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1.  Clinical Characteristics and Outcomes of Pediatric Oncology Patients with Aggressive Biology Enrolled in Phase I Clinical Trials Designed for Adults: The University of Texas MD Anderson Cancer Center Experience 
Oncoscience  2014;1(7):522-530.
Background
Children (patients ≤ 18 years of age) are not usually included on pharmaceutical industry sponsored Phase I trials.
Methods
We reviewed the medical records of 40 patients ≤ 18 years treated in ≥ 1 phase I trial at MD Anderson.
Results
The median OS was 8.5 months (95% CI, 5.5–13.2 months). In the multivariate analysis, age ≥15 only predicted increased OS (P = 0.0065), and >3 prior therapies (P = 0.053) predicted decreased OS. The median PFS was 2.8 months (95% CI, 2.3–4.1 months). In the multivariate analysis, independent factors that predicted increased PFS were age ≥15 years (P < 0.001) and prior radiation therapy (P = 0.049); performance status >1 (P < 0.001) and >3 prior therapies (P = 0.002) predicted decreased PFS. RMH score ≥ 2 and MDACC score ≥ 3 were associated with decreased median OS (P = 0.029 and P = 0.031 respectively).
Conclusions
It is feasible to conduct phase I studies in pediatric patients based on adult protocols. In the era of targeted therapy more trials should allow pediatric patients earlier in the drug development especially if deemed safe in adults in early phase trials.
Translational Relevance
Most pharmaceutical industry sponsored trials exclude patients less than 18 years in phase I clinical trials. Even in the era of targeted therapy pediatric patients usually have to wait for most phases of trials to be completed in adults before being allowed to enroll in clinical trials of new therapies, even in the advanced metastatic and relapsed setting. Some investigator initiated phase 1 trials of combinations of US FDA approved agents allow patients less than 18 years. We report the preliminary analyses of the outcomes of pediatric patients enrolled in phase I studies initially designed for adults, but allowing for enrollment of patients under 18.
PMCID: PMC4278323  PMID: 25587555
phase I trials; children; prognostic scores; targeted therapy
2.  Genetics on a WHIM 
British journal of haematology  2013;164(1):15-23.
We initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone marrow). Translational research led to the discovery that this rare immunodeficiency disease is caused by a heterozygous mutation in the CXCR4 gene. Recently, Plerixafor has been suggested as a treatment for WHIM syndrome due to its efficacy as a CXCR4 antagonist, closing the translational research loop. In this review, we will focus on the clinical manifestations, pathophysiology, diagnosis and possible therapies for this rare entity.
doi:10.1111/bjh.12574
PMCID: PMC3961560  PMID: 24111611
CXCR4; myelokathexis; neutropenia; plerixafor; WHIM
3.  Barriers to Study Enrollment in Patients With Advanced Cancer Referred to a Phase I Clinical Trials Unit 
The Oncologist  2013;18(12):1315-1320.
This retrospective study was conducted to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial. Approximately 55% of patients were enrolled on a phase I trial, and those referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution. Major reasons for failure to enroll included failure to return to the clinic, opting for treatment in another clinic, hospice referral, early death, and lack of financial clearance.
Learning Objectives
Assess barriers for advanced cancer patients to participate in phase I trials.Discuss strategies to improve the rate of enrollment of cancer patients in phase I trials.
Background.
We conducted this retrospective study to identify reasons that patients referred to a phase I clinical trial failed to enroll or delayed enrollment onto the trial.
Materials and Methods.
Outcome analyses were conducted independently on data collected from electronic medical records of two sets of consecutive patients referred to a phase I clinical trial facility at MD Anderson Cancer Center. Data from the first set of 300 patients were used to determine relevant variables affecting enrollment; data from the second set of 957 patients were then analyzed for these variables.
Results.
Results from the two sets of patients were similar. Approximately 55% of patients were enrolled in a phase I trial. Patients referred from within MD Anderson were more likely to be enrolled than patients seen originally outside the institution (p = .006); black patients were more likely than white patients to enroll (69% vs. 43%; p = .04). The median interval from the initial visit to initiation of treatments was 19 days. Major reasons for failure to enroll included failure to return to the clinic (36%), opting for treatment in another clinic (17%), hospice referral (11%), early death (10%), and lack of financial clearance (5%). Treatment was delayed for three weeks or more in 250 patients; in 85 patients (34%), the delay was caused by financial and insurance issues.
Conclusion.
Failure to return to the clinic, pursuit of other therapy, and rapid deterioration were the major reasons for failure to enroll; lengthy financial clearance was the most common reason for delayed enrollment onto a phase I trial.
doi:10.1634/theoncologist.2013-0202
PMCID: PMC3868426  PMID: 24153239
Phase I trial; Enrollment; Consults; New patients; Patient referral; Barrier
4.  Target-Based Therapeutic Matching in Early-Phase Clinical Trials in Patients with Advanced Colorectal Cancer and PIK3CA mutations 
Molecular cancer therapeutics  2013;12(12):2857-2863.
Target-matched treatment with PI3K/AKT/mTOR pathway inhibitors in patients with diverse advanced cancers with PIK3CA mutations have shown promise. Tumors from patients with colorectal cancer (CRC) were analyzed for PIK3CA, KRAS and BRAF mutations. PIK3CA mutated tumors were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway. Of 194 patients analyzed, 31 (16%) had PIK3CA mutations, and 189 (97%) were assessed for KRAS mutations. Patients with PIK3CA mutations had a higher prevalence of simultaneous KRAS mutations than patients with wild-type (wt) PIK3CA (71%, 22/31 vs. 43%, 68/158; p=0.006). Of 31 patients with PIK3CA mutations, 17 (55%) were treated with protocols containing PI3K/AKT/mTOR pathway inhibitors (median age, 57; median number of prior therapies, 4; mTORC1 inhibitors [11], PI3K inhibitors [5] or an AKT inhibitor [1]). None (0/17) had a partial or complete response (PR/CR) and only 1 (6%, 95% CI 0.01–0.27) had stable disease (SD)≥6 months, which was not significantly different from a SD≥6 month/PR/CR rate of 16% (11/67; 95% CI 0.09–0.27) in CRC patients without PIK3CA mutations treated with PI3K/AKT/mTOR pathway inhibitors (p=0.44). Median progression-free survival was 1.9 months (95% CI 1.5–2.3). In conclusion, our data provide preliminary evidence that in heavily pretreated patients with PIK3CA-mutant advanced CRC, protocols incorporating PI3K/AKT/mTOR inhibitors have minimal activity. PIK3CA mutations are associated with simultaneous KRAS mutations, possibly accounting for therapeutic resistance.
doi:10.1158/1535-7163.MCT-13-0319-T
PMCID: PMC4158732  PMID: 24092809
PIK3CA mutation; PI3K/AKT/mTOR; Colorectal cancer; Target-matched therapy; KRAS mutation; Phase I trial
5.  Promoting Precision Cancer Medicine through a Community-Driven Knowledgebase 
Journal of Personalized Medicine  2014;4(4):475-488.
Increasing efforts are being dedicated towards improving cancer care via personalized medicine. These efforts depend to a large degree on the availability of a knowledge foundation. Unfortunately, existing knowledge linking cancer drugs and potential efficacy biomarkers is in its infancy; and where links are known, they are frequently unstructured and poorly documented. We have developed a new open-access knowledgebase for precision cancer medicine (the PCM Wiki and Knowledgebase). This knowledgebase was constructed using an innovative, two-pronged approach involving a structured knowledgebase at the back-end, and an intuitive knowledge-sharing interface and user-friendly query engine in front. The knowledgebase was seeded with several patient case reports and information was mined via text-mining and literature review by human curators. Using our novel Wiki-based platform to present and share knowledge stored in the PCM knowledgebase, users are able to suggest corrections, propose additions or point to errors in the knowledgebase. The result is a community-driven evolving knowledgebase holding integrated and consolidated knowledge of markers and indications for personalized cancer medicine. We suggest that the PCM Knowledgebase and Wiki could serve as an important tool for the advancement of clinical trials and care in the field of precision cancer medicine.
doi:10.3390/jpm4040475
PMCID: PMC4282884  PMID: 25563458
cancer; case reports; genetics; knowledgebase; personalized medicine; precision medicine
6.  Phase I Study Evaluating the Combination of Lapatinib (a Her2/Neu and EGFR Inhibitor) and Everolimus (an mTOR Inhibitor) in Patients with Advanced Cancers: South West Oncology Group (SWOG) Study S0528 
Cancer chemotherapy and pharmacology  2013;72(5):1089-1096.
Purpose
Everolimus, an oral inhibitor of mTOR, can augment the efficacy of HER inhibitors in pre-clinical studies. This study was conducted to determine the safety and pharmacokinetics (PK) of the combination of lapatinib, a Her1 and 2 inhibitor, and everolimus, and to describe its antitumor activity in the Phase I setting.
Methods
In Part I, dose escalation to define the maximum tolerated dose (MTD) was performed. In Part II, PK of both drugs were analyzed to assess drug-drug interaction.
Results
Twenty-three evaluable patients with advanced cancers were treated on six different dose levels in Part I of the study. The dose-limiting toxicities were diarrhea, rash, mucositis and fatigue. The MTD of the combination was 1250 mg of lapatinib and 5 mg of everolimus once daily. In Part II of the study, 54 patients were treated with the combination at the MTD. The mean everolimus time to maximum concentration was increased by 44% and mean clearance was decreased by 25% when co-administered with lapatinib, though these differences were not statistically significant. There was no significant influence on the PK of lapatinib by everolimus. Two patients achieved a partial response (thymic cancer (45+ months) and breast cancer (unconfirmed PR; 7 months); eleven patients attained stable disease of at least 4 months
Conclusions
Lapatinib and everolimus are well tolerated at doses of 1250 mg and 5 mg po daily, respectively. Stable disease >4 months/PR was achieved in 13 of 78 patients (17%).
doi:10.1007/s00280-013-2297-4
PMCID: PMC4072025  PMID: 24057042
everolimus; lapatinib; phase I; mTOR; Her2
7.  Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: A phase I trial of bortezomib plus bevacizumab 
Oncotarget  2014;5(21):10280-10292.
Purpose
We hypothesized that bortezomib, an agent that suppresses HIF-1α transcriptional activity, when combined with bevacizumab, would obviate the HIF-1α resistance pathway. The objectives of this phase I trial were to assess safety and biological activity of this combination.
Experimental Design
Patients with advanced, refractory malignancies were eligible. Patients received bevacizumab and bortezomib (3-week cycle) with dose expansions permitted if responses were seen and for assessing correlates. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and HIF-1α tumor expression.
Results
Ninety-one patients were treated (median=6 prior treatments). The FDA-approved doses of both drugs were safely reached, and the recommended phase 2 dose (RP2D) is bevacizumab 15 mg/kg with bortezomib 1.3 mg/m2. Four patients attained partial response (PR) and seven patients achieved stable disease (SD) ≥6 months (Total SD≥6 months/PR=11 (12%)). The most common drug-related toxicities included thrombocytopenia (23%) and fatigue (19%). DCE-MRI analysis demonstrated no dose-dependent decreases in Ktrans although analysis was limited by small sample size (N=12).
Conclusion
Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated advanced malignancy. Pharmacodynamic assessment suggests that inhibition of angiogenic activity was achieved.
PMCID: PMC4279372  PMID: 25373733
bevacizumab; bortezomib; phase 1; proteasome; HIF-1α
8.  A framework for genomic biomarker actionability and its use in clinical decision making 
Oncoscience  2014;1(10):614-623.
The increasing scope and availability of genetic testing options for patients suffering from cancer has raised questions about how to use results of molecular diagnostics to inform patient care. For some biomarkers (e.g. BRAF mutations in melanoma), standards exist that outline treatments for individuals harboring aberrations in the biomarker; however for the vast majority of genomic abnormalities, few guidelines exist. Clinical decision making and the therapeutic approach for a patient with a given cancer characterized by aberrations in different genes may be aided by the use of a biomarker actionability framework that provides levels of evidence regarding whether and how a molecular abnormality can be considered a therapeutically relevant biomarker. A gene may be considered theoretically actionable if it has a basis of actionability, such that clinically available drugs can target a gene product that drives the cancer or is differentially expressed in tumor versus normal elements. Herein, we discuss a possible framework for developing guidelines for actionability, as they relate to genomically-based cancer therapeutics.
PMCID: PMC4278279  PMID: 25593991
Biomarker; Clinical decision making; Targeted therapies; Predictive biomarkers
9.  Methylation and histone deacetylase inhibition in combination with platinum treatment in patients with advanced malignancies 
Investigational new drugs  2013;31(5):10.1007/s10637-013-0003-3.
Purpose
The combination of DNA methylation inhibitors and histone deacetylase inhibitors is synergistic in gene expression activation and may overcome platinum resistance. Sequential treatment with azacitidine and valproic acid (VPA) in combination with carboplatin may overcome resistance to platinum-based therapy, and we conducted a phase I trial to assess safety, maximum tolerated dose (MTD), and clinical correlates.
Experimental Design
Patients with advanced solid tumors refractory to standard therapy were eligible. In cohorts of escalating doses, patients received azacitidine for 5 days from days 1 to 5, VPA for 7 days from days 5 to 11, and carboplatin starting in the second cycle on days 3 and 10. Clinical correlates included evaluation of epigenetic changes, methylation patterns, and histone acetylation levels in peripheral blood mononuclear cells.
Results
Thirty-two patients were treated. The MTD was 75 mg/m2 azacitidine, 20 mg/kg VPA, and AUC 3.0 carboplatin. Minor responses or stable disease lasting ≥4 months were achieved by six patients (18.8%), including three with platinum-resistant or platinum-refractory ovarian cancer. The most common adverse events grade ≥3 were fatigue (81%) and neutropenia (69%). Dose-limiting toxicity occurred in six patients (18.8%), including four patients with grade 3 altered mental status. Death receptor 4 (DR4) methylation was shown to decrease in a subset of patients, but there was no relationship with tumor response or number of cycles received.
Conclusions
Combination of azacitidine, VPA, and carboplatin demonstrates decreased DR4 methylation and modest evidence of antitumor activity in patients with heavily treated advanced malignancies.
doi:10.1007/s10637-013-0003-3
PMCID: PMC3809091  PMID: 23907406
azacitidine; valproic acid; carboplatin; methylation; histone deacetylase inhibition
10.  Outcomes of patients with advanced cancer and KRAS mutations in phase I clinical trials 
Oncotarget  2014;5(19):8937-8946.
Background
KRAS mutation is common in human cancer. We assessed the clinical factors, including type of KRAS mutation and treatment, of patients with advanced cancer and tumor KRAS mutations and their association with treatment outcomes.
Methods
Patients referred to the Phase I Clinic for treatment who underwent testing for KRAS mutations were analyzed.
Results
Of 1,781 patients, 365 (21%) had a KRAS mutation. The G12D mutation was the most common mutation (29%). PIK3CA mutations were found in 24% and 10% of patients with and without KRAS mutations (p<0.0001). Of 223 patients with a KRAS mutation who were evaluable for response, 56 were treated with a MEK inhibitor-containing therapy and 167 with other therapies. The clinical benefit (partial response and stable disease lasting ≥ 6 months) rates were 23% and 9%, respectively, for the MEK inhibitor versus other therapies (p=0.005). The median progression-free survival (PFS) was 3.3 and 2.2 months, respectively (p=0.09). The respective median overall survival was 8.4 and 7.0 months (p=0.38). Of 66 patients with a KRAS mutation and additional alterations, higher rates of clinical benefit (p=0.04), PFS (p=0.045), and overall survival (p=0.02) were noted in patients treated with MEK inhibitor-containing therapy (n=9) compared to those treated with targeted therapy matched to the additional alterations (n=24) or other therapy (n=33).
Conclusions
MEK inhibitors in patients with KRAS-mutated advanced cancer were associated with higher clinical benefit rates compared to other therapies. Therapeutic strategies that include MEK inhibitors or novel agents combined with other targeted therapies or chemotherapy need further investigation.
PMCID: PMC4253408  PMID: 25313136
Personalized medicine; Phase I; Clinical trials; Targeted therapy; Molecular alterations
11.  Survival of 1,181 Patients in a Phase I Clinic: The MD Anderson Clinical Center for Targeted Therapy Experience 
Background
In order to determine if the Royal Marsden Hospital (RMH) prognostic score for phase I patients can be validated in a large group of individuals seen in a different center, and if other prognostic variables are also relevant, we present an analysis of 1,181 patients treated in the MD Anderson Cancer Center (MDACC) Phase I clinic.
Methods
Medical records of 1,181 consecutive patients who were treated on at least one trial in the Phase I clinic were reviewed.
Results
The median age was 58 years and 50% were women. The median number of prior therapies was four; median survival, 10 months (95% CI-9.1 to 10.9 months). Independent factors that predicted shorter survival in a multivariate Cox model and could be internally validated included: RMH score >1 (p<0.0001) (albumin <3.5 mg/dL, LDH >upper limit of normal, and >2 sites of metastases); gastrointestinal tumor type (p<0.0001); and, ECOG performance status ≥1 (p=0.0004). The median survival was 24.0, 15.2, 8.4, 6.2 and 4.1 months for patients with 0, 1, 2, 3, and 4 or 5 of the above risk factors respectively.
Conclusion
The RMH score was validated in a large group of patients at MDACC. Internal validation of the independent prognostic factors for survival led to the development of the MDACC prognostic score, a modification of the RMH score that strengthens it.
doi:10.1158/1078-0432.CCR-11-2217
PMCID: PMC4176886  PMID: 22452943
ECOG performance status; Phase I trials; prognostic score; survival
12.  Bevacizumab-Based Treatment in Colorectal Cancer with a NRAS Q61K Mutation 
Targeted oncology  2013;8(3):183-188.
Despite development of new therapies, metastatic colorectal cancer (mCRC) largely remains an incurable disease. Approximately 2–6% of colorectal cancers harbor NRAS mutations. The anti-VEGF antibody bevacizumab is a backbone of most therapeutic regimens; however, biomarkers predicting its activity are not known. We report two cases of mCRC with a Q61K NRAS mutation that had a favorable response to bevacizumab and the histone deacetylase inhibitor valproic acid. In contrast, none of 10 patients with wild-type NRAS or unknown NRAS status and mutated KRAS (NRAS and KRAS mutations are mutually exclusive) responded to the same regimen. These results suggest that NRAS mutation merits further investigation as a potential biomarker predicting the efficacy of bevacizumab-based treatment.
doi:10.1007/s11523-013-0266-9
PMCID: PMC3766504  PMID: 23400451
NRAS mutation; Colorectal cancer; Bevacizumab; Q61K
13.  Phase I Study of BIIB028, a selective heat shock protein 90 inhibitor, in patients with refractory metastatic or locally advanced solid tumors 
Purpose
Heat shock protein 90 (Hsp90) is a ubiquitous molecular chaperone involved in protein folding, activation, and assembly, including key mediators of signal transduction, cell cycle control, and transcriptional regulation. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of BIIB028, a prodrug designed to inhibit Hsp90 activity.
Patients and Methods
Patients with advanced solid tumors were enrolled and received escalating doses of BIIB028 intravenously twice a week in 21-day cycles (3+3 design). Response was evaluated after 2 cycles.
Results
Forty-one patients received doses of 6 to 192 mg/m2. The maximum tolerated dose was 144 mg/m2. Dose-limiting toxicities were syncope (n=1) and fatigue (n=1). Common toxicities at least possibly related to drug were grade 1–2, including fatigue (46%), diarrhea (44%), nausea (44%), vomiting (29%), hot flushes (29%) and abnormal dreams (17%). The concentration-time curves for Day 1 and Day 18 for both prodrug and active metabolite (CF2772) showed a negligible difference. There was a dose-dependent increase in plasma exposure for BIIB028 (CF3647) and CF2772 with plasma half-life of 0.5 and 2.1 hours, respectively. Pharmacodynamic analyses demonstrated significant increases in Hsp70 in peripheral blood mononuclear cells and significantly decreased circulating human epidermal growth factor receptor 2- extracellular domain in all patients who received BIIB028 at dose levels ≥48mg/m2. Stable disease for at least 8 cycles (24 weeks) was achieved in 5 (12%) patients (6, 6, 8, 12.5 and 19 months).
Conclusion
BIIB028 is a well-tolerated molecule that demonstrated target impact and was associated with prolonged stable disease in 2 patients.
doi:10.1158/1078-0432.CCR-13-0477
PMCID: PMC3935614  PMID: 23873691
Biomarker; hsp90; BIIB028; Phase I trial; Malignancy
14.  Phase I Study of Anti-VEGF Monoclonal Antibody Bevacizumab and Histone Deacetylase Inhibitor Valproic Acid in Patients with Advanced Cancers 
Purpose
Anti-angiogenic agents combined with histone deacetylase inhibitors act synergistically in vitro and in vivo. We conducted a phase I study of the combination of the anti-VEGF monoclonal antibody bevacizumab and histone deacetylase inhibitor valproic acid in patients with advanced cancers.
Methods
Bevacizumab was administered at escalating doses of 2.5–11 mg/kg on days 1 and 15, and oral valproic acid at doses of 5.3–10 mg/kg on days 1–28 every 28 days to determine the maximum tolerated dose (MTD). Pharmacodynamic (PD) parameters were assessed in peripheral blood mononuclear cells (histone H3 acetylation) and serum (valproic acid levels).
Results
Fifty-seven patients were enrolled. Dose-limiting toxicities were grade 3 altered mental status (n=2), related to valproic acid. Bevacizumab 11 mg/kg given on days 1 and 15 and valproic acid 5.3 mg/kg daily was the recommended phase II dose. Stable disease (SD) ≥ 6 months was reported in 4/57 (7%) of patients, including 2 patients with colorectal cancer who had progressed previously on bevacizumab. Of the 39 patients evaluated for histone acetylation, 2 of 3 (67%) patients with SD ≥ 6 months showed histone acetylation, while 8 of 36 (22%) without SD ≥ 6 months demonstrated histone acetylation (p=0.16). Patients with any grade of hypertension, compared to others, had a prolonged median survival (11.1 months versus 5.8 months; p=0.012).
Conclusions
The combination of bevacizumab 11 mg/kg and valproic acid 5.3 mg/kg is safe in patients with advanced malignancies, with activity in colorectal, gastroesophageal junction and prostate cancer. Patients with hypertension had improved overall survival.
doi:10.1007/s00280-014-2384-1
PMCID: PMC4148903  PMID: 24435060
bevacizumab; histone deacetylase; hypertension; VEGF; valproic acid
15.  Combining Erlotinib and Cetuximab is Associated with Activity in Patients with Non Small Cell Lung Cancer (including Squamous Cell Carcinomas) and Wild-Type EGFR or Resistant Mutations 
Molecular cancer therapeutics  2013;12(10):2167-2175.
Preclinical data suggest that combined epidermal growth factor receptor (EGFR) targeting with an EGFR tyrosine kinase inhibitor and an anti-EGFR monoclonal antibody may be superior over single-agent targeting. Therefore, as part of a phase I study, we analyzed the outcome of 20 patients with non-small cell lung cancer treated with the combination of erlotinib and cetuximab. EGFR mutation status was ascertained in a CLIA-approved lab. There were 10 men; median number of prior therapies, 5. Overall, 2 of 20 patients (10%) achieved partial response (PR), one of whom had a TKI-resistant EGFR insertion in exon 20, time to treatment failure (TTF) = 24+ months; and, the other patient had squamous cell histology (EGFR wild-type), TTF=7.4 months. In addition, 3 of 20 patients (15%) achieved stable disease (SD) ≥6 months (one of whom had wild-type EGFR and squamous cell histology, and two patients had an EGFR TKI-sensitive mutation, one of whom had failed prior erlotinib therapy). Combination therapy with ertotinib plus cetuximab was well tolerated. The most common toxicities were rash, diarrhea, and hypomagnesemia. The recommended phase II dose was erlotinib 150 mg oral daily and cetuximab 250 mg/m2 IV weekly. In summary, erlotinib and cetuximab treatment was associated with SD ≥6 months/PR in 5 of 20 patients with non-small cell lung cancer (25%), including individuals with squamous histology, TKI-resistant EGFR mutations, and wild-type EGFR, and those who had progressed on prior erlotinib after an initial response. This combination warrants further study in select populations of non-small cell lung cancer.
doi:10.1158/1535-7163.MCT-12-1208
PMCID: PMC4138057  PMID: 23963360
cetuximab; EGFR; erlotinib; NSCLC; resistance
16.  Novel Secondary Somatic Mutations in Ewing's Sarcoma and Desmoplastic Small Round Cell Tumors 
PLoS ONE  2014;9(8):e93676.
Background
Ewing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are small round blue cell tumors driven by an N-terminal containing EWS translocation. Very few somatic mutations have been reported in ES, and none have been identified in DSRCT. The aim of this study is to explore potential actionable mutations in ES and DSRCT.
Methodology
Twenty eight patients with ES or DSRCT had tumor tissue available that could be analyzed by one of the following methods: 1) Next-generation exome sequencing platform; 2) Multiplex PCR/Mass Spectroscopy; 3) Polymerase chain reaction (PCR)-based single- gene mutation screening; 4) Sanger sequencing; 5) Morphoproteomics.
Principal Findings
Novel somatic mutations were identified in four out of 18 patients with advanced ES and two of 10 patients with advanced DSRCT (six out of 28 (21.4%));KRAS (n = 1), PTPRD (n = 1), GRB10 (n = 2), MET (n = 2) and PIK3CA (n = 1). One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment. One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression.
Conclusions
We have reported several different mutations in advanced ES and DSRCT that have direct implications for molecularly-directed targeted therapy. Our technology agnostic approach provides an initial mutational roadmap used in the path towards individualized combination therapy.
doi:10.1371/journal.pone.0093676
PMCID: PMC4131855  PMID: 25119929
17.  Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer 
Oncoscience  2014;1(8):540-549.
Preclinical studies demonstrate that epidermal growth factor receptor (EGFR) signals through both kinase-dependent and independent pathways and that combining a small-molecule EGFR inhibitor, EGFR antibody, and/or anti-angiogenic agent is synergistic. We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with metastatic colorectal cancer was analyzed for safety and antitumor activity. Forty-one patients with heavily pretreated metastatic colorectal cancer received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (68%), hypomagnesemia (37%), and fatigue (15%). Thirty of 34 patients (88%) treated at the full FDA-approved doses of all three drugs tolerated treatment without drug-related dose-limiting effects. Eleven patients (27%) achieved stable disease (SD) ≥6 months and three (7%) achieved a partial response (PR) (total SD>6 months/PR= 14 (34%)). Of the 14 patients with SD≥6 months/PR, eight (57%) had received prior sequential bevacizumab and cetuximab, two (5%) had received bevacizumab and cetuximab concurrently, and four (29%) had received prior bevacizumab but not cetuximab or erlotinib (though three had received prior panitumumab). The combination of bevacizumab, cetuximab, and erlotinib was well tolerated and demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer.
PMCID: PMC4278330  PMID: 25594061
Erolotinib; Cetuximab; Bevacizumab; EGFR; VEGF
18.  Clinical characteristics and outcomes of pediatric oncology patients with aggressive biology enrolled in phase I clinical trials designed for adults: The university of Texas MD Anderson cancer center experience 
Oncoscience  2014;1(7):522-530.
Background
Children (patients ≤ 18 years of age) are not usually included on pharmaceutical industry sponsored Phase I trials.
Methods
We reviewed the medical records of 40 patients ≤ 18 years treated in ≥ 1 phase I trial at MD Anderson.
Results
The median OS was 8.5 months (95% CI, 5.5-13.2 months). In the multivariate analysis, age ≥15 only predicted increased OS (P = 0.0065), and >3 prior therapies (P = 0.053) predicted decreased OS. The median PFS was 2.8 months (95% CI, 2.3-4.1 months). In the multivariate analysis, independent factors that predicted increased PFS were age ≥15 years (P < 0.001) and prior radiation therapy (P = 0.049); performance status >1 (P < 0.001) and >3 prior therapies (P = 0.002) predicted decreased PFS. RMH score ≥ 2 and MDACC score ≥ 3 were associated with decreased median OS (P = 0.029 and P = 0.031 respectively).
Conclusions
It is feasible to conduct phase I studies in pediatric patients based on adult protocols. In the era of targeted therapy more trials should allow pediatric patients earlier in the drug development especially if deemed safe in adults in early phase trials.
Translational Relevance
Most pharmaceutical industry sponsored trials exclude patients less than 18 years in phase I clinical trials. Even in the era of targeted therapy pediatric patients usually have to wait for most phases of trials to be completed in adults before being allowed to enroll in clinical trials of new therapies, even in the advanced metastatic and relapsed setting. Some investigator initiated phase 1 trials of combinations of US FDA approved agents allow patients less than 18 years. We report the preliminary analyses of the outcomes of pediatric patients enrolled in phase I studies initially designed for adults, but allowing for enrollment of patients under 18.
PMCID: PMC4278323  PMID: 25587555
phase I trials; children; prognostic scores; targeted therapy
19.  Activity of the MEK Inhibitor Trametinib (GSK1120212) in Advanced Melanoma in a Phase I, Dose-escalation Trial 
The lancet oncology  2012;13(8):782-789.
Summary
Purpose
The mitogen-activated extracellular signal-related kinase kinase (MEK) is a member of the RAS/RAF/MEK/ERK signalling cascade, which is commonly activated in melanoma. Direct inhibition of MEK inhibits ERK signalling.
Methods
We conducted a multicentre, first-in-human, three-part study (dose escalation, cohort expansion, and pharmacodynamic evaluation) to evaluate the oral small-molecule MEK inhibitor trametininb (GSK1120212) in advanced cancer. Intermittent and continuous dosing regimens were evaluated. Safety and efficacy data in patients with melanoma are presented here, with exploratory analyses of available tumour tissues performed on an Illumina genotyping platform. This completed study is registered with ClinicalTrials.gov, number NCT00687622.
Findings
Ninety-seven melanoma patients, including 81 with cutaneous or unknown primary melanoma (36 BRAF-mutant, 39 BRAF wild-type, six BRAF status unknown) and 16 uveal melanoma patients were enrolled. The most common treatment-related adverse events were rash/dermatitis acneiform (80 out of 97; 82%) and diarrhoea (n=44; 45%), most of which were grade 2 or lower. No cutaneous squamous cell carcinomas were observed. Among the 36 BRAF-mutant patients, 30 were BRAF-inhibitor naïve. Among these 30 patients, 2 complete responses (CRs) and 10 partial responses (PRs) were observed (unconfirmed response rate=40%) including 2 confirmed CRs and 8 confirmed PRs (confirmed response rate=33%); the median progression-free survival was 5·7 months (95% CI, 4·0–7·4). Among the 6 BRAF-mutant patients who received prior BRAF inhibitor therapy, 1 unconfirmed PR was observed. Among 39 patients with BRAF wild-type melanoma, 4 PRs (all confirmed) were observed (confirmed response rate=10%).
Conclusions
To our knowledge, this is the first demonstration of substantial clinical activity by a MEK inhibitor in melanoma. These data suggest that MEK is a valid therapeutic target.
doi:10.1016/S1470-2045(12)70269-3
PMCID: PMC4109286  PMID: 22805292
20.  It’s About Time: Lessons For Solid Tumors From Chronic Myelogenous Leukemia Therapy 
Molecular cancer therapeutics  2012;11(12):2549-2555.
The use of imatinib in chronic myelogenous leukemia (CML) transformed the disease, rapidly changing the median survival from 4 years to at least 20 years. In this review, we outline the causes of this revolution, including the identification of a critical driving molecular aberration--BCR-ABL--and the development of a potent and specific inhibitor--imatinib. Equally important was the timing of the targeted therapy, specifically its administration to patients with newly diagnosed disease. In solid tumors, targeted therapies are often both developed and used in metastatic malignancies after conventional approaches have failed.
We postulate that this strategy is similar to using imatinib in blast crisis CML, where response rates are <15%, all patients relapse, and median survival remains only about one year. We hypothesize that the imatinib-led revolution in CML, including the critically important factor of timing, may be applicable to other cancers as well. Therefore, it will be important to utilize promising targeted therapies in the earliest phases of biomarker-defined solid tumors, prior to metastatic progression, to determine if outcomes can be significantly improved, and hence establish if the success of imatinib in CML is an anomaly or a paradigm.
doi:10.1158/1535-7163.MCT-12-0473
PMCID: PMC4107422  PMID: 23204432
Cancer; chronic myelogenous leukemia; early stage cancer; imatinib; targeted therapy; time
21.  Merkel Cell Polyomavirus and HPV-17 Associated with Cutaneous Squamous Cell Carcinoma Arising in a Melanoma Patient Treated with a BRAF Inhibitor 
JAMA dermatology  2013;149(3):322-326.
Background
Approximately 10–25% of patients treated with BRAF inhibitors develop cutaneous squamous cell carcinoma (SCC), but the mechanism responsible has not yet been determined. We report the first case in which Merkel cell polyomavirus (MCPyV) and HPV-17 are associated with cutaneous SCC which developed during treatment with BRAF inhibitor GSK2118436.
Observations
A 62 year-old woman with V600E BRAF-mutant metastatic melanoma enrolled on a phase I trial of GSK2118436, a selective inhibitor of V600-mutant BRAF kinase. During the first six weeks of treatment, the patient developed multiple skin lesions, including a 6-mm crusted papule on the left eyebrow, which was resected and revealed SCC. DNA extracted from paraffin-embedded tissue was amplified by polymerase chain reaction (PCR) for detection of MCPyV and epidermodysplasia verruciformis HPV (EV-HPV) types. Analysis of the cloned and sequenced PCR products revealed the presence of MCPyV and HPV-17 DNA. Other EV-HPV subtypes were not detected.
Conclusions
To our knowledge, this is the first report demonstrating the co-existence of MCPyV and HPV-17 in cutaneous SCC. Because both viruses have known oncogenic potential, the role of these viruses in the etiology of BRAF inhibitor-related SCC merits further investigation.
doi:10.1001/jamadermatol.2013.2023
PMCID: PMC4085990  PMID: 23552670
22.  Impact of decitabine on immunohistochemistry expression of the putative tumor suppressor genes FHIT, WWOX, FUS1 and PTEN in clinical tumor samples 
Clinical Epigenetics  2014;6(1):13.
Background
Since tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) and phosphatase and tensin homolog (PTEN), immunohistochemistry scores from pre- and post-decitabine tumor biopsies (25 patients) were correlated with methylation of the long interspersed nuclear element-1 (LINE-1) repetitive DNA element (as a surrogate for global DNA methylation) and with tumor regression.
Results
With negative staining pre-decitabine (score = 0), the number of patients converting to positive staining post-decitabine was 1 of 1 for FHIT, 3 of 6 for WWOX, 2 of 3 for FUS1 and 1 of 10 for PTEN. In tumors with low pre-decitabine tumor suppressor gene scores (≤150), expression was higher post-treatment in 8 of 8 cases for FHIT (P = 0.014), 7 of 17 for WWOX (P = 0.0547), 7 of 12 for FUS1 (P = 0.0726), and 1 of 16 for PTEN (P = 0.2034). If FHIT, WWOX and FUS1 were considered together, median pre- versus post-decitabine scores were 60 versus 100 (P = 0.0002). Overall, tumor suppressor gene expression change did not correlate with LINE-1 demethylation, although tumors converting from negative to positive had a median decrease in LINE-1 methylation of 24%, compared to 6% in those not converting (P = 0.069). Five of 15 fully evaluable patients had reductions in tumor diameter (range 0.2% to 33.4%). Of these, three had simultaneous increases in three tumor suppressor genes (including the two patients with the greatest tumor regression) compared to 2 of 10 with tumor growth (P = 0.25).
Conclusions
In tumors with low tumor suppressor gene expression, decitabine may be associated with increased expression of the tumor suppressor genes FHIT, FUS1, and WWOX, but not PTEN.
doi:10.1186/1868-7083-6-13
PMCID: PMC4094901  PMID: 25024751
Decitabine; FHIT; FUS1; WWOX; PTEN; Tumor suppressor genes; LINE-1 methylation
23.  BRAF V600E mutations in urine and plasma cell-free DNA from patients with Erdheim-Chester disease 
Oncotarget  2014;5(11):3607-3610.
Erdheim-Chester disease (ECD) is a rare histiocytosis with a high prevalence of BRAF V600E mutation (>50% of patients). Patients with BRAF-mutant ECD can respond to BRAF inhibitors. Unfortunately, the lack of adequate archival tissue often precludes BRAF testing. We hypothesized that cell-free DNA (cfDNA) from plasma or urine can offer an alternative source of biologic material for testing. We tested for BRAF V600E mutation in cfDNA from the plasma and urine of 6 ECD patients. In patients with available archival tissue, the result of BRAF mutation analysis was concordant with plasma and urine cfDNA results in all 3 patients (100% agreement, kappa 1.00). In all 6 patients, BRAF mutation analysis of plasma and urine cfDNA was concordant in 5 of 6 patients (83% agreement, kappa 0.67). Testing for BRAF V600E mutation in plasma and urine cfDNA should be further investigated as an alternative to archival tissue mutation analysis.
PMCID: PMC4116506  PMID: 25003820
BRAF; cell-free DNA; plasma; urine; Erdheim-Chester disease
24.  Characteristics and survival of patients with advanced cancer and p53 mutations 
Oncotarget  2014;5(11):3871-3879.
P53 mutations are associated with invasive tumors in mouse models. We assessed the p53mutations and survival in patients with advanced cancer treated in the Phase I Program. Of 691 tested patients, 273 (39.5%) had p53 mutations. Patients with p53 mutations were older (p<.0001) and had higher numbers of liver metastases (p=.005). P53 mutations were associated with higher numbers of other aberrations; PTEN (p=.0005) and HER2 (p=.003)aberrations were more common in the p53 mutation group. No survival difference was observed between patients with p53 mutations and those with wild-type p53. In patients with wild-type p53 and other aberrations, patients treated with matched-therapy against the additional aberrations had longer survival compared to those treated with non-matched-therapy or those who received no therapy (median survival, 26.0 vs. 11.8 vs. 9.8 months, respectively; p= .0007). Results were confirmed in a multivariate analysis (p= .0002). In the p53 mutation group with additional aberrations, those who received matched-therapy against the additional aberrations had survival similar to those treated with non-matched-therapy or those who received no therapy (p=.15). In conclusion, our results demonstrated resistance to matched-targeted therapy to the other aberrations in patients with p53 mutations and emphasize the need to overcome this resistance.
PMCID: PMC4116527  PMID: 25003695
p53 mutations; matched therapy; molecular aberrations
25.  Unique molecular signatures as a hallmark of patients with metastatic breast cancer: Implications for current treatment paradigms 
Oncotarget  2014;5(9):2349-2354.
Our analysis of the tumors of 57 women with metastatic breast cancer with next generation sequencing (NGS) demonstrates that each patient's tumor is unique in its molecular fingerprint. We observed 216 somatic aberrations in 70 different genes, including 131 distinct aberrations. The most common gene alterations (in order of decreasing frequency) included: TP53, PIK3CA, CCND1, MYC, HER2 (ERBB2), MCL1, PTEN, FGFR1, GATA3, NF1, PIK3R1, BRCA2, EGFR, IRS2, CDH1, CDKN2A, FGF19, FGF3 and FGF4. Aberrations included mutations (46%), amplifications (45%), deletions (5%), splices (2%), truncations (1%), fusions (0.5%) and rearrangements (0.5%), with multiple distinct variants within the same gene. Many of these aberrations represent druggable targets, either through direct pathway inhibition or through an associated pathway (via ‘crosstalk’). The ‘molecular individuality’ of these tumors suggests that a customized strategy, using an “N-of-One” model of precision medicine, may represent an optimal approach for the treatment of patients with advanced tumors.
PMCID: PMC4058010  PMID: 24811890
Genomics; Breast Cancer; PI3K; Clinical Trials

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