Clinical next generation sequencing to identify actionable aberrations in a phase I program.

Purpose: We determined the frequency of recurrent hotspot mutations in 46 cancer-related genes across tumor histologies in patients with advanced cancer.

Methods: We reviewed data from 500 consecutive patients who underwent genomic profiling on an IRB-approved prospective clinical protocol in the Phase I program at the MD Anderson Cancer Center. Archival tumor DNA was tested for 740 hotspot mutations in 46 genes (Ampli-Seq Cancer Panel; Life Technologies, CA).

Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials.

Purpose: We report the experience with 2,000 consecutive patients with advanced cancer who underwent testing on a genomic testing protocol, including the frequency of actionable alterations across tumor types, subsequent enrollment onto clinical trials, and the challenges for trial enrollment.

Patients And Methods: Standardized hotspot mutation analysis was performed in 2,000 patients, using either an 11-gene (251 patients) or a 46- or 50-gene (1,749 patients) multiplex platform. Thirty-five genes were considered potentially actionable based on their potential to be targeted with approved or investigational therapies.

Dose-finding study of hepatic arterial infusion of irinotecan-based treatment in patients with advanced cancers metastatic to the liver.

Background: Liver metastases are associated with a poor prognosis. We investigated the use of hepatic arterial infusion (HAI) of irinotecan combination therapy in patients with liver metastases.

Patients And Methods: Patients with histologically confirmed advanced cancer with liver metastases that was refractory to standard therapy were eligible.

Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.

Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.

Proceedings from the Turner Resource Network symposium: the crossroads of health care research and health care delivery.

Turner syndrome, a congenital condition that affects ∼1/2,500 births, results from absence or structural alteration of the second sex chromosome. There has been substantial effort by numerous clinical and genetic research groups to delineate the clinical, pathophysiological, cytogenetic, and molecular features of this multisystem condition. Questions about the molecular-genetic and biological basis of many of the clinical features remain unanswered, and health care providers and families seek improved care for affected individuals.

Phase I combination of pazopanib and everolimus in PIK3CA mutation positive/PTEN loss patients with advanced solid tumors refractory to standard therapy.

Purpose: Combining agents that block both the VEGF and PI3K/AKT/mTOR pathways may be synergistic. We explored a novel dosing schedule to assess safety, toxicity and activity in patients with advanced solid tumors.

Patients And Methods: Patients with refractory solid tumors were enrolled in a modified 3 + 3 Phase I dose escalation study to determine dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a combination of everolimus (mTOR inhibitor) and pazopanib (tyrosine kinase inhibitor with anti-VEGF activity).

Next generation sequencing of exceptional responders with BRAF-mutant melanoma: implications for sensitivity and resistance.

Background: Patients with BRAF mutation-positive advanced melanoma respond well to matched therapy with BRAF or MEK inhibitors, but often quickly develop resistance.

Methods: Tumor tissue from ten patients with advanced BRAF mutation-positive melanoma who achieved partial response (PR) or complete response (CR) on BRAF and/or MEK inhibitors was analyzed using next generation sequencing (NGS) assay. Genomic libraries were captured for 3230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer and sequenced to average median depth of 734X with 99% of bases covered >100X.

A decision support framework for genomically informed investigational cancer therapy.

Rapidly improving understanding of molecular oncology, emerging novel therapeutics, and increasingly available and affordable next-generation sequencing have created an opportunity for delivering genomically informed personalized cancer therapy. However, to implement genomically informed therapy requires that a clinician interpret the patient's molecular profile, including molecular characterization of the tumor and the patient's germline DNA. In this Commentary, we review existing data and tools for precision oncology and present a framework for reviewing the available biomedical literature on therapeutic implications of genomic alterations.

Xilonix, a novel true human antibody targeting the inflammatory cytokine interleukin-1 alpha, in non-small cell lung cancer.

Background: Advanced non-small cell lung cancer (NSCLC) patients were treated as part of a Phase I dose escalation and expansion study evaluating a true human monoclonal antibody targeting IL-1α (Xilonix), which is intended to modulate the malignant phenotype-inhibiting tumor growth, spread and offering relief of symptoms.

Methods: Sixteen NSCLC patients were included. Patients failed a median of 4 chemotherapy regimens, including 10/16 failing anti-EGFR therapy.

Olanzapine for cachexia in patients with advanced cancer: an exploratory study of effects on weight and metabolic cytokines.

Background: Olanzapine is used for treatment of psychiatric conditions but causes substantial weight gain. This study assessed safety, efficacy, and changes in metabolic cytokines associated with olanzapine administration in patients with cachexia due to advanced cancer.

Methods: Patients with cancer-related cachexia were treated with olanzapine (doses ranging from 2.

Phase I trial of valproic acid and lenalidomide in patients with advanced cancer.

Purpose: The objectives of this study were to evaluate the tolerability and efficacy of valproic acid (VPA) and lenalidomide.

Methods: In this 3+3 design study, VPA was administered daily on a 7-day-on, 7-day-off schedule, and lenalidomide was administered daily for 28 days. Because of the response noted during the dose-escalation phase, 12 additional patients with adenoid cystic carcinoma (ACC) received the maximum tolerated dose (MTD) in a dose-expansion phase.

Dual EGFR inhibition in combination with anti-VEGF treatment in colorectal cancer.

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.

MET nucleotide variations and amplification in advanced ovarian cancer: characteristics and outcomes with c-Met inhibitors.

Purpose: MET alterations including amplifications and nucleotide variations have been associated with resistance to therapy and aggressive clinical behavior.

Experimental Design: The medical records of patients presenting to the University of Texas MD Anderson Cancer Center Phase I Clinic with relapsed or metastatic ovarian cancers and known MET nucleotide variation or amplification status were reviewed retrospectively (n=178). Categorical and continuous clinical and molecular characteristics were compared using Fisher's exact and Wilcoxon rank-sum tests, respectively.

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.

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.

Characteristics and outcomes for patients with advanced vaginal or vulvar cancer referred to a phase I clinical trials program: the MD Anderson cancer center experience.

Background: Early-stage vaginal and vulvar cancer can be cured. But outcomes of patients with metastatic disease are poor. Thus, new therapeutic strategies are urgently required.

Mutation profiling in cholangiocarcinoma: prognostic and therapeutic implications.

Background: Cholangiocarcinoma (CCA) is clinically heterogeneous; intra and extrahepatic CCA have diverse clinical presentations. Next generation sequencing (NGS) technology may identify the genetic differences between these entities and identify molecular subgroups for targeted therapeutics.

Methods: We describe successful NGS-based testing of 75 CCA patients along with the prognostic and therapeutic implications of findings.

Liquid biopsies in lung cancer: the new ambrosia of researchers.

In the last decades the approach to cancer patient management has been deeply revolutionized. We are moving from a "one-fits-all" strategy to the "personalized medicine" based on the molecular characterization of the tumor. In this new era it is becoming more and more clear that the monitoring of the disease is fundamental for the success of the treatment, thus there is the need of new biomarker discovery.

Targeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: A phase I clinical experience.

Background: Activated PI3K/AKT/mTOR pathway frequently occurs in metastatic or recurrent cervical carcinomas. However, the clinical benefits of matched therapy, a therapeutic approach targeting a specific mutational abnormality, have not yet been established.

Methods: We analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received ≥1 phase I therapeutic regimen between January 2006 and June 2013.

Targeting hypoxia-inducible factor-1α (HIF-1α) in combination with antiangiogenic therapy: a phase I trial of bortezomib plus bevacizumab.

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.

Dual antiangiogenic inhibition: a phase I dose escalation and expansion trial targeting VEGF-A and VEGFR in patients with advanced solid tumors.

Purpose: Angiogenesis plays a pivotal role in tumor growth and metastasis. Sorafenib, a tyrosine kinase inhibitor of vascular endothelial growth factor receptor (VEGFR), combined with bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF-A), would vertically inhibit VEGF/VEGFR signaling. A phase I trial was performed to assess safety, maximum tolerated dose (MTD), and clinical correlates.

Analysis of 1,115 patients tested for MET amplification and therapy response in the MD Anderson Phase I Clinic.

Purpose: This study aimed to assess MET amplification among different cancers, association with clinical factors and genetic aberrations and targeted therapy response modifications.

Experimental Design: From May 2010 to November 2012, samples from patients with advanced tumors referred to the MD Anderson Phase I Clinic were analyzed for MET gene amplification by FISH. Patient demographic, histologic characteristics, molecular characteristics, and outcomes in phase I protocols were compared per MET amplification status.

A phase I trial of combination trastuzumab, lapatinib, and bevacizumab in patients with advanced cancer.

Purpose: Preclinical data indicate that combination HER2-directed and anti-VEGF therapy may bypass resistance to trastuzumab. A phase I trial was performed to assess safety, activity, and correlates.

Experimental Design: Patients with advanced, refractory malignancy were enrolled (modified 3 + 3 design with expansions for responding tumor types).

Synergy between VEGF/VEGFR inhibitors and chemotherapy agents in the phase I clinic.

Purpose: We hypothesized that chemotherapy synergizes with VEGF/VEGFR (VEGF/R) inhibitors in patients with advanced solid malignancies.

Experimental Design: Patients treated on phase I protocols between December 2004 and July 2013 (n = 1,498) were included in this analysis. The primary outcome was clinical benefit, defined as stable disease ≥ 6 months, complete response, or partial response.