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1.  Assessing the discordance rate between local and central HER2 testing in women with locally determined HER2-negative breast cancer 
Cancer  2014;120(17):2657-2664.
The importance of human epidermal growth factor receptor 2 (HER2) as a prognostic and predictive marker in invasive breast cancer is well established. Accurate assessment of HER2 status is essential to determine optimal treatment options.
Breast cancer tumor tissue samples from the VIRGO observational cohort tissue substudy that were locally HER2-negative were retested centrally with both US Food and Drug Administration (FDA)-approved immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) assays, using FDA-approved assay cutoffs; results were compared.
Of the 552 unique patient samples centrally retested with local HER2-negative results recorded, tumor samples from 22 (4.0%) patients were determined to be HER2-positive (95% confidence interval [CI] = 2.5%-5.7%). Of these, 18 had been tested locally by only one testing methodology; 15 of 18 were HER2-positive after the central retesting, based on the testing methodology not performed locally. Compared with the 530 patients with centrally confirmed HER2-negative tumors, the 22 patients with centrally determined HER2-positive tumors were younger (median age 56.5 versus 60.0 years) and more likely to have ER/PR-negative tumors (27.3% versus 22.3%). These patients also had shorter median progression-free survival (6.4 months [95% CI = 3.8-15.9 months] versus 9.1 months [95% CI = 8.3-10.3 months]) and overall survival (25.9 months [95% CI = 13.8-not estimable] versus 27.9 months [95% CI = 25.0-32.9 months]).
This study highlights the limitations of employing just one HER2 testing methodology in current clinical practice. It identifies a cohort of patients who did not receive potentially efficacious therapy because their tumor HER2-positivity was not determined by the test initially used. Because of inherent limitations in testing methodologies, it is inadvisable to rely on a single test to rule out potential benefit from HER2-targeted therapy. Cancer 2014;120:2657–2664.
PMCID: PMC4232097  PMID: 24930388
breast cancer; human epidermal growth factor receptor 2; immunohistochemistry; fluorescence in situ hybridization; local and central HER2 testing; discordance rate
2.  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.
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.
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, number NCT00687622.
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%).
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.
PMCID: PMC4109286  PMID: 22805292
3.  Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma 
Characterize bortezomib pharmacokinetics/pharmacodynamics in relapsed myeloma patients after single and repeat intravenous administration at two doses.
Forty-two patients were randomized to receive bortezomib 1.0 or 1.3 mg/m2, days 1, 4, 8, 11, for up to eight 21-day treatment cycles (n = 21, each dose group). Serial blood samples for pharmacokinetic/pharmacodynamic analysis were taken on days 1 and 11, cycles 1 and 3. Observational efficacy and safety data were collected.
Twelve patients in each dose group were evaluable for pharmacokinetics/pharmacodynamics. Plasma clearance decreased with repeat dosing (102–112 L/h for first dose; 15–32 L/h following repeat dosing), with associated increases in systemic exposure and terminal half-life. Systemic exposures of bortezomib were similar between dose groups considering the relatively narrow dose range and the observed pharmacokinetic variability, although there was no readily apparent deviation from dose-proportionality. Blood 20S proteasome inhibition profiles were similar between groups with mean maximum inhibition ranging from 70 to 84% and decreasing toward baseline over the dosing interval. Response rate (all 42 patients) was 50%, including 7% complete responses. The safety profile was consistent with the predictable and manageable profile previously established; data suggested milder toxicity in the 1.0 mg/m2 group.
Bortezomib pharmacokinetics change with repeat dose administration, characterized by a reduction in plasma clearance and associated increase in systemic exposure. Bortezomib is pharmacodynamically active and tolerable at 1.0 and 1.3 mg/m2 doses, with recovery toward baseline blood proteasome activity over the dosing interval following repeat dose administration, supporting the current clinical dosing regimen.
PMCID: PMC3951913  PMID: 20306195
Pharmacodynamics; Pharmacokinetics; Bortezomib; Multiple myeloma; Proteasome inhibition
6.  Everolimus Plus Exemestane in Postmenopausal Patients with HR+ Breast Cancer: BOLERO-2 Final Progression-Free Survival Analysis 
Advances in Therapy  2013;30(10):870-884.
Effective treatments for hormone-receptor-positive (HR+) breast cancer (BC) following relapse/progression on nonsteroidal aromatase inhibitor (NSAI) therapy are needed. Initial Breast Cancer Trials of OraL EveROlimus-2 (BOLERO-2) trial data demonstrated that everolimus and exemestane significantly prolonged progression-free survival (PFS) versus placebo plus exemestane alone in this patient population.
BOLERO-2 is a phase 3, double-blind, randomized, international trial comparing everolimus (10 mg/day) plus exemestane (25 mg/day) versus placebo plus exemestane in postmenopausal women with HR+ advanced BC with recurrence/progression during or after NSAIs. The primary endpoint was PFS by local investigator review, and was confirmed by independent central radiology review. Overall survival, response rate, and clinical benefit rate were secondary endpoints.
Final study results with median 18-month follow-up show that median PFS remained significantly longer with everolimus plus exemestane versus placebo plus exemestane [investigator review: 7.8 versus 3.2 months, respectively; hazard ratio = 0.45 (95% confidence interval 0.38–0.54); log-rank P < 0.0001; central review: 11.0 versus 4.1 months, respectively; hazard ratio = 0.38 (95% confidence interval 0.31–0.48); log-rank P < 0.0001] in the overall population and in all prospectively defined subgroups, including patients with visceral metastases, patients with recurrence during or within 12 months of completion of adjuvant therapy, and irrespective of age. The incidence and severity of adverse events were consistent with those reported at the interim analysis and in other everolimus trials.
The addition of everolimus to exemestane markedly prolonged PFS in patients with HR+ advanced BC with disease recurrence/progression following prior NSAIs. These results further support the use of everolimus plus exemestane in this patient population. #NCT00863655.
Electronic supplementary material
The online version of this article (doi:10.1007/s12325-013-0060-1) contains supplementary material, which is available to authorized users.
PMCID: PMC3898123  PMID: 24158787
Advanced breast cancer; Everolimus; Exemestane; Hormone receptor positive; Nonsteroidal aromatase inhibitors; Oncology; Postmenopausal; Progression-free survival
7.  A phase I/II study of carfilzomib 2–10-min infusion in patients with advanced solid tumors 
Tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of carfilzomib, a selective proteasome inhibitor, administered twice weekly by 2–10-min intravenous (IV) infusion on days 1, 2, 8, 9, 15, and 16 in 28-day cycles, were assessed in patients with advanced solid tumors in this phase I/II study.
Adult patients with solid tumors progressing after ≥1 prior therapies were enrolled. The dose was 20 mg/m2 in week 1 of cycle 1 and 20, 27, or 36 mg/m2 thereafter. The maximum tolerated dose or protocol-defined maximum planned dose (MPD) identified during dose escalation was administered to an expansion cohort and to patients with small cell lung, non-small cell lung, ovarian, and renal cancer in phase II tumor-specific cohorts.
Fourteen patients received carfilzomib during dose escalation. The single dose-limiting toxicity at 20/36 mg/m2 was grade 3 fatigue, establishing the MPD as the expansion and phase II dose. Sixty-five additional patients received carfilzomib at the MPD. Adverse events included fatigue, nausea, anorexia, and dyspnea. Carfilzomib PK was dose proportional with a half-life <1 h. All doses resulted in at least 80 % proteasome inhibition in blood. Partial responses occurred in two patients in phase I, with 21.5 % stable disease after four cycles in evaluable patients in the expansion and phase II cohorts.
Carfilzomib 20/36 mg/m2 was well tolerated when administered twice weekly by 2–10-min IV infusion. At this dose and infusion rate, carfilzomib inhibited the proteasome in blood but demonstrated limited antitumor activity in patients with advanced solid tumors.
PMCID: PMC3784064  PMID: 23975329
Proteasome inhibitor; Carfilzomib; Solid tumors; Pharmacokinetics; Pharmacodynamics
8.  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.
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.
PMCID: PMC3913846  PMID: 23525756
ME-143; tNOX; Dose escalation; Isoflavone; Apoptosis
9.  Combined BRAF and MEK Inhibition in Melanoma with BRAF V600 Mutations 
The New England journal of medicine  2012;367(18):1694-1703.
Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. To address this problem, we conducted a phase 1 and 2 trial of combined treatment with dabrafenib, a selective BRAF inhibitor, and trametinib, a selective MAPK kinase (MEK) inhibitor.
In this open-label study involving 247 patients with metastatic melanoma and BRAF V600 mutations, we evaluated the pharmacokinetic activity and safety of oral dabrafenib (75 or 150 mg twice daily) and trametinib (1, 1.5, or 2 mg daily) in 85 patients and then randomly assigned 162 patients to receive combination therapy with dabrafenib (150 mg) plus trametinib (1 or 2 mg) or dabrafenib monotherapy. The primary end points were the incidence of cutaneous squamous-cell carcinoma, survival free of melanoma progression, and response. Secondary end points were overall survival and pharmacokinetic activity.
Dose-limiting toxic effects were infrequently observed in patients receiving combination therapy with 150 mg of dabrafenib and 2 mg of trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of patients receiving combination 150/2 and in 19% receiving monotherapy (P = 0.09), whereas pyrexia was more common in the combination 150/2 group than in the monotherapy group (71% vs. 26%). Median progression-free survival in the combination 150/2 group was 9.4 months, as compared with 5.8 months in the monotherapy group (hazard ratio for progression or death, 0.39; 95% confidence interval, 0.25 to 0.62; P<0.001). The rate of complete or partial response with combination 150/2 therapy was 76%, as compared with 54% with monotherapy (P = 0.03).
Dabrafenib and trametinib were safely combined at full monotherapy doses. The rate of pyrexia was increased with combination therapy, whereas the rate of proliferative skin lesions was nonsignificantly reduced. Progression-free survival was significantly improved. (Funded by GlaxoSmithKline; number, NCT01072175.)
PMCID: PMC3549295  PMID: 23020132
10.  Phase 1 study of MLN8054, a selective inhibitor of Aurora A kinase in patients with advanced solid tumors 
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.
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.
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.
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.
PMCID: PMC3026871  PMID: 20607239
MLN8054; Aurora A kinase; dose-limiting toxicity; pharmacokinetics; pharmacodynamics
11.  A Phase I and Pharmacokinetic Study of Oral Lapatinib Administered Once or Twice Daily in Patients with Solid Malignancies 
This study determined the range of tolerable doses, clinical safety, pharmacokinetics, and preliminary evidence of clinical activity following once or twice daily administration of lapatinib in patients with solid malignancies.
Experimental Design
Cancer patients (n = 81) received oral doses of lapatinib ranging from 175 to 1,800 mg once daily or 500 to 900 mg twice daily. Clinical assessments of safety and antitumor activity were recorded and blood was sampled for pharmacokinetic assessments. The effect of a low-fat meal on lapatinib pharmacokinetics was assessed in a subset of patients.
Lapatinib was well tolerated, such that dose escalation was limited at 1,800 mg once daily only by pill burden. Twice-daily dosing was implemented to further explore tolerability, and was limited by diarrhea to 500 mg twice daily. The most commonly reported adverse events with once-daily dosing were diarrhea (48%), nausea (40%), rash (40%), and fatigue (38%) and with twice-daily dosing were diarrhea (85%), rash (54%), and nausea (34%). Lapatinib serum concentrations accumulated upon repeated dosing, increasing nearly in proportion with dose, and were significantly increased when dosed with food or administered twice daily. One patient with head and neck cancer achieved a confirmed complete response and 22 patients had stable disease of ≥8 weeks including three patients with stable disease of >10 months (renal, lung, and salivary gland cancers).
Lapatinib was well tolerated following once and twice daily administration. Systemic exposure to lapatinib was dependent on the dose, duration and frequency of dosing, and prandial state. Clinical activity was observed.
PMCID: PMC3232441  PMID: 19825948
12.  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.
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.
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.
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.
PMCID: PMC3227920  PMID: 21147873
Pazopanib; Paclitaxel; Vascular endothelial growth factor receptor tyrosine kinase inhibitor
13.  Immune modulation with weekly dosing of an agonist CD40 antibody in a phase I study of patients with advanced solid tumors 
Cancer Biology & Therapy  2010;10(10):983-993.
Single-dose infusion of the agonistic anti-CD40 monoclonal antibody (mAb) CP-870,893 accomplishes immune activation and clinical responses in patients with advanced cancers, but repeat dosing of this agent has not been reported.
Twenty-seven patients were enrolled. The most common adverse event was transient, infusion-related cytokine release syndrome (CRS). Dose-limiting toxicities included grade 3 CRS and grade 3 urticaria; the maximum tolerated dose (MTD) was estimated to be 0.2 mg/kg. Seven patients (26%) had stable disease as the best clinical response; no partial or complete responses were observed. At the MTD, patient B lymphocytes exhibited persistently increased expression of costimulatory and adhesion molecules without resetting to baseline between doses. In four of eight patients (50%) evaluated at the MTD, there were marked declines in total CD3+ T lymphocytes, as well as CD4+ and CD8+ subsets.
Patients and Methods
Patients with advanced solid tumor malignancies received weekly intravenous infusions of CP-870,893 in four dose level cohorts. Safety and immune pharmacodynamics were assessed.
Weekly infusions of the agonist CD40 antibody CP-870,893 were well-tolerated, but there was little clinical activity in advanced cancer patients. Correlative studies demonstrate chronic B-cell activation and in some patients, T-cell depletion. Longer dosing intervals may be desirable for optimal immune pharmacodynamics.
PMCID: PMC3047092  PMID: 20855968
CD40; immunotherapy; antibody; T cell; B cell
14.  Radiation Recall with Anticancer Agents 
The Oncologist  2010;15(11):1227-1237.
There is still much that needs to be understood about radiation recall, and it is not currently possible to predict which patients will be affected and to which drugs they will react. Furthermore, there are no clearly defined characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of full-dose chemotherapy.
Radiation recall is an acute inflammatory reaction confined to previously irradiated areas that can be triggered when chemotherapy agents are administered after radiotherapy. It remains a poorly understood phenomenon, but increased awareness may aid early diagnosis and appropriate management. A diverse range of drugs used in the treatment of cancer has been associated with radiation recall. As most data come from case reports, it is not possible to determine the true incidence, but to date the antineoplastic drugs for which radiation recall reactions have been most commonly reported include the anthracycline doxorubicin, the taxanes docetaxel and paclitaxel, and the antimetabolites gemcitabine and capecitabine. Radiation recall is drug-specific for any individual patient; it is not possible to predict which patients will react to which drugs, and rechallenge does not uniformly induce a reaction. There are no identifiable characteristics of drugs that cause radiation recall, and thus, it is a possibility that must be kept in mind with use of any drug after radiotherapy, including those from new drug classes. Although it is not yet possible to design treatment regimens to eliminate the risk of radiation recall, it seems likely that risks can be minimized by prolonging the interval between completion of radiotherapy and initiation of chemotherapy.
PMCID: PMC3227903  PMID: 21045191
Chemotherapy; Antineoplastic agents; Radiation recall; Radiation recall dermatitis
15.  A Phase I Study of Sunitinib Plus Capecitabine in Patients With Advanced Solid Tumors 
Journal of Clinical Oncology  2010;28(29):4513-4520.
This open-label, phase I, dose-escalation study assessed the maximum-tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib in combination with capecitabine in patients with advanced solid tumors.
Patients and Methods
Sunitinib (25, 37.5, or 50 mg) was administered orally once daily on three dosing schedules: 4 weeks on treatment, 2 weeks off treatment (Schedule 4/2); 2 weeks on treatment, 1 week off treatment (Schedule 2/1); and continuous daily dosing (CDD schedule). Capecitabine (825, 1,000, or 1,250 mg/m2) was administered orally twice daily on days 1 to 14 every 3 weeks for all patients. Sunitinib and capecitabine doses were escalated in serial patient cohorts.
Seventy-three patients were treated. Grade 3 adverse events included abdominal pain, mucosal inflammation, fatigue, neutropenia, and hand-foot syndrome. The MTD for Schedule 4/2 and the CDD schedule was sunitinib 37.5 mg/d plus capecitabine 1,000 mg/m2 twice per day; the MTD for Schedule 2/1 was sunitinib 50 mg/d plus capecitabine 1,000 mg/m2 twice per day. There were no clinically significant pharmacokinetic drug-drug interactions. Nine partial responses were confirmed in patients with pancreatic cancer (n = 3) and breast, thyroid, neuroendocrine, bladder, and colorectal cancer, and cholangiocarcinoma (each n = 1).
The combination of sunitinib and capecitabine resulted in an acceptable safety profile in patients with advanced solid tumors. Further evaluation of sunitinib in combination with capecitabine may be undertaken using the MTD for any of the three treatment schedules.
PMCID: PMC2988641  PMID: 20837944
16.  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.
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.
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.
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.
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.
PMCID: PMC3228036  PMID: 20798192
Topotecan; Pemetrexed; Hematologic toxicity; Pharmacokinetics; Advanced solid tumors
17.  Safety and Pharmacokinetics of Motesanib in Combination with Panitumumab and Gemcitabine-Cisplatin in Patients with Advanced Cancer 
Journal of Oncology  2011;2011:853931.
Purpose. The aim of this study was to assess the safety and tolerability of motesanib (an orally administered small-molecule antagonist of vascular endothelial growth factor receptors 1, 2, and 3, platelet-derived growth factor receptor, and Kit) when administered in combination with panitumumab, gemcitabine, and cisplatin. Methods. This was an open-label, multicenter phase 1b study in patients with advanced solid tumors with an ECOG performance status ≤1 and for whom a gemcitabine/cisplatin regimen was indicated. Patients received motesanib (0 mg [control], 50 mg once daily [QD], 75 mg QD, 100 mg QD, 125 mg QD, or 75 mg twice daily [BID]) with panitumumab (9 mg/kg), gemcitabine (1250 mg/m2) and cisplatin (75 mg/m2) in 21-day cycles. The primary endpoint was the incidence of dose-limiting toxicities (DLTs). Results. Forty-one patients were enrolled and received treatment (including 8 control patients). One of eight patients in the 50 mg QD cohort and 5/11 patients in the 125 mg QD cohort experienced DLTs. The maximum tolerated dose was established as 100 mg QD. Among patients who received motesanib (n = 33), 29 had motesanib-related adverse events. Fourteen patients had serious motesanib-related events. Ten patients had motesanib-related venous thromboembolic events and three had motesanib-related arterial thromboembolic events, two of which were considered serious. One patient had a complete response and nine had partial responses as their best objective response. Conclusions. The combination of motesanib, panitumumab, and gemcitabine/cisplatin could not be administered consistently and, at the described doses and schedule, may be intolerable. However, encouraging antitumor activity was noted in some cases.
PMCID: PMC3087488  PMID: 21559248
18.  A Phase I Dose-Escalation Study of Danusertib (PHA-739358) Administered as a 24-hour Infusion With and Without G-CSF in a 14-day Cycle in Patients with Advanced Solid Tumors 
This study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of the intravenous pan-aurora kinase inhibitor PHA-739358, danusertib, in patients with advanced solid tumors.
Experimental Design
In Part 1, patients received escalating doses of danusertib (24-h infusion every 14 days) without filgrastim (G-CSF). Febrile neutropenia was the dose-limiting toxicity without G-CSF. Further dose escalation was performed in part 2 with G-CSF. Blood samples were collected for danusertib pharmacokinetics and pharmacodynamics. Skin biopsies were collected to assess histone H3 phosphorylation (pH3).
Fifty-six patients were treated, 40 in part 1 and 16 in part 2. Febrile neutropenia was the dose limiting toxicity in Part 1 without G-CSF. Most other adverse events were grade 1–2, occurring at doses ≥360 mg/m2 with similar incidence in parts 1 and 2. The MTD without G-CSF is 500 mg/m2. The recommended phase 2 dose (RP2D) in Part 2 with G-CSF is 750 mg/m2. Danusertib demonstrated dose-proportional pharmacokinetics in parts 1 and 2 with a median half-life of 18–26 hours. pH3 modulation in skin biopsies was observed at ≥500 mg/m2. One patient with refractory small cell lung cancer (1000 mg/m2 with G-CSF) had an objective response lasting 23 weeks. One patient with refractory ovarian cancer had 27% tumor regression and 30% CA125 decline.
Danusertib was well tolerated with target inhibition in skin at ≥500 mg/m2. Preliminary evidence of anti-tumor activity, including a PR and several occurrences of prolonged stable disease (SD), was seen across a variety of advanced refractory cancers. Phase II studies are ongoing.
PMCID: PMC2826106  PMID: 19825950
Danusertib; PHA-739358; Aurora Kinase Inhibitor; phase I trial; solid tumors
19.  Pegfilgrastim on the Same Day Versus Next Day of Chemotherapy in Patients With Breast Cancer, Non–Small-Cell Lung Cancer, Ovarian Cancer, and Non-Hodgkin's Lymphoma: Results of Four Multicenter, Double-Blind, Randomized Phase II Studies 
Journal of Oncology Practice  2010;6(3):133-140.
Four tumor-specific studies were designed to assess the safety and efficacy of pegfilgrastim administered concurrently with chemotherapy.
To compare data on severe (grade 4) neutropenia duration and febrile neutropenia incidence in patients receiving chemotherapy with pegfilgrastim administered the same day or 24 hours after chemotherapy.
Patients and Methods:
These were similar, randomized, double-blind phase II noninferiority studies of patients with lymphoma or non–small-cell lung (NSCLC), breast, or ovarian cancer. Each study was analyzed separately. The primary end point in each study was cycle-1 severe neutropenia duration. Approximately 90 patients per study were to be randomly assigned at a ratio of 1:1 to receive pegfilgrastim 6 mg once per cycle on the day of chemotherapy or the day after (with placebo on the alternate day).
In four studies, 272 patients received chemotherapy and one or more doses of pegfilgrastim (133 same day, 139 next day). Three studies (breast, lymphoma, NSCLC) enrolled an adequate number of patients for analysis. However, in the NSCLC study, the neutropenic rate was lower than expected (only two patients per arm experienced grade 4 neutropenia). In the breast cancer study, the mean cycle-1 severe neutropenia duration was 1.2 days (95% confidence limit [CL], 0.7 to 1.6) longer in the same-day compared with the next-day group (mean, 2.6 v 1.4 days). In the lymphoma study, the mean cycle-1 severe neutropenia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the same-day compared with the next-day group (mean, 2.1 v 1.2 days). In the breast and lymphoma studies, the absolute neutrophil count profile for same-day patients was earlier, deeper, and longer compared with that for next-day patients, although the results indicate that same-day administration was statistically noninferior to next-day administration according to neutropenia duration.
For patients receiving pegfilgrastim with chemotherapy, pegfilgrastim administered 24 hours after chemotherapy completion is recommended.
PMCID: PMC2868638  PMID: 20808556
20.  Phase 1-2a multicenter dose-escalation study of ezatiostat hydrochloride liposomes for injection (Telintra®, TLK199), a novel glutathione analog prodrug in patients with myelodysplastic syndrome 
Ezatiostat hydrochloride liposomes for injection, a glutathione S-transferase P1-1 inhibitor, was evaluated in myelodysplastic syndrome (MDS). The objectives were to determine the safety, pharmacokinetics, and hematologic improvement (HI) rate. Phase 1-2a testing of ezatiostat for the treatment of MDS was conducted in a multidose-escalation, multicenter study. Phase 1 patients received ezatiostat at 5 dose levels (50, 100, 200, 400 and 600 mg/m2) intravenously (IV) on days 1 to 5 of a 14-day cycle until MDS progression or unacceptable toxicity. In phase 2, ezatiostat was administered on 2 dose schedules: 600 mg/m2 IV on days 1 to 5 or days 1 to 3 of a 21-day treatment cycle.
54 patients with histologically confirmed MDS were enrolled. The most common adverse events were grade 1 or 2, respectively, chills (11%, 9%), back pain (15%, 2%), flushing (19%, 0%), nausea (15%, 0%), bone pain (6%, 6%), fatigue (0%, 13%), extremity pain (7%, 4%), dyspnea (9%, 4%), and diarrhea (7%, 4%) related to acute infusional hypersensitivity reactions. The concentration of the primary active metabolites increased proportionate to ezatiostat dosage. Trilineage responses were observed in 4 of 16 patients (25%) with trilineage cytopenia. Hematologic Improvement-Erythroid (HI-E) was observed in 9 of 38 patients (24%), HI-Neutrophil in 11 of 26 patients (42%) and HI-Platelet in 12 of 24 patients (50%). These responses were accompanied by improvement in clinical symptoms and reductions in transfusion requirements. Improvement in bone marrow maturation and cellularity was also observed.
Phase 2 studies of ezatiostat hydrochloride liposomes for injection in MDS are supported by the tolerability and HI responses observed. An oral formulation of ezatiostat hydrochloride tablets is also in phase 2 clinical development.
Trial Registration NCT00035867
PMCID: PMC2694211  PMID: 19439093
21.  Medical Errors: Physician and Institutional Responsibilities 
Journal of Oncology Practice  2009;5(1):24-26.
When it comes to medical errors, honesty is always the best practice for your practice.
PMCID: PMC2790625  PMID: 20856711

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