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// Jennifer B. Goldstein 1 , Chad Tang 2 , Kenneth R. Hess 3 , David Hong 4 , Vivek Subbiah 4 , Filip Janku 4 , Siqing Fu 4 , Daniel D. Karp 4 , Aung Naing 4 , Apostolia Maria Tsimberidou 4 , Jennifer Wheler 4 , Ralph Zinner 4 , Milind Javle 5 , Gauri R. Varadhachary 5 , Robert A. Wolff 5 , David R. Fogelman 5 , Funda Meric-Bernstam 4 and Sarina A. Piha-Paul 4 1 Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 5 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Correspondence to: Jennifer B. Goldstein, email: jbgoldstein@mdanderson.org Keywords: pancreatic cancer, phase I trial, biomarker, chemotherapy, targeted therapy Received: November 02, 2016 Accepted: July 17, 2017 Published: August 03, 2017 ABSTRACT Background: In 2011, we reported the outcomes of pancreatic cancer (PC) patients enrolled in phase I trials at our institution from 2004 through 2009. At the time, gemcitabine and erlotinib were the only Food and Drug Administration-approved drugs for PC and median overall survival (OS) from consultation in the phase I clinic was 5 months. We sought to determine the impact of novel therapeutics on PC patients in phase I trials. Methods: We reviewed records of PC patients treated in phase I trials at our institution from January 2009 through December 2014. Survival was analyzed using the Kaplan-Meier method. Results: Ninety-five patients were identified. The median age was 61 years (range, 40-84), 59% were men, and 41% had stage IV disease. The median OS from consultation in the phase I clinic was 5.8 months (95% confidence interval [CI], 4.5-6.8), and the 1-year OS rate was 9% (95% CI, 4%-17%). Three patients had partial responses and 18 had stable disease ≥ 4 months. Conclusion: We observed no improvement in OS between PC patients enrolled in phase I trials in 2004-2009 and 2009-2015. To substantially improve OS in this challenging disease, improved patient selection and science-driven, innovative trial designs will be key.

// Ming-Mo Hou 1, 3, * , Zhijie Wang 4, * , Filip Janku 1 , Sarina Piha-Paul 1 , Aung Naing 1 , David Hong 1 , Shannon Westin 2 , Robert L. Coleman 2 , Anil K. Sood 2 , Apostolia M. Tsimberidou 1 , Vivek Subbiah 1 , Jennifer Wheler 1 , Ralph Zinner 1 , Karen Lu 2 , Funda Meric-Bernstam 1 , Siqing Fu 1 1 Departments of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 2 Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 3 Division of Hematology-Oncology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan 4 Department of Thoracic Medical Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital & Beijing Institute for Cancer Research, Beijing, China * These authors have contributed equally to this work Correspondence to: Siqing Fu, e-mail: siqingfu@mdanderson.org Keywords: epithelial ovarian cancer, anti-angiogenesis, tumor progression, progression-free survival, overall survival Received: March 01, 2016 Accepted: April 10, 2016 Published: April 27, 2016 ABSTRACT High-grade epithelial ovarian cancer (HG-EOC) is the most lethal gynecologic malignancy worldwide Once patients develop chemoresistance, effective novel strategies are required to improve prognosis We analyzed characteristics and outcomes of 242 consecutive patients with HG-EOC participating in 94 phase I clinical trials at The University of Texas MD Anderson Cancer Center. Baseline lactate dehydrogenase levels, albumin levels, and number of metastatic sites were independent predictors of overall survival (OS). Receiving more than 1 phase I protocol was associated with improved OS (p < 0.001). Regimens including a chemotherapeutic agent plus bevacizumab or Aurora A kinase inhibitor led to a median progression-free survival (PFS) duration of more than 6 months. Although patients receiving bevacizumab-based regimens in the phase I clinical trials had significantly longer PFS than those receiving other anti-angiogenic therapies (p = 0.017), patients treated with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) had significantly longer OS (12.2 months) than those not treated with VEGFR-TKIs (8.6 months, p = 0.015). In conclusion, anti-angiogenic therapy is one of the most important strategies for the treatment of HG-EOC, even in those who have already experienced tumor progression. Therefore, eligible patients with HG-EOC should be encouraged to participate in novel phase I studies of anti-angiogenic therapies, even after disease progression.

// Xiaochun Liu 1 , Susan Kambrick 1 , Siqing Fu 1 , Aung Naing 1 , Vivek Subbiah 1 , George R. Blumenschein 2 , Bonnie S. Glisson 2 , Merrill S. Kies 2 , Apostolia M. Tsimberidou 1 , Jennifer J. Wheler 1 , Ralph G. Zinner 1 , David S. Hong 1 , Razelle Kurzrock 3 and Sarina A. Piha-Paul 1 1 Department of Investigational Cancer Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas, USA 2 Department of Thoracic/Head & Neck Medical Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA 3 Division of Hematology and Oncology, University of California San Diego, Moores Cancer Center, San Diego, CA, USA Correspondence to: Sarina A. Piha-Paul, email: // Keywords : solid tumors, bevacizumab, cetuximab, temsirolimus Received : August 20, 2015 Accepted : February 05, 2016 Published : February 24, 2016 Abstract BACKGROUND: Bevacizumab and temsirolimus are active agents in advanced solid tumors. Temsirolimus inhibits mTOR in the PI3 kinase/AKT/mTOR pathway as well as CYP2A, which may be a resistance mechanism for cetuximab. In addition, temsirolimus attenuates upregulation of HIF-1α levels, which may be a resistance mechanism for bevacizumab. RESULTS: The median age of patients was 60 years (range, 23-80 years). The median number of prior systemic therapies was 3 (range, 1-6). The maximum tolerated dose (MTD) was determined to be bevacizumab 10 mg/kg biweekly, temsirolimus 5 mg weekly and cetuximab 100/75 mg/m2 weekly. Grade 3 or 4 toxicities were seen in 52% of patients with the highest prevalence being hyperglycemia (14%) and hypophosphatemia (14%). Eighteen of the 21 patients were evaluable for response. Three patients were taken off the study before restaging for toxicities. Partial response (PR) was observed in 2/18 patients (11%) and stable disease (SD) lasting ≥ 6 months was observed in 4/18 patients (22%) (total = 6/18 (33%)). In 8 evaluable patients with squamous cell carcinoma of the head and neck (HNSCC) there were partial responses in 2/8 (25%) patients and SD ≥ 6 months in 1/8 (13%) patients (total = 3/8, (38%)). PATIENTS AND METHODS: We analyzed safety and responses in 21 patients with advanced solid tumors treated with bevacizumab, cetuximab, and temsirolimus. CONCLUSION: The combination of bevacizumab, cetuximab, and temsirolimus showed activity in HNSCC; however, there were numerous toxicities reported, which will require careful management for future clinical development.

// Jennifer J. Wheler 1 , Stacy L. Moulder 2 , Aung Naing 1 , Filip Janku 1 , Sarina A. Piha-Paul 1 , Gerald S. Falchook 1 , Ralph Zinner 1 , Apostolia M. Tsimberidou 1 , Siqing Fu 1 , David S. Hong 1 , Johnique T. Atkins 1 , Roman Yelensky 3 , Philip J. Stephens 3 , Razelle Kurzrock 4 1 Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, Houston, TX 2 Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 3 Foundation Medicine, Cambridge, MA 4 Center for Personalized Cancer Therapy, Moores Cancer Center, University of California, San Diego, La Jolla, CA Correspondence: Jennifer J Wheler, email: // Keywords : Anastrozole, Breast Cancer, Everolimus, Gynecologic Cancer, Hormone therapy Received : January 22, 2014 Accepted : March 12, 2014 Published : March 14, 2014 Abstract Background: Since PI3K/AKT/mTOR pathway activation diminishes the effects of hormone therapy, combining aromatase inhibitors (anatrozole) with mTOR inhibitors (everolimus) was investigated. Patients and Methods: We evaluated anastrozole and everolimus in 55 patients with metastatic estrogen (ER) and/or progesterone receptor (PR)-positive breast and gynecologic tumors. Endpoints were safety, antitumor activity and molecular correlates. Results: Full doses of anastrozole (1 mg PO daily) and everolimus (10 mg PO daily) were well tolerated. Twelve of 50 evaluable patients (24%) (median = 3 prior therapies) achieved stable disease (SD) ≥ 6 months/partial response (PR)/complete response (CR) (n = 5 (10%) with PR/CR): 9 of 32 (28%) with breast cancer (n=5 (16%) with PR/CR); 2 of 10 (20%), ovarian cancer; and 1 of 6 (17%), endometrial cancer. Six of 22 patients (27%) with molecular alterations in the PI3K/AKT/mTOR pathway achieved SD ≥ 6 months/PR/CR. Six of 8 patients (75%) with SD ≥ 6 months/PR/CR with molecular testing demonstrated at least one alteration in the PI3K/AKT/mTOR pathway: mutations in PIK3CA (n=3) and AKT1 (n=1) or PTEN loss (n=3). All three responders (CR (n = 1); PR (n=2)) who had next generation sequencing demonstrated additional alterations: amplifications in CCNE1, IRS2, MCL1, CCND1, FGFR1 and MYC and a rearrangement in PRKDC. Conclusions: Combination anastrozole and everolimus is well tolerated at full approved doses, and is active in heavily-pretreated patients with ER and/or PR-positive breast, ovarian and endometrial cancers. Responses were observed in patients with multiple molecular aberrations. Clinical Trails Included: NCT01197170

// Gerald S. Falchook 1 , Aung Naing 1 , David S. Hong 1 , Ralph Zinner 1 , Siqing Fu 1 , Sarina A. Piha-Paul 1 , Apostolia M. Tsimberidou 1 , Sonia K. Morgan-Linnell 1 , Yunfang Jiang 1 , Christel Bastida 1 , Jennifer J. Wheler 1 , and Razelle Kurzrock 2 1 Department of Investigational Cancer Therapeutics (Phase I Program), U.T. MD Anderson Cancer Center, Houston, TX 2 Moores Cancer Center at the University of California, San Diego Correspondence: Gerald Falchook, email: // Keywords : Erlotinib, Cetuximab, Bevacizumab, EGFR, VEGF Received : December 06, 2012, Accepted : January 12, 2013, Published : January 14, 2013 Abstract BACKGROUND: Preclinical data indicate 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 in animal models. METHODS: We conducted a dose-escalation, phase I study combining erlotinib, cetuximab, and bevacizumab. The subset of patients with non-small cell lung cancer (NSCLC) was analyzed for safety and response. RESULTS: Thirty-four patients with NSCLC (median four prior therapies) received treatment on a range of dose levels. The most common treatment-related grade ≥2 adverse events were rash (n=14, 41%), hypomagnesemia (n=9, 27%), and fatigue (n=5, 15%). Seven patients (21%) achieved stable disease (SD) ≥6 months, two achieved a partial response (PR) (6%), and two achieved an unconfirmed partial response (uPR) (6%) (total=32%). We observed SD≥6 months/PR/uPR in patients who had received prior erlotinib and/or bevacizumab, those with brain metastases, smokers, and patients treated at lower dose levels. Five of 16 patients (31%) with wild-type EGFR experienced SD≥6 months or uPR. Correlation between grade of rash and rate of SD≥6 months/PR was observed (p

The Abstract is incorrect in PubMed. The corrected Abstract is provided here.