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1.  Molecular Markers for Novel Therapeutic Strategies in Pancreatic Endocrine Tumors 
Pancreas  2013;42(3):411-421.
Objectives
Pancreatic endocrine tumors (PETs) share numerous features with gastrointestinal neuroendocrine (carcinoid) tumors. Targets of novel therapeutic strategies previously assessed in carcinoid tumors were analyzed in PETs (44 cases).
Methods
Activating mutations in EGFR, KIT, and PDGFRA, and non-response mutations in KRAS, were evaluated. Copy number of EGFR and HER-2/neu was quantified by fluorescence in situ hybridization. Expression of EGFR, PDGFRA, VEGFR1, TGFBR1, Hsp90, SSTR2A, SSTR5, IGF1R, mTOR, and MGMT was measured immunohistochemically.
Results
Elevated EGFR copy number was found in 38% of cases, but no KRAS non-response mutations. VEGFR1, TGFBR1, PDGFRA, SSTR5, SSTR2A, and IGF1R exhibited the highest levels of expression in the largest percentages of PETs.
Anticancer drugs BMS-754807 (selective for IGF1R/IR), 17-(allylamino)-17-demethoxygeldanamycin (17-AAG, targeting Hsp90), and axitinib (directed toward VEGFR1–3/PDGFRA-B/KIT) induced growth inhibition of human QGP-1 PET cells with IC50 values (nM) of 273, 723, and 743, respectively. At growth-inhibiting concentrations, BMS-754807 inhibited IGF1R phosphorylation; 17-AAG induced loss of EGFR, IGF1R, and VEGFR2; and axitinib increased p21Waf1/Cip1(CDKN1A) expression without inhibiting VEGFR2 phosphorylation.
Conclusions
Results encourage further research into multi-drug strategies incorporating inhibitors targeting IGF1R or Hsp90 and into studies of axitinib combined with conventional chemotherapeutics toxic to tumor cells in persistent growth arrest.
doi:10.1097/MPA.0b013e31826cb243
PMCID: PMC3594087  PMID: 23211371
pancreatic endocrine tumors; molecular analysis
2.  UGT1A1 Genotype-guided Phase I Study of Irinotecan, Oxaliplatin, and Capecitabine 
Investigational new drugs  2013;31(6):10.1007/s10637-013-0034-9.
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/m2) 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).
doi:10.1007/s10637-013-0034-9
PMCID: PMC3880122  PMID: 24114122
Irinotecan; Capecitabine; Oxaliplatin; UGT1A1
3.  A Phase I Study of Vorinostat in Combination with Bortezomib in Patients with Advanced Malignancies 
Investigational new drugs  2013;31(6):1539-1546.
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/m2). 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/m2 to 1.5 mg/m2. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m2. DLTs consisted of grade 3 fatigue in three patients (1 mg/m2,1.3 mg/m2 and 1.5 mg/m2) and grade 3 hyponatremia in one patient (1.5 mg/m2). 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 x 14 days and bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11 of a 21-day cycle.
doi:10.1007/s10637-013-0029-6
PMCID: PMC3901262  PMID: 24114121
SAHA; vorinostat; PS-341; bortezomib; phase I
4.  CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8 
Background
Controversy exists regarding CYP2D6 genotype and tamoxifen efficacy.
Methods
A matched case-control study was conducted utilizing the Austrian Breast and Colorectal Cancer Study Group Trial 8 that randomized post-menopausal women with estrogen receptor positive breast cancer to tamoxifen for 5 years (Arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (Arm B). Cases had disease recurrence, contralateral breast cancer, second non-breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and TNM stage. Genotyping was performed for alleles associated with no (PM; *3, *4, *6); reduced (IM; *10, and *41); and extensive (EM: absence of these alleles) CYP2D6 metabolism.
Findings
The common CYP2D6 *4 allele was in Hardy Weinberg Equilibrium. In Arm A during the first 5 years of therapy, women with 2 poor alleles (PM/PM: OR=2.45, 95% CI: 1.05–5.73, p=0.04) and women with one poor allele (PM/IM or PM/EM: OR=1.67, 95% CI: 0.95–2.93, p=0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3–5 when patients remained on tamoxifen (Arm A) or switched to anastrozole (Arm B), PM/PM tended towards a higher likelihood of a disease event relative to EM/EM (OR= 2.40, 95% CI: 0.86–6.66, p=0.09) among women on Arm A but not among women on Arm B (OR= 0.28; 95% CI: 0.03–2.30).
Conclusion
In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration, and not after switching to anastrozole.
doi:10.1158/1078-0432.CCR-12-2153
PMCID: PMC3548984  PMID: 23213055
Tamoxifen; CYP2D6; metabolism; anastrozole; breast cancer; estrogen receptor
5.  Gemcitabine Cytotoxicity: Interaction of Efflux and Deamination 
Gemcitabine is a cytidine analogue used in the treatment of various solid tumors. Little is known about how gemcitabine and its metabolites are transported out of cells. We set out to study the efflux of gemcitabine and the possible consequences of that process in cancer cells. We observed the efflux of gemcitabine and its deaminated metabolite, 2’,2’-difluorodeoxyuridine (dFdU) using high performance liquid chromatography and tandem mass spectrometry (LC-MS/MS) after gemcitabine treatment. Non-selective ABCC-transport inhibition with probenecid significantly increased intracellular dFdU concentrations, with a similar trend observed with verapamil, a non-selective ABCB1 and ABCG2 transport inhibitor. Neither probenecid nor verapamil altered intracellular gemcitabine levels after the inhibition of deamination with tetrahydrourudine, suggesting that efflux of dFdU, but not gemcitabine, was mediated by ABC transporters. MTS assays showed that probenecid increased sensitivity to gemcitabine. While dFdU displayed little cytotoxicity, intracellular dFdU accumulation inhibited cytidine deaminase, resulting in increased gemcitabine levels and enhanced cytotoxicity. Knockdown of ABCC3, ABCC5 or ABCC10 individually did not significantly increase gemcitabine sensitivity, suggesting the involvement of multiple transporters. In summary, ABCC-mediated efflux may contribute to gemcitabine resistance through increased dFdU efflux that allows for the continuation of gemcitabine deamination. Reversing efflux-mediated gemcitabine resistance may require broad-based efflux inhibition.
doi:10.4172/2157-7609.1000107
PMCID: PMC3144579  PMID: 21804948
Gemcitabine; Cytotoxicity; Drug Efflux; Transport
6.  A Pediatric Phase 1 Trial Of Vorinostat And Temozolomide In Relapsed Or Refractory Primary Brain Or Spinal Cord Tumors: A Children’s Oncology Group Phase 1 Consortium Study 
Pediatric blood & cancer  2013;60(9):1452-1457.
Purpose
We conducted a pediatric phase I study to estimate the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetic properties of vorinostat, a histone deacetylase (HDAC) inhibitor, when given in combination with temozolomide in children with refractory or recurrent CNS malignancies.
Patients and Methods
Vorinostat, followed by temozolomide approximately one hour later, was orally administered, once daily, for 5 consecutive days every 28 days at 3 dose levels using the rolling 6 design. Studies of histone accumulation in peripheral blood mononuclear cells were performed on day 1 at 0, 6, and 24 h after vorinostat dosing. Vorinostat pharmacokinetics (PK) and serum MGMT promoter status were also assessed
Results
Nineteen eligible patients were enrolled and eighteen patients were evaluable for toxicity. There were no DLTs observed at dose level 1 or 2. DLTs occurred in 4 patients at dose level 3: thrombocytopenia (4), neutropenia (3), and leucopenia (1). Non-dose limiting grade 3 or 4 toxicities related to protocol therapy were also hematologic and included neutropenia, lymphopenia, thrombocytopenia, anemia, and leucopenia. Three patients exhibited stable disease and one patient had a partial response. There was no clear relationship between vorinostat dosage and drug exposure over the dose range studied. Accumulation of acetylated H3 histone in PBMC was observed after administration of vorinostat.
Conclusion
Five-day cycles of vorinostat in combination with temozolomide are well tolerated in children with recurrent CNS malignancies with myelosuppression as the DLT. The recommended phase II combination doses are vorinostat, 300 mg/m2/day and temozolomide,150 mg/m2/day.
doi:10.1002/pbc.24541
PMCID: PMC4139006  PMID: 23554030
vorinostat; temozolomide phase I trial; pediatric cancer; Children’s Oncology Group
7.  Gemcitabine Pharmacogenomics: Deoxycytidine Kinase (DCK) and Cytidylate Kinase (CMPK) Gene Resequencing and Functional Genomics 
Gemcitabine and other cytidine antimetabolites require metabolic activation by phosphorylation. Deoxycytidine kinase (DCK) and cytidine monophosphate kinase (CMPK) catalyze these reactions. We have applied a genotype-to-phenotype strategy to study DCK and CMPK pharmacogenomics. Specifically, we resequenced DCK and CMPK using 240 DNA samples, 60 each from African-American, Caucasian-American, Han Chinese-American and Mexican-American subjects. We observed 28 DCK polymorphisms and 28 polymorphisms in CMPK, 33 of which were novel. Expression in COS-1 cells showed that variant allozyme enzyme activities ranged from 32 to 105% of the wild type (WT) for DCK, and from 78 to 112% of WT for CMPK – with no significant differences in apparent Km values for either enzyme except for a DCK Val24/Ser122 double variant allozyme. Relative levels of DCK and CMPK immunoreactive protein in the COS-1 cells paralleled relative levels of enzyme activity and were significantly correlated for DCK (Rp = 0.89, P = 0.0004) but not for CMPK (Rp = 0.82, P = 0.095). The results of an analysis of DCK and CMPK structural models were compatible with the observed functional consequences of sequence alterations in variant allozymes. We also confirmed that the CMPK protein expressed in COS-1 cells and in a rabbit reticulocyte lysate was 196 rather than 228 amino acids in length. In summary, we determined common sequence variation in DCK and CMPK and systematically evaluated its functional implications. These gene sequence differences may contribute to variation in the metabolic activation of gemcitabine and other cytidine antimetabolites.
doi:10.1124/dmd.108.020925
PMCID: PMC3066084  PMID: 18556440
8.  Selective Estrogen Receptor Modulators and Pharmacogenomic Variation in ZNF423 Regulation of BRCA1 Expression: Individualized Breast Cancer Prevention 
Cancer discovery  2013;3(7):812-825.
The selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene can reduce the occurrence of breast cancer in high risk women by 50%, but this FDA-approved prevention therapy is not often used. We attempted to identify genetic factors that contribute to variation in SERM breast cancer prevention using DNA from the NSABP P-1 and P-2 breast cancer prevention trials. An initial discovery genome-wide association study identified common single nucleotide polymorphisms (SNPs) in or near the ZNF423 and CTSO genes that were associated with breast cancer risk during SERM therapy. We then showed that both ZNF423 and CTSO participated in the estrogen-dependent induction of BRCA1 expression, in both cases with SNP-dependent variation in induction. ZNF423 appeared to be an estrogen-inducible BRCA1 transcription factor. The odds ratio for differences in breast cancer risk during SERM therapy for subjects homozygous for both protective or both risk alleles for ZNF423 and CTSO was 5.71.
doi:10.1158/2159-8290.CD-13-0038
PMCID: PMC3710533  PMID: 23764426
tamoxifen; raloxifene; breast cancer prevention; ZNF423; CTSO; BRCA1; single nucleotide polymorphisms; genome-wide association study
9.  Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study 
BMC Research Notes  2014;7:256.
Background
Patients with relapsed/refractory stage 4 high-risk neuroblastoma were enrolled on a phase I study (NANT2004-03) of intravenous fenretinide emulsion. Pharmacokinetic samples were collected during and after the infusion, and the levels were measured using an HPLC system. A likely case of a fatal drug interaction between fenretinide, ceftriaxone, and acetaminophen is described, including the pharmacokinetics of fenretinide, laboratory data, and post-mortem autopsy in a pediatric neuroblastoma patient treated on this study.
Case presentation
On Day 4 of a scheduled 5-day-infusion of intravenous fenretinide, the patient developed a fever, acetaminophen was started, ceftriaxone initiated for possible bacteremia, and fenretinide level doubled from 56 to 110 μM. Over the next three days, although blood cultures remained negative, the patient’s condition deteriorated rapidly. Acute liver failure was diagnosed on Day 7, and the patient expired on Day 20 of fulminant hepatic failure with associated renal, cardiac, and hemorrhagic/coagulation toxicities. Autopsy showed extensive hemorrhagic necrosis of the liver, marked bile duct proliferation, and abundant hemosiderin, consistent with cholestasis and drug toxicity.
Conclusions
After extensive review of patient data, the clinical course, and the literature, we conclude that observed hepatic toxicity was likely due to a drug interaction between fenretinide and concomitant ceftriaxone and acetaminophen. None of the other 16 patients treated on this study experienced significant hepatic toxicity. Although the prevalence of cholestasis with ceftriaxone usage is relatively high, the potential drug interaction with these concomitant medications has not been previously reported. Concomitant use of fenretinide, ceftriaxone, and acetaminophen should be avoided.
doi:10.1186/1756-0500-7-256
PMCID: PMC4006848  PMID: 24755475
Ceftriaxone; Fenretinide; Acetaminophen; Drug interaction; Biliary sludge; Fulminant hepatic failure
10.  Evaluation of CYP2D6 and Efficacy of Tamoxifen and Raloxifene in Women Treated for Breast Cancer Chemoprevention: Results from the NSABP P-1 and P-2 Clinical Trials 
Background
Controversy exists regarding the association between CYP2D6 enzyme activity and tamoxifen effectiveness in the adjuvant treatment of invasive breast cancer; however this association in the primary prevention of breast cancer is unknown.
Methods
We performed a nested case-control study in the context of the NSABP P-1 and P-2 prevention trials to determine the impact of CYP2D6 genotype, CYP2D6 inhibitor use, as well as metabolizer status (CYP2D6 genotype combined with CYP2D6 inhibitor use), on breast cancer events. Women who developed breast cancer (both non-invasive and invasive) while on five years of SERM therapy (cases) were matched to controls free of breast cancer. Comprehensive CYP2D6 genotyping was performed for alleles associated with absent (*3, *4, *5, *6), reduced (*10, *17, *41), and increased (*1XN and *2XN) enzyme activity. Information regarding the use of CYP2D6 inhibitors was recorded.
Results
591 cases were matched to 1126 controls and DNA was genotyped in >97%. In patients treated with tamoxifen, there was no association of CYP2D6 genotype [OR(extensive/poor metabolizer): 0.90; 95% CI 0.46-1.74, p=0.74), use of a potent CYP2D6 inhibitor (OR 0.92; 95% CI 0.575-1.486), or CYP2D6 metabolizer status (OR 1.03; 95% CI 0.669-1.607) with breast cancer occurrence. Likewise, there was no association between any CYP2D6 metabolism parameter with breast cancer events in raloxifene treated patients.
Conclusions
In the NSABP P1 and P2 clinical trials, alterations in CYP2D6 metabolism are not associated with either tamoxifen or raloxifene efficacy.
doi:10.1158/1078-0432.CCR-11-0860
PMCID: PMC3207003  PMID: 21880792
tamoxifen; breast cancer; prevention; CYP2D6; polymorphism
11.  CYP2D6 and HOXB13/IL17BR: Combining inherited and tumor gene markers for prediction of tamoxifen resistance 
Purpose
Genetic variation in Cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL-17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen treated breast cancer.
Experimental Design
Retrospective analysis of women with node negative breast cancer randomized to receive 5 years of tamoxifen (NCCTG 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6*4 genotype and presence/absence of a CYP2D6 inhibitor. RT-PCR profiles for HOXB13 and IL-17BR and the cut-point separating patients into high and low risk categories according to disease-free survival (DFS) were utilized. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling.
Results
CYP2D6 metabolism and HOXB13/IL17BR gene ratio was available in 110/160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log rank p=0.004) and OS (p=0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13/IL17BR ratio had significantly worse OS [adjusted hazard ratio (HR) =2.41, 95% confidence interval:1.08-5.37; p=0.031) whereas women with both decreased metabolism and high HOXB13/IL17BR had the shortest survival (adjusted HR=3.15, 95% CI:1.17-8.52, p=0.024).
Conclusions
An index comprised of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.
doi:10.1158/1078-0432.CCR-08-0619
PMCID: PMC2596658  PMID: 18794098
Tamoxifen; Cytochrome P450 2D6; HOXB13/IL17BR; Breast cancer
12.  A Phase I Trial of Vorinostat and Alvocidib in Patients with Relapsed, Refractory or Poor Prognosis Acute Leukemia, or Refractory Anemia with Excess Blasts-2 
Purpose
This phase I study was conducted to identify the MTD of alvocidib when combined vorinostat in patients with relapsed, refractory, or poor prognosis acute leukemia, or refractory anemia with excess blasts-2 (RAEB-2). Secondary objectives included investigating the pharmacokinetic and pharmacodynamic effects of the combination.
Experimental Design
Patients received vorinostat (200 mg orally, 3 times a day [TID], for 14 days), on a 21-day cycle, combined with 2 different alvocidib administration schedules: a 1-h intravenous infusion, daily x 5; or a 30-min loading infusion followed by a 4-h maintenance infusion, weekly x 2. The alvocidib dose was escalated using a standard 3+3 design.
Results
Twenty-eight patients were enrolled and treated. The alvocidib MTD was 20 mg/m2 (30-min loading infusion) followed by 20 mg/m2 (4-h maintenance infusion) on days 1 and 8, in combination with vorinostat. The most frequently encountered toxicities were cytopenias, fatigue, hyperglycemia, hypokalemia, hypophosphatemia, and QT prolongation. Dose limiting toxicities (DLTs) were cardiac arrhythmia-atrial fibrillation and QT prolongation. No objective responses were achieved, although 13 of 26 evaluable patients exhibited stable disease. Alvocidib appeared to alter vorinostat pharmacokinetics, whereas alvocidib pharmacokinetics were unaffected by vorinostat. Ex vivo exposure of leukemia cells to plasma obtained from patients after alvocidib treatment blocked vorinostat-mediated p21CIP1 induction and down-regulated Mcl-1 and p-RNA Pol II for some specimens, although parallel in vivo bone marrow responses were infrequent.
Conclusions
Alvocidib combined with vorinostat is well tolerated. Although disease stabilization occurred in some heavily pretreated patients, objective responses were not obtained with these schedules.
doi:10.1158/1078-0432.CCR-12-2926
PMCID: PMC3618599  PMID: 23515411
Vorinostat; Alvocidib; Acute Leukemia; Clinical Trial; Phase I
13.  Phase I Study of Vorinostat in Combination with Temozolomide in Patients with High-Grade Gliomas: North American Brain Tumor Consortium Study 04-03 
Purpose
A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG).
Experimental Design
This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day × 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day × 5 days of the first cycle and 200 mg/m2/day × 5 days of the subsequent 28-day cycles.
Results
In Part 1, the MTD of vorinostat administered on days 1-7 and 15-21 of every 28 day cycle in combination with TMZ was 500 mg daily. Dose-limiting toxicities (DLTs) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In Part 2, the MTD of vorinostat on days 1-7 and 15-21 of every 28 day cycle combined with TMZ was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells.
Conclusion
Vorinostat in combination with temozolomide is well-tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway.
doi:10.1158/1078-0432.CCR-12-1841
PMCID: PMC3947570  PMID: 22923449
High-grade glioma; Temozolomide; Vorinostat; HDAC Inhibitor
14.  A Phase I Trial of Vorinostat and Bortezomib in Children with Refractory or Recurrent Solid Tumors: A Children’s Oncology Group Phase I Consortium Study (ADVL0916) 
Pediatric blood & cancer  2012;60(3):390-395.
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/m2/day with dose escalations to 230 and 300 mg/m2/day). Bortezomib (1.3 mg/m2 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/m2/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 NF-κB activity or Grp78 induction after bortezomib treatment in PBMCs from solid tumor patients.
Conclusion
The recommended phase 2 dose and schedule is vorinostat (230 mg/m2/day PO on days 1–5 and 8–12) in combination with bortezomib (1.3 mg/m2/day i.v. on days 1,4, 8, and 11 of a 21 day cycle) in children with recurrent or refractory solid tumors.
doi:10.1002/pbc.24271
PMCID: PMC3511610  PMID: 22887890
vorinostat; bortezomib; phase I trial; pediatric cancer; solid tumors; Children’s Oncology Group
15.  Phase I study of tanespimycin in combination with bortezomib in patients with advanced solid malignancies 
Investigational new drugs  2013;31(5):1251-1256.
Summary
Purpose
To determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of tanespimycin when given in combination with bortezomib.
Experimental design
Phase I dose-escalating trial using a standard cohort “3+3” design performed in patients with advanced solid tumors. Patients were given tanespimycin and bortezomib twice weekly for 2 weeks in a 3 week cycle (days 1, 4, 8, 11 every 21 days).
Results
Seventeen patients were enrolled in this study, fifteen were evaluable for toxicity, and nine patients were evaluable for tumor response. The MTD was 250 mg/m2 of tanespimycin and 1.0 mg/m2 of bortezomib when used in combination. DLTs of abdominal pain (13%), complete atrioventricular block (7%), fatigue (7%), encephalopathy (7%), anorexia (7%), hyponatremia (7%), hypoxia (7%), and acidosis (7%) were observed. There were no objective responses. One patient had stable disease.
Conclusions
The recommended phase II dose for twice weekly 17-AAG and PS341 are 250 mg/m2 and 1.0 mg/m2respectively, on days 1, 4, 8 and 11 of a 21 day cycle.
doi:10.1007/s10637-013-9946-7
PMCID: PMC3929968  PMID: 23543109
Phase I Trials; tanespimycin; bortezomib; solid tumors
16.  Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen 
Context
The growth inhibitory effect of tamoxifen, which is used for the treatment of hormone receptor–positive breast cancer, is mediated by its metabolites, 4-hydroxytamoxifen and endoxifen. The formation of active metabolites is catalyzed by the polymorphic cytochrome P450 2D6 (CYP2D6) enzyme.
Objective
To determine whether CYP2D6 variation is associated with clinical outcomes in women receiving adjuvant tamoxifen.
Design, Setting, and Patients
Retrospective analysis of German and US cohorts of patients treated with adjuvant tamoxifen for early stage breast cancer. The 1325 patients had diagnoses between 1986 and 2005 of stage I through III breast cancer and were mainly postmenopausal (95.4%). Last follow-up was in December 2008; inclusion criteria were hormone receptor positivity, no metastatic disease at diagnosis, adjuvant tamoxifen therapy, and no chemotherapy. DNA from tumor tissue or blood was genotyped for CYP2D6 variants associated with reduced (*10, *41) or absent (*3, *4, *5) enzyme activity. Women were classified as having an extensive (n = 609), heterozygous extensive/intermediate (n = 637), or poor (n = 79) CYP2D6 metabolism.
Main Outcome Measures
Time to recurrence, event-free survival, disease-free survival, and overall survival.
Results
Median follow-up was 6.3 years. At 9 years of follow-up, the recurrence rates were 14.9% for extensive metabolizers, 20.9% for heterozygous extensive/intermediate metabolizers, and29.0%for poor metabolizers, and all-cause mortality rates were 16.7%, 18.0%, and 22.8%, respectively. Compared with extensive metabolizers, there was a significantly increased risk of recurrence for heterozygous extensive/intermediate metabolizers (time to recurrence adjusted hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.04–1.90) and for poor metabolizers (time to recurrence HR, 1.90; 95% CI, 1.10–3.28). Compared with extensive metabolizers, those with decreased CYP2D6 activity (heterozygous extensive/intermediate and poor metabolism) had worse event-free survival (HR, 1.33; 95% CI, 1.06–1.68) and disease-free survival (HR, 1.29; 95% CI, 1.03–1.61), but there was no significant difference in overall survival (HR, 1.15; 95% CI, 0.88–1.51).
Conclusion
Among women with breast cancer treated with tamoxifen, there was an association between CYP2D6 variation and clinical outcomes, such that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of nonfunctional or reduced-function alleles with worse outcomes.
doi:10.1001/jama.2009.1420
PMCID: PMC3909953  PMID: 19809024
17.  Phase 2 Trial of Pemetrexed in Children and Adolescents with Refractory Solid Tumors: a Children’s Oncology Group Study 
Pediatric blood & cancer  2012;60(2):237-241.
Background
Pemetrexed is a multi-targeted antifolate that inhibits key enzymes involved in nucleotide biosynthesis. We performed a phase 2 trial of pemetrexed in children with refractory or recurrent solid tumors, including CNS tumors, to estimate the response rate and further define its toxicity profile.
Procedure
Pemetrexed, at a dose of 1910 mg/m2, was administered as a 10-minute intravenous infusion every 21 days. Patients also received vitamin B12, daily multivitamin supplementation, and dexamethasone. A two-stage design (10 + 10) was employed in each of the following disease strata: osteosarcoma, Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET), rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/supratentorial PNET, and non-brainstem high-grade glioma.
Results
Seventy-two eligible subjects (39 males) were enrolled. Median age was 11 years (range 3–23). Sixty-eight were evaluable for response. The median number of cycles administered was 2 (range 1–13). No complete or partial responses were observed. Stable disease, for a median of 5 (range 4–13) cycles, was observed in 5 patients (ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma; n=1 each). Neutropenia (44%), anemia (35%), and elevated alanine transaminase (35%) attributable to pemetrexed were the most commonly recurring toxicities observed in patients receiving multiple cycles. Other toxicities attributed to pemetrexed occurring in ≥10% of cycles included thrombocytopenia (30%), fatigue (18%), nausea (14), hyperglycemia (13%), rash (11%), vomiting (13%), and hypophosphatemia (11%).
Conclusions
Pemetrexed, administered as an intravenous infusion every 21 days, was tolerable in children and adolescents with refractory solid tumors, including CNS tumors, but did not show evidence of objective anti-tumor activity in the childhood tumors studied.
doi:10.1002/pbc.24244
PMCID: PMC3463652  PMID: 22745043
pemetrexed; phase 2; antifolate
18.  The genomic landscape of small intestine neuroendocrine tumors 
The Journal of Clinical Investigation  2013;123(6):2502-2508.
Small intestine neuroendocrine tumors (SI-NETs) are the most common malignancy of the small bowel. Several clinical trials target PI3K/Akt/mTOR signaling; however, it is unknown whether these or other genes are genetically altered in these tumors. To address the underlying genetics, we analyzed 48 SI-NETs by massively parallel exome sequencing. We detected an average of 0.1 somatic single nucleotide variants (SNVs) per 106 nucleotides (range, 0–0.59), mostly transitions (C>T and A>G), which suggests that SI-NETs are stable cancers. 197 protein-altering somatic SNVs affected a preponderance of cancer genes, including FGFR2, MEN1, HOOK3, EZH2, MLF1, CARD11, VHL, NONO, and SMAD1. Integrative analysis of SNVs and somatic copy number variations identified recurrently altered mechanisms of carcinogenesis: chromatin remodeling, DNA damage, apoptosis, RAS signaling, and axon guidance. Candidate therapeutically relevant alterations were found in 35 patients, including SRC, SMAD family genes, AURKA, EGFR, HSP90, and PDGFR. Mutually exclusive amplification of AKT1 or AKT2 was the most common event in the 16 patients with alterations of PI3K/Akt/mTOR signaling. We conclude that sequencing-based analysis may provide provisional grouping of SI-NETs by therapeutic targets or deregulated pathways.
doi:10.1172/JCI67963
PMCID: PMC3668835  PMID: 23676460
19.  A phase I pharmacokinetic study of pulse-dose vorinostat with flavopiridol in solid tumors 
Investigational new drugs  2010;29(5):1004-1012.
Summary
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/m2 bolus. On the 28-d schedule, the MTD was V 800 mg/d and F 30 mg/m2 over 30 min and 30 mg/m2 over 4 h. V Cmax at the 800 mg dose was 4.8 μM (± 2.8). V Cmax ≥2.5 μM was achieved in 86% of patients at the MTD. F increased the Cmax of V by 27% (95% CI 11%–43%). F Cmax 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.
doi:10.1007/s10637-010-9447-x
PMCID: PMC3545439  PMID: 20461440
CDKs and CDK inhibitors; Histone deacetylase inhibitors; Phase I trials; Combination chemotherapy; Pharmacokinetics
20.  Phase II study of oral capsular 4-hydroxyphenylretinamide (4-HPR/fenretinide) in pediatric patients with refractory or recurrent neuroblastoma: A report from the Children’s Oncology Group NSC #374551; IND# 40294 
Purpose
To determine the response rate to oral capsular fenretinide in children with recurrent or biopsy proven refractory high-risk neuroblastoma.
Experimental Design
Patients received 7 days of fenretinide: 2475 mg/m2/day divided TID (<18 years) or 1800 mg/m2/day divided BID (≥18 years) every 21 days for a maximum of 30 courses. Patients with stable or responding disease after course 30 could request additional compassionate courses. Best response by course 8 was evaluated in Stratum 1 (measurable disease on CT/MRI +/− bone marrow and/or MIBG avid sites) and Stratum 2 (bone marrow and/or MIBG avid sites only).
Results
Sixty-two eligible patients, median age 5 years (range 0.6–19.9), were treated in Stratum 1 (n=38) and Stratum 2 (n=24). One partial response (PR) was seen in Stratum 2 (n=24 evaluable). No responses were seen in Stratum 1 (n=35 evaluable). Prolonged stable disease (SD) was seen in 7 patients in Stratum 1 and 6 patients in Stratum 2 for 4–45+ (median 15) courses. Median time to progression was 40 days (range 17–506) for Stratum 1 and 48 days (range 17–892) for Stratum 2. Mean 4-HPR steady state trough plasma concentrations were 7.25 µM (coefficient of variation 40–56%) at day 7 course 1. Toxicities were mild and reversible.
Conclusions
Although neither stratum met protocol criteria for efficacy, 1 PR + 13 prolonged SD occurred in 14/59 (24%) of evaluable patients. Low bioavailability may have limited fenretinide activity. Novel fenretinide formulations with improved bioavailability are currently in pediatric Phase I studies.
doi:10.1158/1078-0432.CCR-11-0995
PMCID: PMC3207022  PMID: 21908574
fenretinide; neuroblastoma; Phase II; ANBL0321
21.  SULT1A1, CYP2C19 and disease-free survival in early breast cancer patients receiving tamoxifen 
Pharmacogenomics  2011;12(11):1535-1543.
Aim
Tamoxifen biotransformation to endoxifen, a potent antiestrogen, is catalyzed by CYP2D6. In addition, CYP2C19 and SULT1A1 have also been implicated in the metabolism of tamoxifen. We sought to evaluate the importance of SULT1A1 copy number and CYP2C19*17 on disease-free survival (DFS) in postmenopausal women randomized to tamoxifen monotherapy in North Central Cancer Treatment Group 89-30-52 from January 1991 to April 1995.
Materials & methods
We extracted DNA from paraffin-embedded tumors and determined tumor SULT1A1 copy number and CYP2C19*17 genotype. The association of genotype with DFS was determined using the log-rank test. Multivariate cox modeling was performed using traditional prognostic factors, as well as CYP2D6 genotype. SULT1A1 copy number and CYP2C19*17 genotype was determined in 190 out of 256 patients (95% Caucasian).
Results
The median follow-up for living patients was 14 years. DFS did not differ according to SULT1A1 copy number (p = 0.482) or CYP2C19*17 genotype (p = 0.667). Neither SULT1A1 copy number or CYP2C19*17 genotype was associated with disease recurrence in this cohort.
Conclusion
Future studies are needed to identify whether other genetic and environmental factors which affect tamoxifen metabolism are associated with tamoxifen clinical outcomes.
doi:10.2217/pgs.11.97
PMCID: PMC3235041  PMID: 21961651
breast cancer; copy number polymorphism; CYP2C19; pharmacogenomic; polymorphism; single nucleotide; SULT1A1; tamoxifen
22.  Gemcitabine and Irinotecan as First-Line Therapy for Carcinoma of Unknown Primary: Results of a Multicenter Phase II Trial 
PLoS ONE  2012;7(7):e39285.
Metastatic carcinoma of unknown primary (CUP) has a very poor prognosis, and no standard first-line therapy currently exists. Here, we report the results of a phase II study utilizing a combination of gemcitabine and irinotecan as first-line therapy. Treatment was with gemcitabine 1000 mg/m2 and irinotecan 75 mg/m2 weekly times four on a six week cycle (Cohort I). Due to excessive toxicity, the dose and schedule were modified as follows: gemcitabine 750 mg/m2 and irinotecan 75 mg/m2 given weekly times three on a four week cycle (Cohort II). The primary endpoint was the confirmed response rate (CR + PR). Secondary endpoints consisted of adverse events based upon the presence or absence of the UDP glucuronosyltransferase 1 family, polypeptide A1*28 (UGT1A1*28) polymorphism, time to progression, and overall survival. Thirty-one patients were enrolled with a median age of 63 (range: 38–94), and 26 patients were evaluable for efficacy. Significant toxicity was observed in Cohort 1, characterized by 50% (7/14) patients experiencing a grade 4+ adverse event, but not in cohort II. The confirmed response rate including patients from both cohorts was 12% (95% CI: 2–30%), which did not meet the criteria for continued enrollment. Overall median survival was 7.2 months (95% CI: 4.0 to 11.6) for the entire cohort but notably longer in cohort II than in cohort I (9.3 months (95% CI: 4.1 to 12.1) versus 4.0 months (95% CI: 2.2 to 15.6)). Gemcitabine and irinotecan is not an active combination when used as first line therapy in patients with metastatic carcinoma of unknown primary. Efforts into developing novel diagnostic and therapeutic approaches remain important for improving the outlook for this heterogeneous group of patients.
Trial Registration
ClinicalTrials.gov NCT00066781
doi:10.1371/journal.pone.0039285
PMCID: PMC3398897  PMID: 22815703
23.  Phase 0 Clinical Chemoprevention Trial of the AKT Inhibitor SR13668 
Purpose
SR13668, an orally active AKT pathway inhibitor, has demonstrated cancer chemopreventive potential in preclinical studies. To accelerate the clinical development of this promising agent, we designed and conducted the first-ever phase 0 chemoprevention trial to evaluate and compare the effects of food and formulation on SR13668 bioavailability.
Patients and Methods
Healthy adult volunteers were randomly assigned to receive a single, 38 mg oral dose of SR13668 in one of five different formulations, with or without food. Based on existing animal data, SR13668 in a PEG400/Labrasol® oral solution was defined as the reference formulation. Blood samples were obtained pre- and post-agent administration for pharmacokinetic analyses. Area under the plasma concentration-time curve (AUC0-∞) was defined as the primary endpoint. Data were analyzed and compared using established statistical methods for phase 0 trials with a limited sample size.
Results
Participants (N=20) were rapidly accrued over a 5-month period. Complete pharmacokinetic data were available for 18 randomized participants. AUC0-∞ values were highest in the fed state (range = 122–439 ng/mL × hours) and were statistically significantly different across formulations (p = 0.007), with Solutol® HS15 providing the highest bioavailability. SR13668 time to peak plasma concentration (3 hours; range, 2 – 6 hours) and half-life were (11.2 ± 3.1 hours) were not formulation dependent.
Conclusions
Using a novel, highly efficient study design, we rapidly identified a lead formulation of SR13668 for further clinical testing. Our findings support application of the phase 0 trial paradigm to accelerate chemoprevention agent development.
doi:10.1158/1940-6207.CAPR-10-0313
PMCID: PMC3061470  PMID: 21372034
24.  Pediatric Phase I Trial and Pharmacokinetic Study of Vorinostat: A Children's Oncology Group Phase I Consortium Report 
Journal of Clinical Oncology  2010;28(22):3623-3629.
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/m2/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/m2/d with dose-limiting neutropenia, thrombocytopenia, and hypokalemia at 300 mg/m2/d. DLTs observed with the combination of 13cRA and vorinostat included thrombocytopenia, neutropenia, anorexia, and hypertriglyceridemia, resulting in a MTD of vorinostat 180 mg/m2/d 4 times per week and 13cRA 80 mg/m2/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/m2/d for the capsule (range, 1,415 to 9,291 ng/mL × hr) and oral suspension (range, 1,186 to 4,780 ng/mL × 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/m2/d, with a modest dose reduction being required when combining vorinostat with 13cRA. Drug disposition is similar to that observed in adults.
doi:10.1200/JCO.2009.25.9119
PMCID: PMC2917318  PMID: 20606092
25.  Coprescription of Tamoxifen and Medications That Inhibit CYP2D6 
Journal of Clinical Oncology  2010;28(16):2768-2776.
Evidence has emerged that the clinical benefit of tamoxifen is related to the functional status of the hepatic metabolizing enzyme cytochrome P450 2D6 (CYP2D6). CYP2D6 is the key enzyme responsible for the generation of the potent tamoxifen metabolite, endoxifen. Multiple studies have examined the relationship of CYP2D6 status to breast cancer outcomes in tamoxifen-treated women; the majority of studies demonstrated that women with impaired CYP2D6 metabolism have lower endoxifen concentrations and a greater risk of breast cancer recurrence. As a result, practitioners must be aware that some of the most commonly prescribed medications coadministered with tamoxifen interfere with CYP2D6 function, thereby reducing endoxifen concentrations and potentially increasing the risk of breast cancer recurrence. After reviewing the published data regarding tamoxifen metabolism and the evidence relating CYP2D6 status to breast cancer outcomes in tamoxifen-treated patients, we are providing a guide for the use of medications that inhibit CYP2D6 in patients administered tamoxifen.
doi:10.1200/JCO.2009.23.8931
PMCID: PMC2881853  PMID: 20439629

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