Philip C Mack

University of California, Davis, Davis, California, United States

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Publications (117)705.7 Total impact

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    ABSTRACT: Background: Overall response rate is frequently used as an end point in phase 2 trials of platinum-treated extensive stage (ES) small-cell lung cancer (SCLC). We hypothesized that disease control rate (DCR) would be a superior surrogate for subsequent survival outcomes. Methods: Updated patient-level data from Southwest Oncology Group (SWOG) trials in second- and/or third-line ES-SCLC patients were pooled. Landmark analysis was performed among patients alive at 8 weeks for overall survival (OS) measured from the 8-week landmark. Association of clinical prognostic factors with DCR was assessed using logistic regression. A Cox proportional hazard model was used to assess the associations between DCR at the landmark time and subsequent OS, adjusted for prognostic factors. Results: Of the 319 ES-SCLC patients, 263 were alive at the 8-week landmark and constituted the pooled study population. Only 8 patients had a response. Disease control at 8 weeks was seen in 98 patients. Bivariate analysis of OS from the 8-week landmark revealed that DCR (hazard ratio [HR], 0.47; P < .0001) and elevated lactate dehydrogenase (HR, 1.70; P = .0004) were significantly associated with OS. In multivariable analysis, DCR remained an independent predictor of subsequent survival from the 8-week landmark (HR, 0.50; P < .0001). Conclusion: In this large second- and third-line ES-SCLC database, DCR at 8 weeks was found to be a significant predictor of subsequent survival in patients receiving investigational therapy. These results have critical implications in the selection of surrogate end points in future prospective ES-SCLC trials.
    Clinical Lung Cancer 10/2015; DOI:10.1016/j.cllc.2015.09.003 · 3.10 Impact Factor
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    ABSTRACT: One strategy for combating cancer-drug resistance is to deploy rational polytherapy up front that suppresses the survival and emergence of resistant tumor cells. Here we demonstrate in models of lung adenocarcinoma harboring the oncogenic fusion of ALK and EML4 that the GTPase RAS-mitogen-activated protein kinase (MAPK) pathway, but not other known ALK effectors, is required for tumor-cell survival. EML4-ALK activated RAS-MAPK signaling by engaging all three major RAS isoforms through the HELP domain of EML4. Reactivation of the MAPK pathway via either a gain in the number of copies of the gene encoding wild-type K-RAS (KRAS(WT)) or decreased expression of the MAPK phosphatase DUSP6 promoted resistance to ALK inhibitors in vitro, and each was associated with resistance to ALK inhibitors in individuals with EML4-ALK-positive lung adenocarcinoma. Upfront inhibition of both ALK and the kinase MEK enhanced both the magnitude and duration of the initial response in preclinical models of EML4-ALK lung adenocarcinoma. Our findings identify RAS-MAPK dependence as a hallmark of EML4-ALK lung adenocarcinoma and provide a rationale for the upfront inhibition of both ALK and MEK to forestall resistance and improve patient outcomes.
    Nature medicine 08/2015; 21(9). DOI:10.1038/nm.3930 · 27.36 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):5242-5242. DOI:10.1158/1538-7445.AM2015-5242 · 9.33 Impact Factor
  • David R Gandara · Primo N Lara · Philip C Mack ·

    Journal of Clinical Oncology 07/2015; 33(26). DOI:10.1200/JCO.2015.61.9692 · 18.43 Impact Factor
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    ABSTRACT: Preclinical modeling in non-small cell lung cancer (NSCLC) showed that stimulation with hepatocyte growth factor (HGF), the ligand for MET, could reverse the cytostatic and cytotoxic effects of the epidermal-growth factor receptor (EGFR) inhibitor erlotinib in erlotinib-sensitive cell lines. Inhibitors of AKT signaling mitigated this HGF-mediated resistance, partially restoring erlotinib activity. We conducted a phase II trial of erlotinib plus MK2206, a highly selective inhibitor of AKT, in NSCLC patients. Eligible patients must have progressed following prior benefit from erlotinib, defined as response or stable disease > 12 weeks. Treatment consisted of erlotinib 150 mg po QD + MK-2206 45 mg po QOD on a 28 day cycle. Primary endpoints were RECIST response rate > 30% (stratum 1: EGFR mutant) and disease control rate (DCR) > 20% at 12 weeks (stratum 2: EGFR wild type). Eighty patients were enrolled, 45 and 35 in stratum 1 and 2, respectively. Most common attributable adverse events (all grade 3) were rash, diarrhea, fatigue, and mucositis. Response and DCR were respectively 9% and 40% in stratum 1; 3% and 47% in stratum 2. Median progression free survival was 4.4 months in stratum 1 and 4.6 months in stratum 2. Combination MK2206 and erlotinib met its primary endpoint in erlotinib-pretreated patients with EGFR wild type NSCLC. While activity was seen in EGFR mutated NSCLC, this did not exceed a priori estimates. AKT pathway inhibition merits further clinical evaluation in EGFR wild type NSCLC. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 06/2015; 21(19). DOI:10.1158/1078-0432.CCR-14-3281 · 8.72 Impact Factor
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    ABSTRACT: Circulating tumor cells (CTC) are promising biomarkers in metastatic castration resistant prostate cancer (mCRPC), and telomerase activity (TA) is a recognized cancer marker. Therefore, we hypothesized that CTC TA may be prognostic of overall survival (OS) in mCRPC. To test this, we used a novel Parylene-C slot microfilter to measure live CTC TA in S0421, a phase 3 SWOG-led therapeutic trial. Blood samples underwent CTC capture and TA measurement by microfilter, as well as parallel enumeration by CellSearch (Janssen/J&J). Cox regression was used to assess baseline (pre-treatment) TA vs. OS, and recursive partitioning was used to explore potential prognostic subgroups and to generate Kaplan-Meier (KM) OS curves. Samples were obtained from 263 patients and generated 215 TA measures. In patients with baseline CTC count ≥5 (47% of patients), higher CTC TA was associated with hazard ratio 1.14 (p=0.001) for OS after adjusting for other clinical covariates including CTC counts and serum PSA at study entry. Recursive partitioning identified new candidate risk groups with KM OS curve separation based on CTC counts and TA. Notably, in men with an intermediate range baseline CTC count (6-54 CTCs/7.5ml), low vs. high CTC TA was associated with median survival of 19 vs. 12 months, respectively (p=0.009). Baseline telomerase activity from CTCs live-captured on a new slot microfilter is the first CTC-derived candidate biomarker prognostic of OS in a large patient subgroup in a prospective clinical trial. CTC telomerase activity thus merits further study and validation as a step towards molecular CTC-based precision cancer management. © 2014 Wiley Periodicals, Inc.
    International Journal of Cancer 04/2015; 136(8). DOI:10.1002/ijc.29212 · 5.09 Impact Factor
  • Philip C Mack ·

    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2015; 10(4):546-7. DOI:10.1097/JTO.0000000000000476 · 5.28 Impact Factor
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    ABSTRACT: New approaches to optimization of cancer drug development in the laboratory and the clinic will be required to fully achieve the goal of individualized, precision cancer therapy. Improved preclinical models that more closely reflect the now recognized genomic complexity of human cancers are needed. Here we describe a collaborative research project that integrates core resources of The Jackson Laboratory Basic Science Cancer Center with genomics and clinical research facilities at the UC Davis Comprehensive Cancer Center to establish a clinically and genomically annotated patient-derived xenograft (PDX) platform designed to enhance new drug development and strategies for targeted therapies. Advanced stage non-small-cell lung cancer (NSCLC) was selected for initial studies because of emergence of a number of "druggable" molecular targets, and recent recognition of substantial inter- and intrapatient tumor heterogeneity. Additionally, clonal evolution after targeted therapy interventions make this tumor type ideal for investigation of this platform. Using the immunodeficient NOD scid gamma mouse, > 200 NSCLC tumor biopsies have been xenotransplanted. During the annotation process, patient tumors and subsequent PDXs are compared at multiple levels, including histomorphology, clinically applicable molecular biomarkers, global gene expression patterns, gene copy number variations, and DNA/chromosomal alterations. NSCLC PDXs are grouped into panels of interest according to oncogene subtype and/or histologic subtype. Multiregimen drug testing, paired with next-generation sequencing before and after therapy and timed tumor pharmacodynamics enables determination of efficacy, signaling pathway alterations, and mechanisms of sensitivity-resistance in individual models. This approach should facilitate derivation of new therapeutic strategies and the transition to individualized therapy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Lung Cancer 03/2015; 16(3). DOI:10.1016/j.cllc.2015.03.001 · 3.10 Impact Factor
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    T Semrad · K Kelly · D Gandara · J Riess · T Li · A Yu · P Mack · E Kim ·
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    ABSTRACT: This phase I study evaluated the safety and tolerability of a combination of gemcitabine and an oral Aurora Kinase A (AKA) inhibitor, alisertib (MLN8237). The primary goal of this study was to determine the maximally tolerated dose (MTD) of alisertib in combination with gemcitabine. Eligible adult patients (pts) had refractory solid tumors that had progressed on standard therapy; ECOG performance status (PS) 0-2; adequate organ function. Pts received 28-day cycles of gemcitabine on days 1, 8, 15 and alisertib twice daily on days 1-3, 8-10, and 15-17. Gemcitabine was given at a standard dose of 1000mg/m(2). Dose level (DL) 1 for alisertib was 20mg BID. Dose escalation: 30mg BID (DL2), 40mg BID (DL3), and 50mg BID (DL4); 3 + 3 design. Formalin-fixed paraffin embedded tumor samples were requested in all cases. Secondary endpoints were objective response, progression-free survival, and safety. Twenty-one pts were treated. Baseline characteristics: median age 57 years (range, 42-75); 10 males and 11 females; PS 0 (7 pts), 1 (13 pts), or 2 (1 pt); median prior therapies was 2 (range 0-7); cancer dx (#pts): NSCLC (7); colorectal (3); poorly differentiated neuroendocrine (3); small cell lung carcinoma (2); head and neck carcinoma (2); 1 each of pancreatic adenocarcinoma, gallbladder, small bowel, mesothelioma. A median of 4 cycles (range, 1-13) were administered. Two pts experienced DLT: 1 pt at DL3 had grade 3 urinary tract infection; 1 pt at DL4 developed grade 3 oral mucositis, hyponatremia, and dehydration. The maximum administered dose (DL4) achieved 900 mg alisertib per cycle and was tolerated (1 DLT in 6 pts). Grade 3-4 hematologic toxicities observed included (%pts): anemia (24%), leukopenia (48%), neutropenia (57%), thrombocytopenia (14%). Hyponatremia (19%) was the only non-hematologic toxicity observed in >10% of the pts. Ten of 14 evaluable pts (71%) had stable disease as their best response with remaining pts having disease progression. Alisertib can be safely administered at 50 mg PO BID on days 1-3. 8-10, and 15-17 in combination with full dose gemcitabine. A pre-planned expansion is ongoing in pts with pancreatic adenocarcinoma. Tumor tissue is being characterized for baseline expression level of AKA. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 03/2015; 26(suppl 2):ii17. DOI:10.1093/annonc/mdv090.6 · 7.04 Impact Factor
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    ABSTRACT: The Lung Master Protocol (Lung-MAP, S1400) is a groundbreaking clinical trial designed to advance the efficient development of targeted therapies for squamous cell cancer (SCCA) of the lung. There are no approved targeted therapies specific to advanced lung SCCA, although The Cancer Genome Atlas (TCGA) project and similar studies have detected a significant number of somatic gene mutations/amplifications in lung SCCA, some of which are targetable by investigational agents. However, the frequency of these changes is low (5-20%), making recruitment and study conduct challenging in the traditional clinical trial setting. Here we describe our approach to development of a biomarker-driven phase 2/3 multi-substudy "Master Protocol," employing a common platform (Next Generation DNA Sequencing) to identify actionable molecular abnormalities, followed by randomization to the relevant targeted therapy versus standard of care. Copyright © 2015, American Association for Cancer Research.
    Clinical Cancer Research 02/2015; 21(7). DOI:10.1158/1078-0432.CCR-13-3473 · 8.72 Impact Factor
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    ABSTRACT: Though the proportion of patients with squamous cell carcinoma of the lung has declined over the last two decades, the disease is still fatal for tens of thousands of patients each year. The treatment of non-small cell lung cancer has advanced rapidly over the past decade, providing novel, targeted therapeutic options to patients, but has mostly been limited to the adenocarcinoma histology. Efforts are currently underway to bring squamous cell carcinoma of the lung into this new era of targeted therapy. This article reviews the rationale and trial design for the "LUNG-MAP: S1400 Phase II/III Biomarker-Driven Master Protocol for Second Line Therapy of Squamous Cell Lung Cancer" study. This multi-institutional, multi-cooperative group trial aims to individualize treatment for patients with metastatic squamous cell carcinoma to one of five arms based on the genomic profile of the tumor. The goal of this clinical trial is to bring new targeted therapies to patients with squamous cell lung cancer by utilizing a novel trial design and involving all key stakeholders in drug development in a national effort. This could serve as a paradigm for drug development for malignancies with wide molecular heterogeneity. This article is protected by copyright. All rights reserved. © 2015 American Society for Clinical Pharmacology and Therapeutics.
    Clinical Pharmacology &#38 Therapeutics 02/2015; 97(5). DOI:10.1002/cpt.88 · 7.90 Impact Factor
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    ABSTRACT: The PI3K/Akt/mammalian target of rapamycin pathway is activated in a majority of malignant pleural mesotheliomas (MPM). We evaluated the activity of everolimus, an oral mammalian target of rapamycin inhibitor, in patients with unresectable MPM. MPM patients who had received at least one but no more than two prior chemotherapy regimens, which must have been platinum-based, were treated with 10 mg of everolimus daily. The primary endpoint was 4-month progression-free survival (PFS) by RECIST 1.1. A total of 59 evaluable patients were included in the analysis. The median duration of treatment was 2 cycles (56 days). Overall response rate was 2% [95% confidence interval (CI): 0-12%] by RECIST 1.1 and 0% (0-10%) by modified RECIST for MPM. The 4-month PFS rate was 29% (95% CI: 17-41%) by RECIST 1.1, and 27% (95% CI: 16-39%) by modified RECIST. The median PFS was 2.8 months (95% CI: 1.8-3.4) by RECIST 1.1. The median overall survival was 6.3 months (95% CI: 4.0-8.0). There was no difference in PFS among patients who received one or two prior chemotherapy regimens (p = 0.74). There was no difference in overall survival between patients with epithelioid histology versus other types (p = 0.47). The most common toxicities were fatigue (59%), hypertriglyceridemia (44%), anemia (42%), oral mucositis (34%), nausea (32%), and anorexia (32%). The most common grade 3 to 4 toxicities were fatigue (10.2%), anemia (6.8%), and lung infection (6.8%). Everolimus has limited clinical activity in advanced MPM patients. Additional studies of single-agent everolimus in advanced MPM are not warranted.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 02/2015; 10(2):387-91. DOI:10.1097/JTO.0000000000000360 · 5.28 Impact Factor
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    ABSTRACT: The aim of this trial was to determine feasibility of incorporating bevacizumab (B) into concurrent chemoradiotherapy (CRT) for locally advanced non-small-cell lung cancer (NSCLC). Patients with unresectable stage III NSCLC, performance status of 0 to 1, and adequate organ function were accrued in 2 strata, low- and high-risk (squamous histology, hemoptysis, tumor with cavitation and/or adjacent to a major vessel). Cohort 1 patients received cisplatin 50 mg/m(2) days (d) 1 and 8, etoposide 50 mg/m(2) (d 1-5) for 2 cycles concurrent with radiotherapy (64.8 Gy) followed by docetaxel (D) 75 mg/m(2) and B 15 mg/kg for 3 cycles. If safety was established, then accrual would continue to cohort 2 (B, d 15, 36, 57) and then subsequently to cohort 3 (B, d 1, 22, 43). Twenty-nine patients (17 low- and 12 high-risk) registered to cohort 1. Twenty-six patients (including 4 squamous, 1 adenosquamous) were assessable. Twenty-five completed CRT. Grade 3/4 toxicities during CRT included acceptable rates of hematologic toxicity, esophagitis, and pneumonitis. Of 21 assessable for safety with D/B consolidation, major adverse events were pneumonitis (2 Grade 3) and 2 episodes of fatal hemoptysis in the high-risk group, resulting in closure of this stratum. The low-risk stratum subsequently closed because of slow accrual. Median overall survival was 46 months for low-risk and 17 months for high-risk strata. Bevacizumab was not safely integrated into CRT for stage III NSCLC in patients considered at high risk for hemoptysis. In lower risk patients, data are insufficient to determine safety or efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.
    Clinical Lung Cancer 01/2015; 16(5). DOI:10.1016/j.cllc.2014.12.014 · 3.10 Impact Factor
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    ABSTRACT: Extensive-stage small-cell lung cancer (SCLC) patients who progress after platinum-based chemotherapy are traditionally categorized as platinum sensitive (progression ≥ 90 days from last platinum dose) or refractory (progression < 90 days), a practice arising from seminal observations of worse survival in refractory patients. Subsequent trials accounted for platinum sensitivity, resulting in higher sample sizes and increased resource use. To assess whether platinum-sensitivity status remains associated with outcomes, patient-level data from recent Southwest Oncology Group trials in second- and/or third-line extensive-stage SCLC were pooled. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) accounting for platinum sensitivity were calculated using unadjusted and adjusted Cox Proportional Hazard models. Recursive partitioning was performed to define prognostic risk groups. Of 329 patients, 151 were platinum sensitive and 178 refractory. HRs from unadjusted Cox PFS and OS models for refractory versus sensitive disease were 1.0 (95% confidence interval, 0.81-1.25; p = 0.98) and 1.24 (0.99-1.57; p = 0.06), respectively. Adjusted Cox models showed that only elevated serum lactate dehydrogenase (HR, 2.04; p < 0.001), males (HR, 1.36; p = 0.04), performance status of 1 (HR, 1.25; p = 0.02), and weight loss greater than or equal to 5% (1.53, p = 0.01) were independently associated with OS. Platinum-sensitivity status was not associated with PFS (HR, 1.11; p = 0.49) or OS (HR, 1.25; p = 0.14), except in a model that excluded 36 patients who received more than one prior chemotherapy regimen (HR, 1.34; p = 0.049). Prognostic groups with differential OS outcomes (high, intermediate, and poor risk) were identified. Platinum-sensitivity status may no longer be strongly associated with PFS or OS in at least one multivariate model. Validation of prognostic risk groups identified here is warranted. These data have critical implications in the design of future SCLC trials.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 12/2014; 10(1). DOI:10.1097/JTO.0000000000000385 · 5.28 Impact Factor
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    ABSTRACT: Purpose: Acquired resistance to erlotinib in patients with EGFR-mutant non-small cell lung cancer can result from aberrant activation of alternative receptor tyrosine kinases, such as the HGF-driven c-MET receptor. We sought to determine whether inhibition of AKT signaling could augment erlotinib activity and abrogate HGF-mediated resistance. Methods: The effects of MK-2206, a selective AKT inhibitor, were evaluated in combination with erlotinib on a large panel of 13 lung cancer cell lines containing different EGFR or KRAS abnormalities. The activity of the combination was assessed using proliferation assays, flow cytometry and immunoblotting. The MEK inhibitor PD0325901 was used to determine the role of the MAP kinase pathway in erlotinib resistance. Results: The combination of MK-2206 and erlotinib resulted in synergistic growth inhibition independent of EGFR mutation status. In cell lines where HGF blocked the anti-proliferative and cytotoxic effects of erlotinib, MK-2206 could restore cell cycle arrest, but MEK inhibition was required for erlotinib-dependent apoptosis. Both AKT and MEK inhibition contributed to cell death independent of erlotinib in the T790M-containing H1975 and the EGFR-WT cell lines tested. Conclusions: These findings illustrate the potential advantages and challenges of combined signal transduction inhibition as a generalized strategy to circumvent acquired erlotinib resistance.
    Journal of Cancer Research and Clinical Oncology 10/2014; 141(4). DOI:10.1007/s00432-014-1855-4 · 3.08 Impact Factor
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    ABSTRACT: Purpose: Erlotinib marginally improves survival when administered continuously with gemcitabine to patients with advanced pancreatic cancer; however, preclinical data suggest that there is antagonism between chemotherapy and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors when these are delivered concurrently. We tested a pharmacodynamic separation approach for erlotinib plus gemcitabine and interrogated EGFR signaling intermediates as potential surrogates for the efficacy of this strategy. Methods: Patients with measurable, previously untreated locally advanced unresectable or metastatic pancreatic cancer were treated with gemcitabine 1000 mg/m(2) as an intravenous infusion over 30-min on days 1, 8, 15 and erlotinib 150 mg/day on days 2-5, 9-12, 16-26 of each 28-day cycle. The primary endpoint was progression-free survival (PFS); secondary endpoints included RECIST objective response rate (ORR) and safety. The study was terminated after thirty patients due to funding considerations. Results: The median PFS was 2.07 months (95% CI; 1.87-5.50 months) and the ORR was 11%. No unexpected safety signals were seen: the most common grade 3 or higher adverse events were neutropenia (23%), lymphopenia (23%), and fatigue (13%). Patients with mutant plasma Kirsten rat sarcoma virus (KRAS) had significantly lower median PFS (1.8 vs. 4.6 months, p = 0.014) and overall survival (3.0 vs. 10.5 months, p = 0.003) than those without detected plasma KRAS mutations. Conclusions: Although pharmacodynamically separated erlotinib and gemcitabine were feasible and tolerable in patients with advanced pancreatic cancer, no signal for increased efficacy was seen in this molecularly unselected cohort. Detection of a KRAS mutation in circulating cell-free DNA was a strong predictor of survival.
    International Journal of Clinical Oncology 08/2014; 20(3). DOI:10.1007/s10147-014-0730-2 · 2.13 Impact Factor
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    ABSTRACT: BACKGROUND This cooperative group adjuvant phase 2 trial in patients with completely resected stage I non-small cell lung cancer with tumor diameters measuring ≥ 2 cm was designed to assess the feasibility and preliminary efficacy of assigning patients to therapy or observation using a molecularly based decision algorithm.METHODS At least a lobectomy and sampling of recommended mediastinal lymph node stations, good Zubrod performance status, adequate organ function, and a formalin-fixed and paraffin-embedded tumor specimen were required. Excision repair cross-complementing group 1 (ERCC1) and ribonucleotide reductase M1 (RRM1) were analyzed using immunofluorescence-based in situ automated quantitative image analysis and categorized as high or low using prespecified cutoff values. Patients with high ERCC1 and RRM1 were assigned to observation and all others to 4 cycles of cisplatin and gemcitabine. Feasibility was defined as treatment assignment within 84 days from surgery in > 85% of patients. Secondary objectives were to estimate the 2-year survival.RESULTSTreatment assignment met the feasibility criteria in 88% of eligible patients (71 of 81 patients). The collective 2-year disease-free and overall survival rates were 80% and 96%, respectively. Protein levels for RRM1 fell within the previously established range, ERCC1 levels were slightly lower than expected, and they were significantly correlated (correlation coefficient, 0.4). The rates of assignment of patients to observation (22%) and chemotherapy (78%) were as expected.CONCLUSIONS Gene expression analysis for treatment assignment is feasible. Survival results are encouraging and require future validation. Real-time performance of quantitative in situ ERCC1 and RRM1 analysis requires further development. Cancer 2014. © 2014 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society.
    Cancer 08/2014; 120(15). DOI:10.1002/cncr.28714 · 4.89 Impact Factor
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    ABSTRACT: Purpose: Development of new therapies for previously treated small-cell lung cancer (SCLC) is a major unmet need. Here, we describe a randomized, phase II trial of weekly topotecan with or without ziv-aflibercept (VEGF-trap) in this clinical setting. Patients and methods: Patients with previously treated SCLC (one line of platinum-based chemotherapy), performance status of 0 to 1, adequate organ function, treated brain metastases, and no recent vascular events or bleeding diatheses were eligible. Eligible patients were stratified as platinum-sensitive or platinum-refractory and randomly assigned to receive weekly topotecan 4 mg/m(2) intravenously (IV) with or without ziv-aflibercept 6 mg/kg IV every 21 days. Progression-free survival (PFS) at 3 months was the primary end point. Results: In 189 randomly assigned patients, treatment arms were well balanced with regard to clinical characteristics. The 3-month PFS was significantly improved with the addition of ziv-aflibercept in patients who had platinum-refractory disease (27% v 10%; P = .02) but not in patients with platinum-sensitive disease (24% v 15%; P = .22). Although response rate was low, disease control rate was higher with combination therapy than with topotecan alone in patients who had platinum-sensitive disease (37% v 18%; P = .05) and in those who had platinum-refractory disease (25% v 15%; P = .14). Overall survival (OS) was not significantly improved in either strata. Grades 3 to 5 toxicities were more common with the addition of ziv-aflibercept. Conclusion: Ziv-aflibercept improved the 3-month PFS in patients who had platinum-refractory SCLC, but its addition increased toxicity. OS was similar with combined ziv-aflibercept and topotecan compared with topotecan in both strata.
    Journal of Clinical Oncology 07/2014; 32(23). DOI:10.1200/JCO.2013.51.4109 · 18.43 Impact Factor
  • Danielle C Chinn · William S Holland · Philip C Mack ·
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    ABSTRACT: Aurora kinases are key regulators of mitotic events. Dysfunction of these kinases can cause polyploidy and chromosomal instability, a contributor to tumorigenesis. MK-5108 is a potent inhibitor of Aurora A kinase that has shown preclinical potent activity in malignancies of breast, cervical, colon, ovarian, and pancreatic origin. We sought to assess the preclinical efficacy of MK-5108 in a panel of non-small-cell lung cancer cell lines as a single agent and in combination with cisplatin and docetaxel. Eleven lung cancer cell lines were studied. Growth inhibition by MK-5108 was assessed with short- and long-term MTT assays. Cell cycling was measured by flow cytometry. Immunoblotting was used to determine targeted activity of MK-5108 on Aurora A and downstream effects (TACC3 and Plk1). Efficacy of combination studies performed with cisplatin and docetaxel was evaluated by median effect analysis. All cell lines demonstrated sustained growth inhibition following MK-5108 at varying nanomolar concentrations. MK-5108 induced G2/M accumulation, polyploidy, and apoptosis (increased sub-G1/PARP cleavage). Levels of Aurora A, TACC3, and Plk1 diminished. Concurrent treatment of MK-5108 with cisplatin or docetaxel synergistically inhibited cell growth with the docetaxel combination performing better. When administered sequentially, treatment with docetaxel first followed by MK-5108 exhibited greater growth inhibition than the inverse; yet concurrent treatment remained superior. MK-5108 has potent anti-proliferative activity in lung cancer cell lines alone and in combination with chemotherapies. Determining how best to integrate Aurora inhibitors into current lung cancer treatment regimens would be beneficial.
    Journal of Cancer Research and Clinical Oncology 04/2014; 140(7). DOI:10.1007/s00432-014-1675-6 · 3.08 Impact Factor
  • Przemyslaw W Twardowski · Philip C Mack · Primo N Lara ·
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    ABSTRACT: Papillary renal cell carcinoma (pRCC) represents the second most common histologic variant of kidney cancer. It exhibits a different molecular signature than clear-cell carcinoma and is typically not associated with mutations in the VHL (von Hippel-Lindau) tumor suppressor gene. pRCC is less responsive to modern drugs introduced in the management of kidney cancer in the past decade. In this article, the heredity and biology of 2 main variants of pRCC are outlined. New targets that are being explored in the treatment of this disease are discussed, with particular emphasis on inhibition of mesenchymal epithelial transition (MET) and epidermal growth factor receptor (EGFR) pathways. We discuss preclinical data providing rationale for the combination of MET and EGFR inhibitors and review recently completed and ongoing clinical trials that attempt to expand our therapeutic options for this important subset of kidney cancer.
    Clinical Genitourinary Cancer 04/2014; 12(2):74-79. DOI:10.1016/j.clgc.2013.11.013 · 2.32 Impact Factor

Publication Stats

2k Citations
705.70 Total Impact Points


  • 1999-2015
    • University of California, Davis
      • • Division of Hematology and Oncology
      • • Department of Internal Medicine
      Davis, California, United States
  • 1997-2015
    • California State University, Sacramento
      Sacramento, California, United States
  • 2009
    • Kinki University
      Ōsaka, Ōsaka, Japan
  • 2008
    • St. Elizabeth's Medical Center
      Boston, Massachusetts, United States
  • 2007
    • Davis School District
      Davis, California, United States