR target genes and those affiliated with cell cycle progression. Translational changes of apoptotic proteins were determined with an antibody array. The preclinical characterization of PS121912 include the determination of metabolic stability and CYP3A4 inhibition.
Results
PS121912 induced apoptosis in all four cancer cells, with HL-60 cells being the most sensitive. At sub-micromolar concentrations, PS121912 amplified the growth inhibition of cancer cells caused by 1,25-(OH)2D3 without being antiproliferative by itself. A knockout study with VDR si-RNA confirmed the mediating role of VDR. VDR target genes induced by 1,25-(OH)2D3 were down-regulated with the co-treatment of PS121912. This process was highly dependent on the recruitment of coregulators that in case of CYP24A1 was SRC2. The combination of PS121912 and 1,25-(OH)2D3 reduced the presence of SRC2 and enriched the occupancy of corepressor NCoR at the promoter site. E2F transcription factor 1 and 4 were down-regulated in the presence of PS121912 and 1,25-(OH)2D3 that in turn reduced the transcription levels of cyclin A and D thus arresting HL-60 cells in the S or G2/M phase. In addition, proteins with hematopietic functions such as cyclin-dependent kinase 6, histone deacetylase 9 and transforming growth factor beta 2 and 3 were down-regulated as well. Elevated levels of P21 and GADD45, in concert with cyclin D1 also mediated the antiproliferative response of HL-60 in the presence of 1,25-(OH)2D3 and PS121912. Studies at higher concentration of P121912 identified a VDR-independent pathway of antiproliferation that included the enzymatic and transcriptional activation of caspase 3/7.
Conclusion
Overall, we conclude that PS121912 behaves like a VDR antagonist at low concentrations but interacts with more targets at higher concentrations leading to apoptosis mediated by caspase 3/7 activation. In addition, PS121912 showed an acceptable metabolic stability to enable in vivo cancer studies.
doi:10.1007/s00280-014-2549-y
PMCID: PMC4177010  PMID: 25107568
Vitamin D receptor; VDR–coregulator inhibitor; leukemia; cell cycle regulation; apoptosis; HL-60; 3-indolylmethanamine
22.  Phase II study of ipilimumab monotherapy in Japanese patients with advanced melanoma 
Purpose
Ipilimumab is designed to block cytotoxic T-lymphocyte antigen-4 to augment antitumor T cell responses. In studies of predominantly Caucasian patients with advanced melanoma, ipilimumab was associated with durable response, long-term survival benefit, and a manageable safety profile. This phase II study assessed the safety of ipilimumab in Japanese patients with unresectable stage III or IV melanoma.
Methods
Patients received ipilimumab 3 mg/kg every 3 weeks for four doses. The database lock for the original analysis was in August 2014. Overall survival, progression-free survival, and data on deaths were based on an updated, follow-up analysis (database lock April 2015).
Results
Data are reported from 20 patients. Fifteen patients (75 %) received all four doses of ipilimumab during induction. Twelve patients (60 %) had at least one drug-related adverse event (AE), and no patients discontinued due to a drug-related AE. There were no deaths related to study drug. The most common drug-related AEs were rash (n = 7), pyrexia (n = 3), increased aspartate aminotransferase (AST; n = 3), and increased alanine aminotransferase (ALT; n = 3). Twelve patients (60 %) reported immune-related AEs (irAEs); most frequent were skin (n = 9) and liver (n = 3) disorders. Grade 3 irAEs were ALT and AST elevation (n = 2) and diabetes mellitus (n = 1). Two patients had a partial response and two had stable disease, yielding a 20 % disease control rate. Median overall survival and progression-free survival were 8.71 and 2.74 months, respectively.
Conclusion
Ipilimumab 3 mg/kg had a manageable AE profile in this Japanese patient population with clinical outcomes similar to that in Caucasian patients.
ClinicalTrials.gov identifier
NCT01990859.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2873-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-015-2873-x
PMCID: PMC4612321  PMID: 26410424
Ipilimumab; Immune-checkpoint inhibitor; Melanoma; Phase II study; Japanese patients
23.  Phase II study of the immune-checkpoint inhibitor ipilimumab plus dacarbazine in Japanese patients with previously untreated, unresectable or metastatic melanoma 
Purpose
Ipilimumab (IPI), a monoclonal antibody against immune-checkpoint receptor cytotoxic T lymphocyte antigen-4, is designed to enhance antitumor T cell function. IPI 10 mg/kg plus dacarbazine (DTIC) significantly improved overall survival in a phase 3 study involving predominantly Caucasian patients, with an adverse event (AE) profile similar to that of IPI monotherapy. We conducted a single-arm, phase 2 study to evaluate the safety and efficacy of IPI plus DTIC in Japanese patients.
Methods
Previously untreated patients with unresectable stage III or IV melanoma received IPI 10 mg/kg plus DTIC 850 mg/m2 every 3 weeks for four doses (q3w × 4), followed by DTIC q3w × 4 and then IPI every 12 weeks until disease progression or intolerable toxicity.
Results
All 15 treated patients reported drug-related AEs, the most common of which were increases in alanine aminotransferase (n = 12, 80 %) and aspartate aminotransferase (n = 11, 73 %). Treatment-related serious AEs were reported in 11 (73 %) patients. Nine patients (60 %) discontinued treatment due to drug-related toxicities. Immune-related AEs (irAEs) were reported in 14 patients (93 %). The most frequent irAEs were liver (n = 12, 80 %) and skin (n = 10, 67 %) toxicities. Five deaths were reported; all were caused by progressive disease. Efficacy evaluation showed one complete response, one partial response and four patients with stable disease. Best overall response rate was 13 % (2/15), and the disease control rate was 40 % (6/15). The study was terminated early due to frequent, high-grade liver toxicities.
Conclusions
IPI 10 mg/kg plus DTIC 850 mg/m2 was not considered tolerable in the Japanese patient population.
ClinicalTrials.gov identifier: NCT01681212.
Electronic supplementary material
The online version of this article (doi:10.1007/s00280-015-2870-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s00280-015-2870-0
PMCID: PMC4612320  PMID: 26407818
Ipilimumab; Dacarbazine; Immune-checkpoint inhibitor; Melanoma; Phase 2 study; Japanese patients
24.  Relationship of promising methods in the detection of anthracycline-induced cardiotoxicity in breast cancer patients 
Purpose
It remains challenging to identify patients at risk of anthracycline-induced cardiotoxicity. To better understand the different risk-stratifying approaches, we evaluated 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy and its interrelationship with conventional echocardiography, 2D strain imaging and several biomarkers.
Methods
We performed 123I-mIBG scintigraphy, conventional and strain echocardiography and biomarker (NT-proBNP, TNF-α, galectin-3, IL-6, troponin I, ST-2 and sFlt-1) assessment in 59 breast cancer survivors 1 year after anthracycline treatment. Interobserver and intermethod variability was calculated on planar and SPECT 123I-mIBG scintigraphy, using the heart/mediastinum (H/M) ratio and washout (WO). Pearson’s r and multivariate analyses were performed to identify correlations and independent predictors of 123I-mIBG scintigraphy results.
Results
Delayed planar anterior whole-heart ROI (WH) H/M ratios and WO were the most robust 123I-mIBG parameters. Significant correlations were observed between 123I-mIBG parameters and several conventional echo parameters, global longitudinal and radial strain (GLS and GRS) and galectin-3. The highest Pearson’s r was observed between delayed H/M ratio and GRS (Pearson’s r 0.36, p = 0.01). Multivariate analysis showed that GRS was the only independent predictor of the delayed WH H/M ratio (p = 0.023).
Conclusion
The delayed planar H/M ratio is the most robust 123I-mIBG parameter. It correlates with several conventional echocardiographic parameters, GLS, GRS and galectin-3. Of these, only GRS predicts the H/M ratio.
doi:10.1007/s00280-015-2874-9
PMCID: PMC4612328  PMID: 26400150
Breast cancer; Anthracyclines; Cardiotoxicity; 2D strain imaging; 123I-mIBG scintigraphy; Biomarkers
25.  Increased sensitivity to glucose starvation correlates with downregulation of glycogen phosphorylase isoform PYGB in tumor cell lines resistant to 2-deoxy-d-glucose 
Background
As tumors evolve, they upregulate glucose metabolism while also encountering intermittent periods of glucose deprivation. Here, we investigate mechanisms by which pancreatic cancer cells respond to therapeutic (2-deoxy-d-glucose, 2-DG) and physiologic (glucose starvation, GS) forms of glucose restriction.
Methods
From a tumor cell line (1420) that is unusually sensitive to 2-DG under normoxia, low (14DG2)- and high (14DG5)-dose resistant cell lines were selected and used to probe the metabolic pathways involved with their response to different forms of glucose deprivation.
Results
Muted induction of the unfolded protein response was found to correlate with resistance to 2-DG. Additionally, 14DG2 displayed reduced 2-DG uptake, while 14DG5 was cross-resistant to tunicamycin, suggesting it has enhanced ability to manage glycosylation defects. Conversely, 2-DG-resistant cell lines were more sensitive than their parental cell line to GS, which coincided with lowered levels of glycogen phosphorylase (PYGB) and reduced breakdown of glycogen to glucose in the 2-DG-resistant cell lines. Moreover, by inhibiting PYGB in the parental cell line, sensitivity to GS was increased.
Conclusions
Overall, the data demonstrate that the manner in which glucose is restricted in tumor cells, i.e., therapeutic or physiologic, leads to differential biological responses involving distinct glucose metabolic pathways. Moreover, in evolving tumors where glucose restriction occurs, the identification of PYGB as a metabolic target may have clinical application.
doi:10.1007/s00280-013-2358-8
PMCID: PMC4570497  PMID: 24292700
2-Deoxy-d-glucose; Glucose starvation; Unfolded protein response; Glycogen

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