"Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma",
Daniel D. Von Hoff, M.D., Patricia M. LoRusso, D.O., Charles M. Rudin, M.D., Ph.D., Josina C. Reddy, M.D., Ph.D., Robert L. Yauch, Ph.D., Raoul Tibes, M.D., Glen J. Weiss, M.D., Mitesh J. Borad, M.D., Christine L. Hann, M.D., Ph.D., Julie R. Brahmer, M.D., Howard M. Mackey, Ph.D., Bertram L. Lum, Pharm.D., Walter C. Darbonne, M.S., James C. Marsters, Jr., Ph.D., Frederic J. de Sauvage, Ph.D., and Jennifer A. Low, M.D., Ph.D.
From the Translational Genomics Research Institute and Scottsdale Healthcare, Scottsdale, AZ (D.D.V.H., R.T., G.J.W., M.J.B.); Karmanos Cancer Institute, Detroit (P.M.L.); Johns Hopkins University, Baltimore (C.M.R., C.L.H., J.R.B.); and Genentech, South San Francisco, CA (J.C.R., R.L.Y., H.M.M., B.L.L., W.C.D., J.C.M., F.J.S., J.A.L.).
Address reprint requests to Dr. Low at Genentech, 1 DNA Way, South San Francisco, CA 94080, or at low.jennifer@gene.com.
Background:
Mutations in hedgehog pathway genes, primarily genes encoding patched
homologue 1 (PTCH1) and smoothened homologue (SMO), occur
in basal-cell carcinoma. In a phase 1 clinical trial, we assessed the safety
and pharmacokinetics of GDC-0449, a small-molecule inhibitor of SMO, and
responses of metastatic or locally advanced basal-cell carcinoma to the
drug.
Methods:
We selected 33 patients with metastatic or locally advanced basal-cell
carcinoma to receive oral GDC-0449 at one of three doses; 17 patients received
150 mg per day, 15 patients received 270 mg per day, and 1 patient received
540 mg per day. We assessed tumor responses with the use of Response Evaluation
Criteria in Solid Tumors (RECIST), physical examination, or both.
Molecular
aspects of the tumors were examined.
Results:
The median duration of the study treatment was 9.8 months. Of the
33 patients, 18 had an objective response to GDC-0449, according
to assessment on imaging (7 patients), physical examination (10 patients),
or both (1 patient). Of the patients who had a response, 2 had a complete
response and 16 had a partial response. The other 15 patients
had either stable disease (11 patients) or progressive disease
(4 patients). Eight grade 3 adverse events that were deemed to be
possibly related to the study drug were reported in six patients, including
four with fatigue, two with hyponatremia, one with muscle spasm, and one
with atrial fibrillation. One grade 4 event, asymptomatic hyponatremia,
was judged to be unrelated to GDC-0449. One patient withdrew from
the study because of adverse events. We found evidence of hedgehog signaling
in tumors that responded to the treatment.
Conclusions:
GDC-0449, an orally active small molecule that targets the hedgehog
pathway, appears to have antitumor activity in locally advanced or metastatic
basal-cell carcinoma. (ClinicalTrials.gov number, NCT00607724 [ClinicalTrials.gov]
.)
Basal-cell carcinoma, the most common skin cancer in the United States, has an estimated annual incidence of 0.1 to 0.5%. (1,2) The disease is largely caused by exposure to ultraviolet radiation, but there are other risk factors. (3,4) Surgery cures most cases of basal-cell carcinoma, but in a few patients there is progression to life-threatening, unresectable, locally advanced (5,6) or metastatic (7,8) tumors. There is no standard therapy for locally advanced or metastatic basal-cell carcinoma. The survival time in metastatic basal-cell carcinoma varies widely, but the median is 8 months.(7, 9 )
Basal-cell carcinoma is associated with mutations in components of
the hedgehog signaling pathway.(10) Hedgehog, a key
regulator of cell growth and differentiation during development, controls
epithelial and mesenchymal interactions in many tissues during embryogenesis.(11)
Extracellular hedgehog protein binds to patched homologue 1 (PTCH1),
a 12-transmembrane receptor, and prevents PTCH1-mediated inhibition of
signaling by smoothened homologue (SMO), a 7-transmembrane protein
(Figure 1A, left).(11,12) Signaling
by SMO results in the activation of transcription factors encoded by GLI
family zinc finger (GLI) and consequent induction of hedgehog target
genes, including GLI1 and PTCH1.(11,12)
The
hedgehog pathway is inactive in adult tissues. However, most basal-cell
tumors have mutations in the hedgehog signaling pathway that inactivate
PTCH1(13,14) (loss-of-function mutation) or,
less commonly, constitutively activate SMO(15) (gain-of-function
mutation) (Figure 1A, center). These mutations cause
constitutive hedgehog pathway signaling, which in basal-cell carcinomas
can mediate unrestrained proliferation of basal cells of the skin.
For this reason, blocking the hedgehog pathway may be useful in treating
patients with basal-cell carcinoma.(10, 12,
16)
Figure 1. Mechanism of Action of GDC-0449 and Response to Treatment.
Figure 1. Mechanism of Action of GDC-0449 and Response to Treatment.
Panel A shows the hedgehog signal transduction pathway (left), loss-of-PTCH1 mutations (center), and inhibition of smoothened homologue (SMO) signaling by GDC-0449 (right). Hedgehog binding to PTCH1 (left) relieves inhibition of SMO activation by PTCH1. In the absence of PTCH1, because of loss-of-PTCH1 mutations, SMO signaling occurs constitutively (center). GDC-0449 inhibits SMO signaling through direct interaction with SMO (right).
Panel B shows the duration of GDC-0449 therapy and best responses for the 33 patients in the study. Patients were assessed according to either Response Evaluation Criteria in Solid Tumors (RECIST) (mainly for patients with metastatic tumors) or clinical criteria (mainly for patients with locally advanced tumors). Patients 15 and 29 were the only ones with locally advanced disease who could be evaluated radiologically and were assessed according to RECIST. Patients with metastatic disease were evaluated with the use of RECIST, except for Patients 10 and 24, who did not have radiologically measurable disease and were evaluated with the use of clinical measures. Patient 20 was evaluated with the use of both RECIST and clinical measures. Clinical criteria consisted of physical examination for reepithelialization of ulcerated lesions, flattening of nodular lesions, or shrinkage of palpable tumor masses. CR denotes complete response, PD progressive disease, PR partial response, SD and stable disease.
The steroidal alkaloid cyclopamine, a teratogen that induces midline deformities in developing embryos,(17) blocks hedgehog signaling by binding to SMO and inhibiting the activation of downstream hedgehog target genes.(18) The novel SMO inhibitor GDC-0449 was discovered by high-throughput screening of a library of small-molecule compounds and subsequent optimization through medicinal chemistry (Figure 1A, right). GDC-0449 is a selective hedgehog pathway inhibitor with greater potency and more favorable pharmaceutical properties than cyclopamine. GDC-0449 has antitumor activity in a mouse model of medulloblastoma and in xenograft models of primary human tumor cells, including colorectal cancer and pancreatic carcinoma, in which its effects correlate with blockade of the hedgehog pathway.(19,20)
A phase 1 trial was initiated to evaluate the safety and adverse-effect
profile of daily oral administration of GDC-0449 in patients with metastatic
or locally advanced basal-cell carcinoma and other solid tumors. Antitumor
activity was observed in the first two patients with basal-cell carcinoma,
prompting enrollment of additional patients to evaluate the activity and
safety of the drug. This report summarizes the results for all patients
with advanced basal-cell carcinoma who were enrolled in the study.
Methods:
Study Design
We conducted an open-label, multicenter, two-stage phase 1 trial to evaluate the safety and tolerability of GDC-0449 in patients with a variety of solid tumors that were refractory to standard therapy. In all, 68 patients enrolled in the study at three centers; of these patients, 33 had advanced basal-cell carcinoma.
In stage 1, the dose-escalation stage, we wanted to estimate the maximum tolerated dose of GDC-0449. Patients received a single oral dose of GDC-0449 on day 1, followed by daily administration at the same dose beginning on day 8. Seven patients were assigned to receive 150 mg per day, nine patients 270 mg per day, and four patients 540 mg per day; each dose cohort included one patient with advanced basal-cell carcinoma. GDC-0449 was to be discontinued in patients who had dose-limiting toxic effects or other intolerable side effects or disease progression or in patients who did not benefit from treatment, as decided by the investigator. No dose-limiting toxic effects were observed. The recommended phase 2 dose was 150 mg per day because pharmacokinetic analyses indicated that doses greater than this did not result in higher plasma concentrations of the drug.
In stage 2, we included an expansion cohort that received the recommended phase 2 dose, with the goal of obtaining additional information on pharmacokinetics, pharmacodynamics, and safety; 12 patients (none with advanced basal-cell carcinoma) enrolled in this cohort, and all received 150 mg per day. The study was amended to include two further cohorts in stage 2. One of these cohorts was added because of evidence of clinical benefit in two patients with advanced basal-cell carcinoma during stage 1; this cohort consisted of 20 patients with advanced basal-cell carcinoma, who were treated with 150 mg per day or 270 mg per day (with the dose chosen on the basis of drug availability) to evaluate the activity and safety of GDC-0449 in this population. The second cohort, which consisted of 16 patients with solid tumors (including 10 with advanced basal-cell carcinoma), was added to investigate the pharmacokinetic properties of a new formulation of GDC-0449 at 150 mg per day. In stage 2, all patients received continuous daily administration of the drug, beginning on day 1, and were treated until disease progression, the occurrence of intolerable toxic effects, or withdrawal from the study.
GDC-0449 was discovered by Genentech and was jointly validated through a series of preclinical studies performed under a collaborative agreement between Genentech and Curis. The study was designed jointly by Genentech and the investigators. Data were collected by the investigators and retained and analyzed by Genentech. The first draft of the manuscript was written by six authors from Genentech and three academic authors. The academic authors had full access to the data, and all authors vouch for the accuracy and completeness of the data and the analysis. The study was reviewed and approved by the institutional review board at each site, according to clinical guidelines. All patients provided written informed consent.
Eligibility
All patients, who were at least 18 years of age, had histologically confirmed locally advanced or metastatic basal-cell carcinomas that had been documented on pathological analysis and that were considered by the investigator to be refractory to standard therapy. All patients had tumors that could be evaluated on physical examination or radiographic imaging and had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less (on a scale ranging from 0 to 5, with higher scores indicating a greater severity of illness). Documentation of a negative pregnancy test was required for women of childbearing potential. GDC-0449 treatment did not begin until more than 3 weeks after the patient's last therapy or major surgical procedure. Exclusion criteria included major organ dysfunction, a long QT interval or any medication known to prolong the QT interval (because preliminary evaluation of the potential of GDC-0449 to prolong the QT interval was an ancillary objective of the study), active infection requiring intravenous antibiotics, pregnancy, other conditions that in the opinion of the investigator would contraindicate investigational drug use, and an inability to swallow pills.
Data Collection
For the first 6 weeks, all patients underwent weekly physical examination, along with monitoring of vital signs, ECOG performance status, electrocardiographic results, and blood counts and chemical analyses; after that, assessments were performed every 4 weeks.
For patients with radiologically measurable disease (generally, those with metastatic tumors), tumor assessment was performed at baseline, at 8 weeks, and every 8 weeks thereafter with the use of Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0) (21) to determine stable disease, progressive disease, and best overall response. A complete or partial response was determined on two consecutive occasions 4 or more weeks apart. For patients with locally advanced tumors (and no radiologically measurable disease), tumors were assessed on physical examination. A complete response was defined as the disappearance of a palpable or visible tumor, and a partial response was defined as a reduction of more than 50% in the diameter of a palpable or visible tumor.
Data concerning adverse events were collected for up to 30 days after the last study treatment. All patients who received any amount of GDC-0449 were included in the safety analyses. Graded adverse events (number and percent) were summarized and reported according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (version 3.0).
Pharmacokinetics and Pharmacodynamics
Baseline and weekly plasma samples were collected from patients in stages 1 and 2 for the first 4 weeks, with more frequent sampling during the first week for stage 1 and then at approximately monthly intervals. Total plasma levels of GDC-0449 were determined on liquid chromatography–tandem mass spectrometry. The maximum plasma level of GDC-0449 was defined as the highest level that was observed in any patient. The steady-state level of GDC-0449 was calculated from arithmetic averages of two consecutive levels.
Pharmacodynamic assessments of GLI1 expression were carried out on RNA extracted from 4-mm biopsy specimens of noninvolved skin at baseline and at 7 and 21 days after the start of daily drug therapy. Patients were not required to provide tumor-biopsy samples. All samples were processed as described below for stored tumor tissue.
Hedgehog Pathway in Stored Tumor Tissue
After the patients provided written informed consent, we evaluated samples of their archival tumor tissue for tumor content and processed the samples for transcriptional profiling or DNA sequence analysis. Expression levels of GLI1 were assessed by TaqMan polymerase-chain-reaction (qPCR) assay and calculated by the 2-CDt method, in which the cycling threshold (Ct) of GLI1 was normalized to the Ct of SMO and expressed as a power of 2 (2Ct(GLI1)-Ct(SMO)). (Primer and probe sequences are available in Table 1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.) Control samples of messenger RNA (mRNA) were obtained from formalin-fixed, paraffin-embedded samples of normal skin from subjects who were not enrolled in the study and from commercially available samples of cutaneous basal-cell carcinoma, normal lung, and lung cancer tissue (Asterand and Cytomyx).
DNA for sequence analysis was extracted from stored sections containing at least 30% tumor. Before sequencing, exons 1 to 23 of PTCH1 and exon 9 of SMO were amplified with the use of nested primers on PCR assay (Table 1 in the Supplementary Appendix). Alterations in these genes were confirmed by independent PCR sequencing assays. For Patient 2, homozygosity of the PTCH1 mutation was confirmed by primer extension and mass spectroscopy with the use of matrix-assisted laser desorption ionization–time of flight (MALDI-TOF) for amplified DNA extracted from tumor cells by laser-capture microdissection (MassARRAY, Sequenom).
Results
Patients
From January 2007 through December 2008, we enrolled 33 patients
with metastatic or locally advanced basal-cell carcinoma. Three of these
patients were enrolled in stage 1 of the study; each of the three received
a different daily dose of GDC-0449: 150 mg, 270 mg, or 540 mg. The 30 other
patients were enrolled in stage 2; 16 received GDC-0449 at 150 mg per day,
and 14 received 270 mg per day. Of the 33 patients, 8 (24%) were women.
A total of 18 patients (55%) had metastatic disease, and 15 (45%) had locally
advanced disease (Table 1).
As of February 28, 2009 (the data cutoff date), all 33 patients had undergone at least one follow-up tumor assessment and could be evaluated for a response to treatment (Figure 1B). Of the 18 patients with metastatic tumors, 15 had radiologically measurable disease, and 7 of these patients had a partial response, as assessed on imaging only (with 6 responses confirmed and 1 unconfirmed at the time of the data cutoff). Two other patients with metastatic tumors had partial responses, one assessed on both imaging and physical examination and the other on physical examination only. Seven patients with metastatic tumors had stable disease (with six patients assessed with the use of RECIST and one on physical examination), and two had progressive disease as the best response. The overall response rate among the 18 patients with metastatic tumors was 50% (95% confidence interval [CI], 29 to 71).
Of the 15 patients with locally advanced tumors, 13 were assessed on physical examination (clinical response), and 2 with measurable disease were assessed on imaging, according to RECIST. Of these 15 patients, 2 had a complete clinical response, and 7 had a partial clinical response; 4 patients had stable disease as the best response, with a duration of participation in the study ranging from 2.1 to 19.0 months; 2 of the patients had progressive disease. Overall, the response rate in patients with locally advanced tumors was 60% (95% CI, 33 to 83).
As of the data cutoff date, the Kaplan–Meier estimate of the median
time of participation in the study was 9.8 months and ongoing, and the
median duration of response was 8.8 months and ongoing. Figure
2 shows the clinical benefit of treatment in two patients, with additional
photographs and scans in Figure 1
in the Supplementary Appendix.
Figure 2. GDC-0449 Activity in Patients with Locally Advanced
Basal-Cell Carcinoma.
Figure 2. GDC-0449 Activity in Patients with Locally Advanced Basal-Cell Carcinoma.
Panel A shows Patient 24, a 60-year-old man with the basal-cell nevus syndrome with lesions of the posterior scalp, at baseline and after 5 months of GDC-0449 therapy. This patient had a partial response to treatment, which was ongoing at the time of data cutoff. Panel B shows Patient 29, a 41-year-old woman with facial lesions, at baseline and after 2 months of GDC-0449 therapy. This patient had stable disease, as assessed on imaging, and continued to receive therapy at the time of data cutoff.
Adverse Events
No dose-limiting toxic effects or grade 5 events were observed during
the study period. A single grade 4 adverse event (asymptomatic hyponatremia)
occurred. The following grade 3 adverse events were seen: fatigue (in four
patients); hyponatremia, weight loss, and dyspnea (in two patients each);
and muscle spasm, atrial fibrillation, aspiration, back pain, corneal abrasion,
dehydration, keratitis, lymphopenia, pneumonia, urinary tract infection,
and a prolonged QT interval (in one patient each). Eleven grade 2 adverse
events that were considered to be related to the study drug occurred (Table
2). A single patient, Patient 11, who had locally advanced tumors and
had a partial clinical response, decided to discontinue treatment after
8 months because of ongoing grade 1 adverse events (abdominal pain, fatigue,
weight loss, and dysgeusia) and grade 2 anorexia.
Pharmacokinetic and Pharmacodynamic Analyses
Figure 3A and 3B show the concentration–time profiles
of GDC-0449 for the 33 patients. The median maximal plasma level was 23.0
µM (interquartile range, 16.8 to 29.7) (Figure 3B).
The median steady-state concentration was 16.1 µM (interquartile
range, 13.7 to 21.6). The median time to steady state was 14 days (interquartile
range, 7 to 22). Increasing the dose from 150 mg to 270 mg did not result
in higher steady-state plasma levels, with a median steady-state level
of 19.8 µM (interquartile range, 13.5 to 25.8) for the 150-mg dose
and 15.9 µM (interquartile range, 13.8 to 17.7) for the 270-mg dose.
A consistent steady-state total plasma level of GDC-0449 was maintained
throughout the treatment period, with no apparent decline at the time of
disease progression.
Figure 3. Pharmacokinetic Analysis and Molecular Correlates of
GDC-0449 Administration.
Figure 3. Pharmacokinetic Analysis and Molecular Correlates of GDC-0449 Administration.
Panel A shows the pharmacokinetic analysis of GDC-0449 for each of the 33 enrolled patients, according to dose. Three patients were exposed to a single dose on day 0, followed by repeated daily administration of GDC-0449, starting on day 7. The remaining 30 patients received daily doses, starting on day 0.
Panel B shows mean concentration–time data for 30 patients who received either 150 mg or 270 mg of GDC-0449. The vertical lines represent standard deviations.
Panel C shows elevated GLI1 messenger RNA (mRNA) expression
in archival tissue obtained from 25 of 26 patients with metastatic or locally
advanced basal-cell carcinoma (BCC), as compared with control specimens.
GLI1
expression levels were assessed with the use of real-time polymerase-chain-reaction
assay and calculated by the 2-DCt
method, in which the cycling threshold (Ct) of GLI1 was normalized
to the Ct of SMO and expressed as a power of 2 (2Ct(GLI1)-Ct(SMO)).
The mean (2Mean(-DCt)) and standard
deviation (2SD(-DCt)) are indicated
below the chart for each tissue type. Data for control subjects with either
normal or malignant lung samples are included, since some specimens of
metastatic basal-cell carcinoma represented lung metastases.
Pharmacodynamic down-modulation in the hedgehog pathway was shown by a decrease in GLI1 expression by more than a factor of two, as compared with pretreatment biopsy-sample analysis, in 10 of 13 patients (data not shown). The extent of GLI1 down-modulation did not correlate with pharmacokinetic levels of GDC-0449 in individual patients.
Molecular Studies
GLI1 mRNA expression levels in tumor-biopsy specimens that were obtained from 25 of 26 patients were consistent with expression levels previously observed in cutaneous basal-cell carcinoma (Figure 3C). GLI1 was overexpressed in tumors obtained from patients with either metastatic or locally advanced tumors, as compared with control samples of normal skin and lung tumor (P<0.001 for all comparisons). GLI1 levels were not elevated in a metastatic liver-biopsy specimen from Patient 33, whose disease progressed during the study. GLI1 mRNA levels were elevated in tissue from two of three additional patients with progressive disease (2-DCt)=9.7 and 10.9, normalized against Smo); tissue was not obtained from the third patient.
The entire coding region of the PTCH1 gene and an exon encoding a
previously identified activating mutation of SMO (SMO-M2)
(15) were sequenced from patients' stored tumor samples
that could be evaluated (Table 3 in
the Supplementary Appendix). Mutations in the PTCH1 gene, including
nonsense and missense mutations, were found in 9 of 10 such specimens.
An intronic point mutation disrupting a consensus splice site that was
detected in tissue from a lung mass in Patient 2 was found to be homozygous
on mass spectrometry of the microdissected tumor epithelium; this finding
was consistent with loss of heterozygosity of the PTCH1 tumor suppressor
gene (Figure 2 in the Supplementary
Appendix). In addition, the oncogenic SMO-M2 mutation (15)
was identified in a patient with stable disease, and two PTCH1 mutations
were detected in a normal skin-biopsy specimen from a patient with the
basal-cell nevus syndrome (Patient 4).
Discussion:
In this study, a tumor response to GDC-0449 was seen in some patients with advanced basal-cell carcinoma. Of 33 patients with locally advanced or metastatic tumors, 18 had a response to GDC-0449. Of the remaining 15 patients, 11 had stable disease for up to 10.8 months, and 4 had progressive disease. There were no dose-limiting toxic effects or grade 5 adverse events, and only one grade 4 adverse event occurred during continuous daily administration of GDC-0449 for up to 19 months.
Basal-cell carcinoma is usually treated with surgical excision and rarely recurs or spreads.(2) The patients we treated in this study had advanced tumors that were no longer amenable to conventional treatment options, including surgery, radiotherapy, or systemic therapy.
The molecular mechanisms that drive the development of advanced basal-cell carcinoma have not been previously characterized. We found high levels of GLI1 mRNA expression in tumors from the patients, similar to the levels in more common resectable basal-cell carcinoma and consistent with constitutive activation of the hedgehog pathway. These results, combined with the responses of some tumors to treatment with GDC-0449, suggest that advanced tumors rely on the activation of the hedgehog pathway for growth and maintenance.
Four subjects in our study had progressive disease. Hedgehog signaling
was not detected in a liver-tumor sample obtained from one of these patients,
who had metastatic basal-cell carcinoma and whose disease rapidly progressed
during the study. Two of the four patients with progressive disease had
increased hedgehog pathway signaling, which suggests that unknown mechanisms
underlie the lack of benefit of GDC-0449 or that the stored tissue was
not representative of the unresponsive tumor. Our findings confirm the
participation of the hedgehog pathway in basal-cell carcinoma and suggest
that inhibition of the hedgehog pathway can be useful in treating inoperable
tumors.
Supplementary Information:
http://content.nejm.org/cgi/content/full/NEJMoa0905360/DC1
Supported by Genentech:
Dr. Von Hoff reports receiving clinical research funding from Genentech; Dr. LoRusso, receiving research funding and lecture fees from Genentech; Dr. Rudin, receiving a BioOncology Grant Program Award from Genentech; Dr. Brahmer, receiving consulting fees from Genentech; Dr. de Sauvage, holding patents in the field of hedgehog signaling; and Drs. Reddy, Yauch, Mackey, Lum, Darbonne, Marsters, de Sauvage, and Low, being employees of Genentech. No other potential conflict of interest relevant to this article was reported.
We thank the patients and their families who participated in this
study; clinical staff members Gayle Jameson, Lisa Blaydorn, Katy Schroeder,
Jie Zhang, Barbara Coleman, Ayesha Rahman, Ilsung Chang, and Ron Korn;
research staff members Chris Callahan, Hartmut Koeppen, Tom Januario, Ling
Fu, Thomas Holcomb, Jeremy Stinson, Kanan Pujara, Thinh Pham, Sravanthi
Cheeti, Richard Graham, Xiao Ding, Patrick Rudewicz, Kenn Zerivitz, Hilary
Nelson, Lisa Nelson, Brandon Arnieri, and Sho-Rong Lee; and Abie Craiu
for assistance with the preparation of the manuscript.
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PubMed Citation:
This article has been cited by other articles:
Dlugosz, A. A., Talpaz, M. (2009). Following the Hedgehog to New Cancer Therapies. NEJM 361: 1202-1205
Rudin, C. M., Hann, C. L., Laterra, J., Yauch, R. L., Callahan, C. A., Fu, L., Holcomb, T., Stinson, J., Gould, S. E., Coleman, B., LoRusso, P. M., Von Hoff, D. D., de Sauvage, F. J., Low, J. A. (2009). Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. NEJM 361: 1173-1178
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Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma.
Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, Hann CL, Gould SE, Low JA, Rudin CM, de Sauvage FJ.
Science. 2009 Sep 2. [Epub ahead of print]
PMID: 19726788 [PubMed - as supplied by publisher]
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Phase II study on paclitaxel in patients with recurrent, metastatic or locally advanced vulvar cancer not amenable to surgery or radiotherapy: a study of the EORTC-GCG (European Organisation for Research and Treatment of Cancer--Gynaecological Cancer Group).
Witteveen PO, van der Velden J, Vergote I, Guerra C, Scarabeli C, Coens C, Demonty G, Reed N.
Ann Oncol. 2009 Sep;20(9):1511-6. Epub 2009 Jun 1.
PMID: 19487487 [PubMed - in process]
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Phase II Study of Plitidepsin 3-Hour Infusion Every 2 Weeks in Patients With Unresectable Advanced Medullary Thyroid Carcinoma.
Baudin E, Droz JP, Paz-Ares L, van Oosterom AT, Cullell-Young M, Schlumberger M.
Am J Clin Oncol. 2009 Aug 21. [Epub ahead of print]
PMID: 19704366 [PubMed - as supplied by publisher]
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Multicenter Phase II Trial of Combination Therapy with Meloxicam, a COX-2 Inhibitor, and Natural Interferon-{alpha} for Metastatic Renal Cell Carcinoma.
Shinohara N, Kumagai A, Kanagawa K, Maruyama S, Abe T, Sazawa A, Nonomura K.
Jpn J Clin Oncol. 2009 Aug 14. [Epub ahead of print]
PMID: 19684042 [PubMed - as supplied by publisher]
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Efficacy and safety of axitinib in patients with advanced non-small-cell lung cancer: results from a phase II study.
Schiller JH, Larson T, Ou SH, Limentani S, Sandler A, Vokes E, Kim S, Liau K, Bycott P, Olszanski AJ, von Pawel J.
J Clin Oncol. 2009 Aug 10;27(23):3836-41. Epub 2009 Jul 13.
PMID: 19597027 [PubMed - indexed for MEDLINE]
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Phase II Study of Axitinib in Sorafenib-Refractory Metastatic Renal Cell Carcinoma.
Rini BI, Wilding G, Hudes G, Stadler WM, Kim S, Tarazi J, Rosbrook B, Trask PC, Wood L, Dutcher JP.
J Clin Oncol. 2009 Aug 3. [Epub ahead of print]
PMID: 19652060 [PubMed - as supplied by publisher]
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Safety and efficacy of patupilone in patients with advanced ovarian, primary fallopian, or primary peritoneal cancer: a phase I, open-label, dose-escalation study.
Ten Bokkel Huinink WW, Sufliarsky J, Smit WM, Spanik S, Wagnerova M, Hirte HW, Kaye S, Johri AR, Oza AM.
J Clin Oncol. 2009 Jul 1;27(19):3097-103. Epub 2009 May 18.
PMID: 19451434 [PubMed - indexed for MEDLINE]
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A phase 2 study with a daily regimen of the oral mTOR inhibitor RAD001 (everolimus) in patients with metastatic clear cell renal cell cancer.
Amato RJ, Jac J, Giessinger S, Saxena S, Willis JP.
Cancer. 2009 Jun 1;115(11):2438-46.
PMID: 19306412 [PubMed - indexed for MEDLINE]
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13:
Lapatinib monotherapy in patients with HER2-overexpressing relapsed or refractory inflammatory breast cancer: final results and survival of the expanded HER2+ cohort in EGF103009, a phase II study.
Kaufman B, Trudeau M, Awada A, Blackwell K, Bachelot T, Salazar V, DeSilvio M, Westlund R, Zaks T, Spector N, Johnston S.
Lancet Oncol. 2009 Jun;10(6):581-8. Epub 2009 Apr 24.
PMID: 19394894 [PubMed - indexed for MEDLINE]
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Phase II study of biweekly plitidepsin as second-line therapy in patients with advanced malignant melanoma.
Eisen T, Thomas J, Miller WH Jr, Gore M, Wolter P, Kavan P, Martín JA, Lardelli P.
Melanoma Res. 2009 Jun;19(3):185-92.
PMID: 19436178 [PubMed - indexed for MEDLINE]
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Phase II trial of sorafenib in metastatic thyroid cancer.
Kloos RT, Ringel MD, Knopp MV, Hall NC, King M, Stevens R, Liang J, Wakely PE Jr, Vasko VV, Saji M, Rittenberry J, Wei L, Arbogast D, Collamore M, Wright JJ, Grever M, Shah MH.
J Clin Oncol. 2009 Apr 1;27(10):1675-84. Epub 2009 Mar 2.
PMID: 19255327 [PubMed - indexed for MEDLINE]
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Phase II study of weekly plitidepsin as second-line therapy for small cell lung cancer.
Eisen T, Thatcher N, Leyvraz S, Miller WH Jr, Couture F, Lorigan P, Lüthi F, Small D, Tanovic A, O'Brien M.
Lung Cancer. 2009 Apr;64(1):60-5. Epub 2008 Aug 9.
PMID: 18692272 [PubMed - indexed for MEDLINE]
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G3139 (Genasense) in Patients With Advanced Merkel Cell Carcinoma.
Shah MH, Varker KA, Collamore M, Zwiebel JA, Coit D, Kelsen D, Chung KY.
Am J Clin Oncol. 2009 Mar 20. [Epub ahead of print]
PMID: 19307957 [PubMed - as supplied by publisher]
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18:
Response of the primary tumor to neoadjuvant sunitinib in patients with advanced renal cell carcinoma.
Thomas AA, Rini BI, Lane BR, Garcia J, Dreicer R, Klein EA, Novick AC, Campbell SC.
J Urol. 2009 Feb;181(2):518-23; discussion 523. Epub 2008 Dec 18.
PMID: 19100579 [PubMed - indexed for MEDLINE]
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19:
Sorafenib: a review of its use in advanced hepatocellular carcinoma.
Keating GM, Santoro A.
Drugs. 2009;69(2):223-40. doi: 10.2165/00003495-200969020-00006. Review.
PMID: 19228077 [PubMed - indexed for MEDLINE]
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Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.
Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z.
Lancet Oncol. 2009 Jan;10(1):25-34. Epub 2008 Dec 16.
PMID: 19095497 [PubMed - indexed for MEDLINE]
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21:
A phase I clinical trial of the histone deacetylase inhibitor belinostat in patients with advanced hematological neoplasia.
Gimsing P, Hansen M, Knudsen LM, Knoblauch P, Christensen IJ, Ooi CE, Buhl-Jensen P.
Eur J Haematol. 2008 Sep;81(3):170-6. Epub 2008 May 27.
PMID: 18510700 [PubMed - indexed for MEDLINE]
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22:
Induction chemotherapy with S-1 plus cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck.
Choi YJ, Chung JS, Shin HJ, Cho GJ, Wang SG, Lee BJ, Cho BM, Joo YD, Sohn CH.
J Laryngol Otol. 2008 Aug;122(8):848-53. Epub 2007 Nov 30.
PMID: 18047761 [PubMed - indexed for MEDLINE]
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23:
Pemetrexed single agent chemotherapy in previously treated patients with locally advanced or metastatic non-small cell lung cancer.
Russo F, Bearz A, Pampaloni G; Investigators of Italian Pemetrexed Monotherapy of NSCLC Group.
BMC Cancer. 2008 Jul 31;8:216.
PMID: 18667090 [PubMed - indexed for MEDLINE]
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24:
An adjuvant autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a multicentre, open-label, randomised phase III trial.
Wood C, Srivastava P, Bukowski R, Lacombe L, Gorelov AI, Gorelov S, Mulders P, Zielinski H, Hoos A, Teofilovici F, Isakov L, Flanigan R, Figlin R, Gupta R, Escudier B; C-100-12 RCC Study Group.
Lancet. 2008 Jul 12;372(9633):145-54. Epub 2008 Jul 3.
PMID: 18602688 [PubMed - indexed for MEDLINE]
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Use of a targeted oncolytic poxvirus, JX-594, in patients with refractory primary or metastatic liver cancer: a phase I trial.
Park BH, Hwang T, Liu TC, Sze DY, Kim JS, Kwon HC, Oh SY, Han SY, Yoon JH, Hong SH, Moon A, Speth K, Park C, Ahn YJ, Daneshmand M, Rhee BG, Pinedo HM, Bell JC, Kirn DH.
Lancet Oncol. 2008 Jun;9(6):533-42. Epub 2008 May 19. Erratum in: Lancet Oncol. 2008 Jul;9(7):613.
PMID: 18495536 [PubMed - indexed for MEDLINE]
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Phase II study of plitidepsin in pretreated patients with locally advanced or metastatic non-small cell lung cancer.
Peschel C, Hartmann JT, Schmittel A, Bokemeyer C, Schneller F, Keilholz U, Buchheidt D, Millan S, Izquierdo MA, Hofheinz RD.
Lung Cancer. 2008 Jun;60(3):374-80. Epub 2007 Dec 3.
PMID: 18054408 [PubMed - indexed for MEDLINE]
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Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study.
Rixe O, Bukowski RM, Michaelson MD, Wilding G, Hudes GR, Bolte O, Motzer RJ, Bycott P, Liau KF, Freddo J, Trask PC, Kim S, Rini BI.
Lancet Oncol. 2007 Nov;8(11):975-84. Epub 2007 Oct 23.
PMID: 17959415 [PubMed - indexed for MEDLINE]
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28:
Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma.
Akaza H, Tsukamoto T, Murai M, Nakajima K, Naito S.
Jpn J Clin Oncol. 2007 Oct;37(10):755-62. Epub 2007 Oct 19.
PMID: 17951335 [PubMed - indexed for MEDLINE]
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29:
First clinical experience of orally active epidermal growth factor receptor inhibitor combined with simplified FOLFOX6 as first-line treatment for metastatic colorectal cancer.
Zampino MG, Magni E, Massacesi C, Zaniboni A, Martignetti A, Zorzino L, Lorizzo K, Santoro L, Boselli S, de Braud F.
Cancer. 2007 Aug 15;110(4):752-8.
PMID: 17594712 [PubMed - indexed for MEDLINE]
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30:
Phase II study of capecitabine and cisplatin in previously untreated advanced biliary tract cancer.
Hong YS, Lee J, Lee SC, Hwang IG, Choi SH, Heo JS, Park JO, Park YS, Lim HY, Kang WK.
Cancer Chemother Pharmacol. 2007 Aug;60(3):321-8. Epub 2006 Dec 2.
PMID: 17143602 [PubMed - indexed for MEDLINE]
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A phase II study of induction chemotherapy followed by concurrent chemoradiotherapy in elderly patients with locally advanced non-small-cell lung cancer.
Giorgio CG, Pappalardo A, Russo A, Santini D, Di Rosa C, Di Salvo C, Castorina S, Marletta F, Bellissima G, Palermo N, Scuderi C, Bordonaro R.
Anticancer Drugs. 2007 Jul;18(6):713-9.
PMID: 17762402 [PubMed - indexed for MEDLINE]
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Phase I trial of sorafenib in combination with IFN alpha-2a in patients with unresectable and/or metastatic renal cell carcinoma or malignant melanoma.
Escudier B, Lassau N, Angevin E, Soria JC, Chami L, Lamuraglia M, Zafarana E, Landreau V, Schwartz B, Brendel E, Armand JP, Robert C.
Clin Cancer Res. 2007 Mar 15;13(6):1801-9.
PMID: 17363536 [PubMed - indexed for MEDLINE]
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33:
Phase I study of radical thoracic radiation, weekly irinotecan, and cisplatin in locally advanced non-small cell lung carcinoma.
Langer CJ, Somer R, Litwin S, Feigenberg S, Movsas B, Maiale C, Sherman E, Millenson M, Nicoloau N, Huang C, Treat J.
J Thorac Oncol. 2007 Mar;2(3):203-9.
PMID: 17410043 [PubMed - indexed for MEDLINE]
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A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma.
Marsh Rde W, Rocha Lima CM, Levy DE, Mitchell EP, Rowland KM Jr, Benson AB 3rd.
Am J Clin Oncol. 2007 Feb;30(1):26-31.
PMID: 17278891 [PubMed - indexed for MEDLINE]
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Overview of resistance to systemic therapy in patients with breast cancer.
Gonzalez-Angulo AM, Morales-Vasquez F, Hortobagyi GN.
Adv Exp Med Biol. 2007;608:1-22. Review.
PMID: 17993229 [PubMed - indexed for MEDLINE]
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Oblimersen: Augmerosen, BCL-2 antisense oligonucleotide - Genta, G 3139, GC 3139, oblimersen sodium.
[No authors listed]
Drugs R D. 2007;8(5):321-34. Review.
PMID: 17767397 [PubMed - indexed for MEDLINE]
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INGN 201: Ad-p53, Ad5CMV-p53, adenoviral p53, p53 gene therapy--introgen, RPR/INGN 201.
[No authors listed]
Drugs R D. 2007;8(3):176-87. Review.
PMID: 17472413 [PubMed - indexed for MEDLINE]
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Phase II study of intravenous TZT-1027 in patients with advanced or metastatic soft-tissue sarcomas with prior exposure to anthracycline-based chemotherapy.
Patel S, Keohan ML, Saif MW, Rushing D, Baez L, Feit K, DeJager R, Anderson S.
Cancer. 2006 Dec 15;107(12):2881-7.
PMID: 17109446 [PubMed - indexed for MEDLINE]
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39:
Sorafenib for the treatment of advanced renal cell carcinoma.
Kane RC, Farrell AT, Saber H, Tang S, Williams G, Jee JM, Liang C, Booth B, Chidambaram N, Morse D, Sridhara R, Garvey P, Justice R, Pazdur R.
Clin Cancer Res. 2006 Dec 15;12(24):7271-8. Review.
PMID: 17189398 [PubMed - indexed for MEDLINE]
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40:
Phase II study of pemetrexed for second-line treatment of transitional cell cancer of the urothelium.
Sweeney CJ, Roth BJ, Kabbinavar FF, Vaughn DJ, Arning M, Curiel RE, Obasaju CK, Wang Y, Nicol SJ, Kaufman DS.
J Clin Oncol. 2006 Jul 20;24(21):3451-7.
PMID: 16849761 [PubMed - indexed for MEDLINE]
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Sunitinib in patients with metastatic renal cell carcinoma.
Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR, Redman BG, Margolin KA, Merchan JR, Wilding G, Ginsberg MS, Bacik J, Kim ST, Baum CM, Michaelson MD.
JAMA. 2006 Jun 7;295(21):2516-24.
PMID: 16757724 [PubMed - indexed for MEDLINE]
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42:
A phase II monocentric study of oxaliplatin in combination with gemcitabine (GEMOX) in patients with advanced/metastatic transitional cell carcinoma (TCC) of the urothelial tract.
Theodore C, Bidault F, Bouvet-Forteau N, Abdelatif M, Fizazi K, di Palma M, Wibault P, de Crevoisier R, Laplanche A.
Ann Oncol. 2006 Jun;17(6):990-4. Epub 2006 Apr 6.
PMID: 16600984 [PubMed - indexed for MEDLINE]
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43:
A Phase II NCCTG study of irinotecan and docetaxel in previously treated patients with non-small cell lung cancer.
Molina JR, Nikcevich D, Hillman S, Geyer S, Drevyanko T, Jett J, Verdirame J, Tazelaar H, Rowland K, Wos E, Kutteh L, Nair S, Fitch T, Flynn P, Stella P, Adjei AA.
Cancer Invest. 2006 Jun-Jul;24(4):382-9.
PMID: 16777690 [PubMed - indexed for MEDLINE]
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44:
Phase II, open-label, randomized study (SIGN) of single-agent gefitinib (IRESSA) or docetaxel as second-line therapy in patients with advanced (stage IIIb or IV) non-small-cell lung cancer.
Cufer T, Vrdoljak E, Gaafar R, Erensoy I, Pemberton K; SIGN Study Group.
Anticancer Drugs. 2006 Apr;17(4):401-9.
PMID: 16549997 [PubMed - indexed for MEDLINE]
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Gefitinib in patients with chemo-sensitive and chemo-refractory relapsed small cell cancers: a Hoosier Oncology Group phase II trial.
Moore AM, Einhorn LH, Estes D, Govindan R, Axelson J, Vinson J, Breen TE, Yu M, Hanna NH.
Lung Cancer. 2006 Apr;52(1):93-7. Epub 2006 Feb 20.
PMID: 16488055 [PubMed - indexed for MEDLINE]
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46:
A Phase II study of gemcitabine and cisplatin in advanced biliary tract cancer.
Kim ST, Park JO, Lee J, Lee KT, Lee JK, Choi SH, Heo JS, Park YS, Kang WK, Park K.
Cancer. 2006 Mar 15;106(6):1339-46.
PMID: 16475213 [PubMed - indexed for MEDLINE]
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47:
Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study.
Hotte SJ, Oza A, Winquist EW, Moore M, Chen EX, Brown S, Pond GR, Dancey JE, Hirte HW.
Ann Oncol. 2006 Feb;17(2):334-40. Epub 2005 Nov 10.
PMID: 16284058 [PubMed - indexed for MEDLINE]
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48:
Randomised phase II trial of gemcitabine and paclitaxel second-line chemotherapy in patients with transitional cell carcinoma (AUO Trial AB 20/99).
Fechner G, Siener R, Reimann M, Kobalz L, Albers P; German Association Of Urologic Oncology (Auo) Bladder Cancer Study Group.
Int J Clin Pract. 2006 Jan;60(1):27-31.
PMID: 16409425 [PubMed - indexed for MEDLINE]
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49:
Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas.
Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O'Neil B, Marcom PK, Ellis MJ, Overmoyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL.
J Clin Oncol. 2005 Aug 10;23(23):5305-13. Epub 2005 Jun 13.
PMID: 15955900 [PubMed - indexed for MEDLINE]
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50:
A phase I clinical trial of thoracic radiotherapy and concurrent celecoxib for patients with unfavorable performance status inoperable/unresectable non-small cell lung cancer.
Liao Z, Komaki R, Milas L, Yuan C, Kies M, Chang JY, Jeter M, Guerrero T, Blumenschien G, Smith CM, Fossella F, Brown B, Cox JD.
Clin Cancer Res. 2005 May 1;11(9):3342-8.
PMID: 15867233 [PubMed - indexed for MEDLINE]
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51:
A pilot trial of gefitinib in combination with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer.
Manegold C, Gatzemeier U, Buchholz E, Smith RP, Fandi A.
Clin Lung Cancer. 2005 May;6(6):343-9.
PMID: 15943894 [PubMed - indexed for MEDLINE]
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52:
Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer.
Agus DB, Gordon MS, Taylor C, Natale RB, Karlan B, Mendelson DS, Press MF, Allison DE, Sliwkowski MX, Lieberman G, Kelsey SM, Fyfe G.
J Clin Oncol. 2005 Apr 10;23(11):2534-43. Epub 2005 Feb 7.
PMID: 15699478 [PubMed - indexed for MEDLINE]
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53:
A phase II study of sabarubicin (MEN-10755) as second line therapy in patients with locally advanced or metastatic platinum/taxane resistant ovarian cancer.
Caponigro F, Willemse P, Sorio R, Floquet A, van Belle S, Demol J, Tambaro R, Comandini A, Capriati A, Adank S, Wanders J.
Invest New Drugs. 2005 Jan;23(1):85-9.
PMID: 15528985 [PubMed - indexed for MEDLINE]
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54:
Effect of gefitinib ('Iressa', ZD1839) on brain metastases in patients with advanced non-small-cell lung cancer.
Hotta K, Kiura K, Ueoka H, Tabata M, Fujiwara K, Kozuki T, Okada T, Hisamoto A, Tanimoto M.
Lung Cancer. 2004 Nov;46(2):255-61.
PMID: 15474674 [PubMed - indexed for MEDLINE]
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5-Fluorouracil as protracted continuous intravenous infusion can be added to full-dose docetaxel (Taxotere)-cisplatin in advanced gastric carcinoma: a phase I-II trial.
Roth AD, Maibach R, Fazio N, Sessa C, Stupp R, Morant R, Herrmann R, Borner MM, Goldhirsch A, de Braud F.
Ann Oncol. 2004 May;15(5):759-64.
PMID: 15111343 [PubMed - indexed for MEDLINE]
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56:
Paclitaxel and cisplatin in patients with recurrent and metastatic head and neck squamous cell carcinoma.
Adamo V, Ferraro G, Pergolizzi S, Sergi C, Laudani A, Settineri N, Alafaci E, Scimone A, Spano F, Spitaleri G.
Oral Oncol. 2004 May;40(5):525-31.
PMID: 15006626 [PubMed - indexed for MEDLINE]
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57:
A phase I study of oral BMS-275291, a novel nonhydroxamate sheddase-sparing matrix metalloproteinase inhibitor, in patients with advanced or metastatic cancer.
Rizvi NA, Humphrey JS, Ness EA, Johnson MD, Gupta E, Williams K, Daly DJ, Sonnichsen D, Conway D, Marshall J, Hurwitz H.
Clin Cancer Res. 2004 Mar 15;10(6):1963-70.
PMID: 15041713 [PubMed - indexed for MEDLINE]
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58:
Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in patients with advanced refractory renal cell carcinoma.
Atkins MB, Hidalgo M, Stadler WM, Logan TF, Dutcher JP, Hudes GR, Park Y, Liou SH, Marshall B, Boni JP, Dukart G, Sherman ML.
J Clin Oncol. 2004 Mar 1;22(5):909-18.
PMID: 14990647 [PubMed - indexed for MEDLINE]
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59:
United States Food and Drug Administration Drug Approval summary: Gefitinib (ZD1839; Iressa) tablets.
Cohen MH, Williams GA, Sridhara R, Chen G, McGuinn WD Jr, Morse D, Abraham S, Rahman A, Liang C, Lostritto R, Baird A, Pazdur R.
Clin Cancer Res. 2004 Feb 15;10(4):1212-8.
PMID: 14977817 [PubMed - indexed for MEDLINE]
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60:
Mitoxantrone: a review of its use in multiple sclerosis.
Scott LJ, Figgitt DP.
CNS Drugs. 2004;18(6):379-96. Review.
PMID: 15089110 [PubMed - indexed for MEDLINE]
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61:
Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors.
Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T, Sznol M.
Clin Cancer Res. 2003 Sep 15;9(11):4092-100.
PMID: 14519631 [PubMed - indexed for MEDLINE]
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62:
Dose-comparative monotherapy trials of ZD1839 in previously treated non-small cell lung cancer patients.
Herbst RS.
Semin Oncol. 2003 Feb;30(1 Suppl 1):30-8. Review.
PMID: 12644982 [PubMed - indexed for MEDLINE]
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63:
Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.
Plosker GL, Figgitt DP.
Drugs. 2003;63(8):803-43. Review.
PMID: 12662126 [PubMed - indexed for MEDLINE]
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64:
FDA drug approval summary: gefitinib (ZD1839) (Iressa) tablets.
Cohen MH, Williams GA, Sridhara R, Chen G, Pazdur R.
Oncologist. 2003;8(4):303-6.
PMID: 12897327 [PubMed - indexed for MEDLINE]
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65:
Phase II trial combining paclitaxel with 24-hour infusion cisplatin for chemotherapy-naïve patients with locally advanced or metastatic breast carcinoma.
Hsu C, Huang CS, Chao TY, Lu YS, Bu CF, Chen MM, Chang KJ, Cheng AL.
Cancer. 2002 Nov 15;95(10):2044-50.
PMID: 12412156 [PubMed - indexed for MEDLINE]
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66:
Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types.
Baselga J, Rischin D, Ranson M, Calvert H, Raymond E, Kieback DG, Kaye SB, Gianni L, Harris A, Bjork T, Averbuch SD, Feyereislova A, Swaisland H, Rojo F, Albanell J.
J Clin Oncol. 2002 Nov 1;20(21):4292-302.
PMID: 12409327 [PubMed - indexed for MEDLINE]
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67:
Phase I trial of interferon alpha2b and liposome-encapsulated all-trans retinoic acid in the treatment of patients with advanced renal cell carcinoma.
Goldberg JS, Vargas M, Rosmarin AS, Milowsky MI, Papanicoloau N, Gudas LJ, Shelton G, Feit K, Petrylak D, Nanus DM.
Cancer. 2002 Sep 15;95(6):1220-7.
PMID: 12216088 [PubMed - indexed for MEDLINE]
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68:
A new cisplatin/gemcitabine schedule in locally advanced (IIIB) and metastatic (IV) non-small cell lung cancer: relationship between dose-intensity and efficacy. A phase II study.
Rossi D, Graziano F, Catalano V, Giordani P, Fedeli SL, Alessandroni P, Fedeli A, Dennetta D, Ugolini M, Catalano G.
Anticancer Res. 2002 Sep-Oct;22(5):3087-92.
PMID: 12530048 [PubMed - indexed for MEDLINE]
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69:
Treatment of advanced neuroendocrine tumours using combination chemotherapy with lomustine and 5-fluorouracil.
Kaltsas GA, Mukherjee JJ, Isidori A, Kola B, Plowman PN, Monson JP, Grossman AB, Besser GM.
Clin Endocrinol (Oxf). 2002 Aug;57(2):169-83. Review.
PMID: 12153595 [PubMed - indexed for MEDLINE]
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70:
Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologia dell'Italia Meridionale.
Colucci G, Giuliani F, Gebbia V, Biglietto M, Rabitti P, Uomo G, Cigolari S, Testa A, Maiello E, Lopez M.
Cancer. 2002 Feb 15;94(4):902-10.
PMID: 11920457 [PubMed - indexed for MEDLINE]
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71:
Cisplatin, raltitrexed, levofolinic acid and 5-fluorouracil in locally advanced or metastatic squamous cell carcinoma of the head and neck: a phase II randomized study.
Caponigro F, Rosati G, De Rosa P, Avallone A, De Rosa V, De Lucia L, Comella P, Comella G.
Oncology. 2002;63(3):232-8.
PMID: 12381902 [PubMed - indexed for MEDLINE]
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