PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-12 (12)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
Document Types
1.  Lenalidomide in combination with gemcitabine as first-line treatment for patients with metastatic carcinoma of the pancreas 
Cancer Biology & Therapy  2013;14(4):340-346.
Objectives: To evaluate the 6-mo overall survival, safety and tolerability of lenalidomide in combination with standard gemcitabine as first-line treatment for patients with metastatic pancreatic cancer. Methods: Eligibility included: previously untreated metastatic adenocarcinoma of the pancreas with metastases incurable by surgery/radiation therapy; ECOG PS 0–2; adequate organ function; prophylactic anticoagulation for venous thromboembolic events (VTEs). Patients received lenalidomide 25 mg PO (days 1–21) and gemcitabine 1,000 mg/m2 IV (days 1, 8 and 15) each 28-day cycle, with response evaluations every eight weeks. Results: Between 5/2009–4/2010, 72 patients (median age 64 years; 68% male; 42% ECOG PS 0) were enrolled in this multicenter, community-based study. Six-month OS was 37% (95% CI 26–48%). Median PFS and OS were 2.3 (95% CI 1.9–3.5) and 4.7 (95% CI 3.4–5.7) months, respectively. Eight partial responses (11%) were documented. Thirty-nine patients (54%) experienced thrombocytopenia (2 patients, 3% grade 4). Hematologic toxicities resulted in dose modifications for the majority of patients. Twenty patients (28%) developed VTEs during treatment. Conclusions: The observed 6-month OS (37%) of lenalidomide with gemcitabine does not suggest improvement compared with historical results with gemcitabine alone. Toxicities and dose modifications likely limited dose intensity. Further development of this regimen in pancreas cancer is not recommended.
doi:10.4161/cbt.23625
PMCID: PMC3667874  PMID: 23358470
pancreas cancer; lenalidomide; phase II; gemcitabine combination
2.  Clinical Impact of Checkpoint Inhibitors as Novel Cancer Therapies 
Drugs  2014;74(17):1993-2013.
Immune responses are tightly regulated via signaling through numerous co-stimulatory and co-inhibitory molecules. Exploitation of these immune checkpoint pathways is one of the mechanisms by which tumors evade and/or escape the immune system. A growing understanding of the biology of immune checkpoints and tumor immunology has led to the development of monoclonal antibodies designed to target co-stimulatory and co-inhibitory molecules in order to re-engage the immune system and restore antitumor immune responses. Anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) antibodies were among the first to be tested in the clinic, and ipilimumab was the first immune checkpoint inhibitor approved for an anticancer indication. Agents targeting the programmed death 1 (PD-1) pathway, either PD-1 or one of its ligands, programmed death ligand 1, are in active clinical development for numerous cancers, including advanced melanoma and lung cancer. Understanding the different mechanisms of action, safety profiles, and response patterns associated with inhibition of the CTLA-4 and PD-1 pathways may improve patient management as these therapies are moved in to the clinical practice setting and may also provide a rationale for combination therapy with different inhibitors. Additional immune checkpoint molecules with therapeutic potential, including lymphocyte activation gene-3 and glucocorticoid-induced tumor necrosis factor receptor-related gene, also have inhibitors in early stages of clinical development. Clinical responses and safety data reported to date on immune checkpoint inhibitors suggest these agents may have the potential to markedly improve outcomes for patients with cancer.
doi:10.1007/s40265-014-0305-6
PMCID: PMC4224737  PMID: 25344022
3.  Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma 
Cell reports  2013;4(6):1090-1099.
Summary
Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.
doi:10.1016/j.celrep.2013.08.023
PMCID: PMC3956616  PMID: 24055054
4.  Activity of the MEK Inhibitor Trametinib (GSK1120212) in Advanced Melanoma in a Phase I, Dose-escalation Trial 
The lancet oncology  2012;13(8):782-789.
Summary
Purpose
The mitogen-activated extracellular signal-related kinase kinase (MEK) is a member of the RAS/RAF/MEK/ERK signalling cascade, which is commonly activated in melanoma. Direct inhibition of MEK inhibits ERK signalling.
Methods
We conducted a multicentre, first-in-human, three-part study (dose escalation, cohort expansion, and pharmacodynamic evaluation) to evaluate the oral small-molecule MEK inhibitor trametininb (GSK1120212) in advanced cancer. Intermittent and continuous dosing regimens were evaluated. Safety and efficacy data in patients with melanoma are presented here, with exploratory analyses of available tumour tissues performed on an Illumina genotyping platform. This completed study is registered with ClinicalTrials.gov, number NCT00687622.
Findings
Ninety-seven melanoma patients, including 81 with cutaneous or unknown primary melanoma (36 BRAF-mutant, 39 BRAF wild-type, six BRAF status unknown) and 16 uveal melanoma patients were enrolled. The most common treatment-related adverse events were rash/dermatitis acneiform (80 out of 97; 82%) and diarrhoea (n=44; 45%), most of which were grade 2 or lower. No cutaneous squamous cell carcinomas were observed. Among the 36 BRAF-mutant patients, 30 were BRAF-inhibitor naïve. Among these 30 patients, 2 complete responses (CRs) and 10 partial responses (PRs) were observed (unconfirmed response rate=40%) including 2 confirmed CRs and 8 confirmed PRs (confirmed response rate=33%); the median progression-free survival was 5·7 months (95% CI, 4·0–7·4). Among the 6 BRAF-mutant patients who received prior BRAF inhibitor therapy, 1 unconfirmed PR was observed. Among 39 patients with BRAF wild-type melanoma, 4 PRs (all confirmed) were observed (confirmed response rate=10%).
Conclusions
To our knowledge, this is the first demonstration of substantial clinical activity by a MEK inhibitor in melanoma. These data suggest that MEK is a valid therapeutic target.
doi:10.1016/S1470-2045(12)70269-3
PMCID: PMC4109286  PMID: 22805292
5.  Accumulation of Extracellular Hyaluronan by Hyaluronan Synthase 3 Promotes Tumor Growth and Modulates the Pancreatic Cancer Microenvironment 
BioMed Research International  2014;2014:817613.
Extensive accumulation of the glycosaminoglycan hyaluronan is found in pancreatic cancer. The role of hyaluronan synthases 2 and 3 (HAS2, 3) was investigated in pancreatic cancer growth and the tumor microenvironment. Overexpression of HAS3 increased hyaluronan synthesis in BxPC-3 pancreatic cancer cells. In vivo, overexpression of HAS3 led to faster growing xenograft tumors with abundant extracellular hyaluronan accumulation. Treatment with pegylated human recombinant hyaluronidase (PEGPH20) removed extracellular hyaluronan and dramatically decreased the growth rate of BxPC-3 HAS3 tumors compared to parental tumors. PEGPH20 had a weaker effect on HAS2-overexpressing tumors which grew more slowly and contained both extracellular and intracellular hyaluronan. Accumulation of hyaluronan was associated with loss of plasma membrane E-cadherin and accumulation of cytoplasmic β-catenin, suggesting disruption of adherens junctions. PEGPH20 decreased the amount of nuclear hypoxia-related proteins and induced translocation of E-cadherin and β-catenin to the plasma membrane. Translocation of E-cadherin was also seen in tumors from a transgenic mouse model of pancreatic cancer and in a human non-small cell lung cancer sample from a patient treated with PEGPH20. In conclusion, hyaluronan accumulation by HAS3 favors pancreatic cancer growth, at least in part by decreasing epithelial cell adhesion, and PEGPH20 inhibits these changes and suppresses tumor growth.
doi:10.1155/2014/817613
PMCID: PMC4131462  PMID: 25147816
6.  Phase I Study of Pazopanib in Combination with Weekly Paclitaxel in Patients with Advanced Solid Tumors 
The Oncologist  2010;15(12):1253-1261.
This phase I study determined the maximum tolerated regimen and dose-limiting toxicities of pazopanib in combination with weekly paclitaxel, assessed the effect of pazopanib on the pharmacokinetic profile of paclitaxel, and evaluated antitumor activity.
Purpose.
To evaluate the maximum tolerated regimen (MTR), dose-limiting toxicities, and pharmacokinetics of pazopanib, an oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, in combination with paclitaxel.
Patients and Methods.
Pazopanib was given daily with weekly paclitaxel on days 1, 8, and 15 every 28 days. Dose levels of pazopanib (mg/day)/paclitaxel (mg/m2) were 400/15, 800/15, 800/50, and 800/80. An expanded cohort was enrolled at the MTR. Plasma samples were collected to evaluate the effect of pazopanib, an inhibitor of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP3A4 and CYP2C8 substrate.
Results.
Of 26 enrolled patients, 17 were treated at the MTR of 800 mg pazopanib and 80 mg/m2 paclitaxel. Dose-limiting toxicities included a grade 3 abscess and grade 2 hyperbilirubinemia. Other toxicities included elevated liver transaminases and diarrhea. Six patients (23%) had partial responses and 15 patients (58%) had stable disease. Administration of 800 mg pazopanib resulted in a 14% lower paclitaxel clearance and a 31% higher paclitaxel maximal concentration than with administration of paclitaxel alone at 15, 50, and 80 mg/m2. At the MTR, coadministration of 800 mg pazopanib and 80 mg/m2 paclitaxel resulted in a 26% higher geometric mean paclitaxel area under the curve.
Conclusion.
Pazopanib, at a dose of 800 mg daily, can be safely combined with a therapeutic dose of paclitaxel at 80 mg/m2 when administered on days 1, 8, and 15, every 28 days. The observed greater plasma concentrations of paclitaxel given concurrently with pazopanib suggest that pazopanib is a weak inhibitor of CYP3A4 and CYP2C8.
doi:10.1634/theoncologist.2010-0095
PMCID: PMC3227920  PMID: 21147873
Pazopanib; Paclitaxel; Vascular endothelial growth factor receptor tyrosine kinase inhibitor
7.  A Phase I Study of Weekly Topotecan in Combination with Pemetrexed in Patients with Advanced Malignancies 
The Oncologist  2010;15(9):954-960.
The safety, tolerability, preliminary antitumor activity, and pharmacokinetic interaction of weekly topotecan plus pemetrexed in patients with advanced solid tumors were investigated. The combination was well tolerated and active.
Introduction.
This phase I study evaluated the safety, tolerability, preliminary antitumor activity, and pharmacokinetic interaction of weekly topotecan (days 1 and 8) in combination with pemetrexed (day 1 only) in patients with advanced solid tumors.
Methods.
Patients received topotecan (3.0–4.0 mg/m2 i.v. days 1 and 8) and pemetrexed (375–500 mg/m2 i.v. day 1) over 21-day cycles. Patients were accrued across five different dose levels and were observed for safety, tolerability, and preliminary activity.
Results.
Twenty-six patients received 120 cycles of pemetrexed and topotecan, including five patients who received 8, 8, 10, 12, and 17 cycles without dose reductions, confirming a lack of cumulative myelosuppression. Four patients received topotecan (4.0 mg/m2 i.v.) and pemetrexed (500 mg/m2 i.v.), but experienced two dose-limiting toxicities (febrile neutropenia, grade 4 thrombocytopenia). As a result, the topotecan (3.5 mg/m2 i.v.) and pemetrexed (500 mg/m2 i.v.) group was expanded to 12 patients. The only grade 3 or 4 nonhematologic toxicity was one episode of grade 3 fatigue; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. One non-small cell lung cancer (NSCLC) patient (12 months) and one soft tissue sarcoma patient (6 months) achieved a partial response.
Conclusions.
Weekly topotecan plus every-3-week pemetrexed was well tolerated and active. Full doses of topotecan plus pemetrexed caused brief reversible myelosuppression with minimal dose delays/reductions; no grade 3 or 4 nausea/vomiting/diarrhea, mucositis, or rash was reported. All six NSCLC patients at the recommended phase II dose had at least stable disease as a best response, including one partial response lasting 12 months. There was no evidence of an effect of pemetrexed on topotecan pharmacokinetics. Collectively, these data suggest that further phase II exploration of weekly topotecan plus every-3-week pemetrexed for advanced malignancies is indicated.
doi:10.1634/theoncologist.2010-0006
PMCID: PMC3228036  PMID: 20798192
Topotecan; Pemetrexed; Hematologic toxicity; Pharmacokinetics; Advanced solid tumors
8.  Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor Dabrafenib (GSK2118436) 
Purpose
Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently demonstrated improved progression free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. The current study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.
Experimental Design
Baseline (pre-treatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.
Results
All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response (BOR) to dabrafenib, but it showed a trend for shorter median progression free survival (PFS) (18.3 [95% confidence interval (CI) 9.1–24.3] vs. 32.1 weeks [95% CI 24.1–33], p=0.059). Higher copy number of CCND1 (p=0.009) and lower copy number of CDKN2A (p=0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.
Conclusions
Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients.
doi:10.1158/1078-0432.CCR-13-0827
PMCID: PMC3924894  PMID: 23833299
Melanoma; BRAF inhibitors; correlative studies; BRAF mutation; PTEN
9.  Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer 
Cancer Medicine  2013;2(6):925-932.
Tigatuzumab is the humanized version of the agonistic murine monoclonal antibody TRA-8 that binds to the death receptor 5 and induces apoptosis of human cancer cell lines via the caspase cascade. The combination of tigatuzumab and gemcitabine inhibits tumor growth in murine pancreatic xenografts. This phase 2 trial evaluated the efficacy of tigatuzumab combined with gemcitabine in 62 chemotherapy-naive patients with histologically or cytologically confirmed unresectable or metastatic pancreatic cancer. Patients received intravenous tigatuzumab (8 mg/kg loading dose followed by 3 mg/kg weekly) and gemcitabine (1000 mg/m2 once weekly for 3 weeks followed by 1 week of rest) until progressive disease (PD) or unacceptable toxicity occurred. The primary end point was progression-free survival (PFS) at 16 weeks. Secondary end points included objective response rate (ORR) (complete responses plus partial responses), duration of response, and overall survival (OS). Safety of the combination was also evaluated. Mean duration of treatment was 18.48 weeks for tigatuzumab and 17.73 weeks for gemcitabine. The PFS rate at 16 weeks was 52.5% (95% confidence interval [CI], 39.3–64.1%). The ORR was 13.1%; 28 (45.9%) patients had stable disease and 14 (23%) patients had PD. Median PFS was 3.9 months (95% CI, 2.2–5.4 months). Median OS was 8.2 months (95% CI, 5.1–9.6 months). The most common adverse events related to tigatuzumab were nausea (35.5%), fatigue (32.3%), and peripheral edema (19.4%). Tigatuzumab combined with gemcitabine was well tolerated and may be clinically active for the treatment of chemotherapy-naive patients with unresectable or metastatic pancreatic cancer.
doi:10.1002/cam4.137
PMCID: PMC3892397  PMID: 24403266
Monoclonal antibodies; pancreatic cancer; phase 2; tigatuzumab; TNF-related apoptosis-inducing ligand
10.  A first-in-human dose-escalation study of ME-143, a second generation NADH oxidase inhibitor, in patients with advanced solid tumors 
Investigational New Drugs  2013;32(1):87-93.
Summary
Background ME-143, a second-generation tumor-specific NADH oxidase inhibitor, is broadly active against human cancers in vitro and in vivo. This first-in-human dose-escalation study evaluated the dose-limiting toxicities (DLTs), pharmacokinetics, safety, tolerability, and preliminary anti-tumor activity of ME-143 in patients with advanced solid tumors. Methods Patients with advanced solid tumors were treated in a 3 + 3 escalation design. ME-143 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle, and weekly thereafter; the final cohort received twice-weekly treatment. Samples for pharmacokinetic analysis were collected during cycle 1. Treatment continued until disease progression or unacceptable toxicity. Results Eighteen patients were treated: 2.5 mg/kg (n = 3); 5 mg/kg (n = 3); 10 mg/kg (n = 3); 20 mg/kg (n = 6); 20 mg/kg twice-weekly (n = 3). There were no DLTs observed. Nearly all treatment-related toxicities were grade 1/2, specifically (all grades) nausea (22 %) and fatigue (17 %). Two patients experienced infusion reactions at the 20 mg/kg dose level, one of which was grade 4. Stable disease was documented in three patients with colorectal cancer, cholangiocarcinoma, and anal cancer. Pharmacokinetic exposures were linear and dose-dependent, with a half-life of approximately 5 h. Conclusions ME-143 was well-tolerated when administered intravenously at the maximally administered/recommended phase 2 dose of 20 mg/kg once weekly to patients with advanced solid tumors. Though limited clinical activity was observed with monotherapy, inhibitors of tumor-specific NADH oxidase such as ME-143 may derive their greatest benefit in combination with cytotoxic chemotherapy.
doi:10.1007/s10637-013-9949-4
PMCID: PMC3913846  PMID: 23525756
ME-143; tNOX; Dose escalation; Isoflavone; Apoptosis
11.  Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors 
Purpose
Aurora A kinase is critical in assembly and function of the mitotic spindle. It is overexpressed in various tumor types and implicated in oncogenesis and tumor progression. This trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of MLN8054, a selective small-molecule inhibitor of Aurora A kinase.
Methods
In this first-in-human, dose-escalation study, MLN8054 was given orally for 7, 14, or 21 days followed by a 14-day treatment-free period. Escalating cohorts of 3–6 patients with advanced solid tumors were treated until DLT was seen in ≥2 patients in a cohort. Serial blood samples were collected for pharmacokinetics and skin biopsies were collected for pharmacodynamics.
Results
Sixty-one patients received 5, 10, 20, 30 or 40 mg once daily for 7 days; 25, 35, 45 or 55 mg/day in four divided doses (QID) for 7 days; or 55, 60, 70 or 80 mg/day plus methylphenidate or modafinil with daytime doses (QID/M) for 7–21 days. DLTs of reversible grade 3 benzodiazepine-like effects defined the estimated MTD of 60 mg QID/M for 14 days. MLN8054 was absorbed rapidly, exposure was dose-proportional, and terminal half-life was 30-40 hours. Three patients had stable disease for >6 cycles.
Conclusions
MLN8054 dosing for up to 14 days of a 28-day cycle was feasible. Reversible somnolence was dose limiting and prevented achievement of plasma concentrations predicted necessary for target modulation. A recommended dose for investigation in phase 2 trials was not established. A second-generation Aurora A kinase inhibitor is in development.
doi:10.1007/s00280-010-1377-y
PMCID: PMC3026871  PMID: 20607239
MLN8054; Aurora A kinase; dose-limiting toxicity; pharmacokinetics; pharmacodynamics
12.  New Markers of Pancreatic Cancer Identified Through Differential Gene Expression Analyses: Claudin 18 and Annexin A8 
Background
New markers to distinguish benign reactive glands from infiltrating ductal adenocarcinoma of the pancreas are needed.
Design
The gene expression patterns of 24 surgically resected primary infiltrating ductal adenocarcinomas of the pancreas were compared with 18 non-neoplastic samples using the Affymetrix U133 Plus 2.0 Arrays and the Gene Logic GeneExpress Software System. Gene fragments from 4 genes (annexin A8, claudin 18, CXCL5, and S100 A2) were selected from the fragments found to be highly expressed in infiltrating adenocarcinomas when compared with normal tissues. The protein expression of these genes was examined using immunohistochemical labeling of tissue microarrays.
Results
Claudin 18 labeled infiltrating carcinomas in a membranous pattern. When compared with normal and reactive ducts, claudin 18 was overexpressed, at least focally, in 159 of 166 evaluable carcinomas (96%). Strong and diffuse claudin 18 overexpression was most often seen in well-differentiated carcinomas (P=0.02). Claudin 18 was overexpressed in 51 of 52 cases (98%) of pancreatic intraepithelial neoplasia. Annexin A8 was at least focally overexpressed in 149 of 154 evaluable infiltrating carcinomas (97%). S100 A2 was at least focally overexpressed in 118 of 154 evaluable infiltrating carcinomas (77%). Non-neoplastic glands also frequently expressed S100 A2 diminishing its potential diagnostic utility. Immunolabeling with antibodies directed against CXCL5 did not reveal any significant differences in protein expression between infiltrating adenocarcinomas and normal pancreatic ducts.
Conclusions
Claudin 18 and annexin A8 are frequently highly overexpressed in infiltrating ductal adenocarcinomas when compared with normal reactive ducts, suggesting a role for these molecules in pancreatic ductal adenocarcinomas. Furthermore, these may serve as diagnostic markers, as screening tests and as therapeutic targets.
doi:10.1097/PAS.0b013e31815701f3
PMCID: PMC2678811  PMID: 18223320
pancreas; pancreatic cancer; claudin; annexin; markers; pancreatic intraepithelial neoplasia

Results 1-12 (12)