Erkut Borazanci

Pancreatic Cancer: “A Riddle Wrapped in a Mystery inside an Enigma”

Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult-to-treat cancers. With an increasing incidence and inability to make major progress, it represents the very definition of unmet medical need. Progress has been made in understanding the basic biology—systematic genomic sequencing has led to the recognition that PDAC is not typically a heavily mutated tumor, although there are exceptions. The most consistently mutated genes are KRAS, CDKN2A, TP53, and SMAD4/DPC4. Study of familial PDAC has led to the recognition that a variety of defects in DNA repair genes can be associated with the emergence of pancreatic cancer. Recent studies suggest that epigenetics may play a larger role than previously recognized. A major new understanding is the recognition that PDAC should be considered a composite of tumor cells, as well as pancreatic stellate cells, immune cells, and extracellular matrix. The individual components contribute to metabolic aberration, immune dysfunction, and chemotherapy resistance, and therapeutic innovations may be needed to address them individually. It has also been recognized that metastatic seeding from PDAC occurs very early in the disease course—in an estimated 73% of cases, once the tumor reaches 2 cm. The implication of this is that therapies directed toward micrometastatic disease and increasing fractional cell kill are most needed. Neoadjuvant approaches have been taken to increase resectability and improve outcome. So much work remains, and most critical is the need to understand how this tumor originates and develops. Clin Cancer Res; 23(7); 1629–37. ©2017 AACR. See all articles in this CCR Focus section, “Pancreatic Cancer: Challenge and Inspiration.”

Potential actionable targets in appendiceal cancer detected by immunohistochemistry, fluorescent in situ hybridization, and mutational analysis

BACKGROUND Appendiceal cancers are rare and consist of carcinoid, mucocele, pseudomyxoma peritonei (PMP), goblet cell carcinoma, lymphoma, and adenocarcinoma histologies. Current treatment involves surgical resection or debulking, but no standard exists for adjuvant chemotherapy or treatment for metastatic disease. METHODS Samples were identified from approximately 60,000 global tumors analyzed at a referral molecular profiling CLIA-certified laboratory. A total of 588 samples with appendix primary tumor sites were identified (male/female ratio of 2:3; mean age =55). Sixty-two percent of samples were adenocarcinomas (used for analysis); the rest consisted of 9% goblet cell, 15% mucinous; 6% pseudomyxoma, and less than 5% carcinoids and 2% neuroendocrine. Tests included sequencing [Sanger, next generation sequencing (NGS)], protein expression/immunohistochemistry (IHC), and gene amplification [fluorescent in situ hybridization (FISH) or CISH]. RESULTS Profiling across all appendiceal cancer histological subtypes for IHC revealed: 97% BRCP, 81% MRP1, 81% COX-2, 71% MGMT, 56% TOPO1, 5% PTEN, 52% EGFR, 40% ERCC1, 38% SPARC, 35% PDGFR, 35% TOPO2A, 25% RRM1, 21% TS, 16% cKIT, and 12% for TLE3. NGS revealed mutations in the following genes: 50.4% KRAS, 21.9% P53, 17.6% GNAS, 16.5% SMAD4, 10% APC, 7.5% ATM, 5.5% PIK3CA, 5.0% FBXW7, and 1.8% BRAF. CONCLUSIONS Appendiceal cancers show considerable heterogeneity with high levels of drug resistance proteins (BCRP and MRP1), which highlight the difficulty in treating these tumors and suggest an individualized approach to treatment. The incidence of low TS (79%) could be used as a backbone of therapy (using inhibitors such as 5FU/capecitabine or newer agents). Therapeutic options includeTOPO1 inhibitors (irinotecan/topotecan), EGFR inhibitors (erlotinib, cetuximab), PDGFR antagonists (regorafenib, axitinib), MGMT (temozolomide). Clinical trials targeting pathways involving KRAS, p53, GNAS, SMAD4, APC, ATM, PIK3CA, FBXW7, and BRAF may be also considered. Overall, appendiceal cancers have similar patterns in their molecular profile to pancreatic cancers (can we say this, any statistical analysis done?) and have differential expression from colorectal cancers. These findings indicate the need to evaluate patient samples for patterns in marker expression and alteration, in order to better understand the molecular biology and formulate a personalized therapy approach in these difficult to treat cancers (supported by a grant from Caris Life Sciences).

Adenosquamous carcinoma of the pancreas: Molecular characterization of 23 patients along with a literature review

Adenosquamous carcinoma of the pancreas (ASCP) is a rare entity. Like adenocarcinoma of the pancreas, overall survival is poor. Characteristics of ASCP include central tumor necrosis, along with osteoclasts and hypercalcemia. Various theories exist as to why this histological subtype exists, as normal pancreas tissue has no benign squamous epithelium. Due to the rarity of this disease, limited molecular analysis has been performed, and those reports indicate unique molecular features of ASCP. In this paper, we characterize 23 patients diagnosed with ASCP through molecular profiling using immunohistochemistry staining, fluorescent in situ hybridization, chromogenic in situ hybridization, and gene sequencing, Additionally, we provide a comprehensive literature review of what is known to date of ASCP. Molecular characterization revealed overexpression in MRP1 (80%), MGMT (79%), TOP2A (75), RRM1 (42%), TOPO1 (42%), PTEN (45%), CMET (40%), and C-KIT (10%) among others. One hundred percent of samples tested were positive for KRAS mutations. This analysis shows heretofore unsuspected leads to be considered for treatments of this rare type of exocrine pancreas cancer. Molecular profiling may be appropriate to provide maximum information regarding the patients tumor. Further work should be pursued to better characterize this disease.

Abstract LB-003: High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer

Background: The genomes of metastatic pancreatic cancers contain a myriad of intrachromosomal aberrations indicating a likely high prevalence of DNA repair deficiencies indicating sensitivity to DNA damaging agents such as the platinum’s. Because of this, the drug cisplatin was added to an albumin-bound paclitaxel + gemcitabine regimen, which has already been determined to improve survival over gemcitabine alone in a randomized phase III trial (NEJM 2013; 369:1691-1703). Objectives: To determine the efficacy and safety of albumin-bound paclitaxel and gemcitabine plus cisplatin for patients with advanced pancreatic cancer Methods: Eligibility criteria included Stage IV pancreatic cancer, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. The doses were albumin-bound paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. Results: To date, 10 patients have been entered on study with all patients being evaluable, (baseline and at least one follow up CT scans completed). There have been 2 complete responses (20%), 6 partial responses (PR), (60%), 1 stable disease (10%), and 1 patient with progressive disease (10%), by RECIST 1.1 criteria. An exponential decrease in CA19-9 correlating with the t1/2 of the marker was noted. Response was seen rapidly with PR observed at the first staging evaluation at 9 weeks in 7 of 10 patients. The 8th patient achieved a PR at 18 weeks. Serious adverse events occurred in 4 patients: non-neutropenic sepsis/pneumonia (n = 1), and non-neutropenic bacteremia (n = 1) in the cisplatin 25 mg/m2 cohort; clostridium difficile colitis (n = 1) with cisplatin 37.5 mg/m2; and neutropenic fever/pneumonia (n = 1) with cisplatin 50mg/m2. Discussion: The study has completed phase Ib and will be expanded at the phase II dose of cisplatin 25 mg/m2 for a total of 25 patients. If this favorable response rate is confirmed, this 3 drug regimen could be further developed both for patients with advanced disease as well as in neoadjuvant and adjuvant settings. Supported by grants from the Seena Magowitz Foundation and the SU2C Dream Team Citation Format: Gayle S. Jameson, Erkut Borazanci, Elizabeth Poplin, Michael T. Barrett, John Crowley, Adam Rosenthal, Amy Stoll-D9Astice, Karen L. Ansaldo, Steven Boone, Leticia Lebron, Ramesh K. Ramanathan, Ronald L. Korn, Daniel D. Von Hoff. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-003. doi:10.1158/1538-7445.AM2015-LB-003

Abstract CT140: Phase I dose escalation study of 177Lu-HuMab-5B1 (MVT-1075) in combination with MVT-5873 as radioimmunotherapy (RIT) in subjects with relapsed / refractory pancreatic cancer or other CA19-9+ malignancies

Objectives and Background: The study is designed to establish a recommended phase 2 dose (RP2D) for the treatment of CA19-9+ malignancies with MVT-1075/MVT-5873 radioimmunotherapy (RIT). 177Lu-CHX-A″-DTPA-HuMab-5B1 (MVT-1075) consists of the fully-human IgG1 mAb Mab-5B1 (MVT-5873) conjugated to CHX-A″-DTPA and radiolabelled with 177Lutetium (177Lu). MVT-5873 targets the sialyl Lewis A (sLea) epitope of CA19-9, which is often overexpressed in pancreatic (PDAC) and other GI cancers and is a marker of aggressive disease. 177Lu is a low-energy β-emitter (max. energy, 0.5 MeV) with relatively short tissue penetration (max. 1.6 mm) that also emits γ-radiation (113 keV, 7%; 208 keV, 11%) suitable for scintigraphic imaging and dosimetry. Methods: An RIT cycle comprises dosing on Days 1 and 15 with a 57 day DLT assessment period. On Day 1, a blocking dose of MVT-5873 70 mg IV is given followed 2-4 hours later by 50% of the MVT-1075 dose estimated to produce a Cohort-defined target bone-marrow exposure. Between Days 1 and 8, dosimetry is obtained with multiple gamma camera planar images and at least 1 SPECT/CT scan. On Day 15, a second MVT-5873 blocking dose is given followed by a dose of MVT-1075 calculated to complete the total bone-marrow exposure for the cycle. Key entry criteria include previously-treated locally-advanced or metastatic PDAC or other CA19-9+ malignancy (CA19-9 ≥ 1.5 x ULN or IHC+ biopsy) and ECOG PS ≤1. Up to 4 cycles of RIT are permitted provided safety criteria (e.g. allowable cumulative organ exposures, adequate resolution of toxicities, and permitted timing between cycles) are met. Trial endpoints include safety, MTD, dosimetry, pharmacokinetics (PK), tumor response, and changes in serum CA19-9 levels. Preliminary Data: As of 23-Jan-2018, data from Cycle 1 are available from 3 subjects in Cohort 1 (n = 4). Median age was 61 (range 60-61); all subjects had PDAC. The mean total dose in Cycle 1 was 60.4 mCi (range 54.6-96.7), calculated to deliver 0.5 Gy to bone marrow. Hematologic toxicities with MVT-1075/MVT-5873 by highest Grade (Gr) in subjects (n) were: WBC - Gr 1,2 (1,1); platelets - Gr 1,2,3 (1,1,1) and Hgb - Gr 1,2 (2,1). Non-hematologic AE9s included chills - Gr 1 (1), AST - Gr 1 (3), and ALT - Gr 1,2 (1,1). No responses were seen after one cycle. MVT-1075 dosimetry to bone marrow and other critical organs were compatible with predictions from human experience with 89Zr-DFO-HuMab-5B1 (MVT-2163). MVT-1075 median biologic half-times were 273 h, 4.7 h and 65 h for whole body, serum α, and serum β, respectively. Dosimetry data illustrate MVT-1075 accumulation on target lesions. Conclusions: RIT with MVT-1075/MVT-5873 was associated with manageable hematologic toxicities, consistent with predictions. MVT-1075 demonstrated target accumulation. Accrual is ongoing and dose escalation is planned. Citation Format: Eileen A. O9Reilly, Christian Lohrmann, Joseph A. O9Donoghue, Erkut Borazanci, Hayley Estrella, Rebecca Teng, Terri Melink, Kirsten Dorr, Christine Kearns, Marvin Peterson, Jack Ostrowski, John Gutheil, Paul W. Maffuid, Jason S. Lewis, Wolfgang Weber. Phase I dose escalation study of 177Lu-HuMab-5B1 (MVT-1075) in combination with MVT-5873 as radioimmunotherapy (RIT) in subjects with relapsed / refractory pancreatic cancer or other CA19-9+ malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT140.

Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma: Genetic Testing in Pancreatic Adenocarcinoma

The objective of this study was to investigate the prevalence of pathogenic germline variants (PGVs) in 32 cancer susceptibility genes in individuals with newly diagnosed pancreatic ductal adenocarcinoma (PDAC). A key secondary objective was to evaluate how often PGVs would have been undetected with existing genetic testing criteria.

Abstract CT153: First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640

Introduction FASN inhibition causes selective disruption of palmitate biosynthesis that, in tumor cells, leads to apoptosis. TVB-2640 is an oral, first-in-class, small molecule reversible inhibitor of FASN that demonstrated in vivo antitumor effects. We previously reported the results of dose escalation and now present evidence of activity in patients (pts) treated in the dose expansion cohorts. Methods This fully enrolled multicenter phase I trial included pts with advanced solid tumors. TVB-2640 was given PO once daily at the MTD (100 mg/m2) as monotherapy (mono) or in combination (combo) with weekly IV paclitaxel (80 mg/m2). Results The most common related AEs observed in both groups (mono, N=44, combo, N=43) included alopecia (41%), palmar-plantar erythrodysesthesia (PPE) (47%), and decreased appetite (13%). Additional common AEs in the mono group included dry skin (19%) and in the combo group included nausea (28%). Gr3 related AEs included decreased appetite (8%) and PPE (9%); all other related AEs were ≤ Gr2. All related AEs were reversible on dose interruption. No enhancement of paclitaxel toxicity was observed with TVB-2640. Pneumonitis in the combo arm was observed uncommonly (9%), but the contribution of TVB-2640 to this effect is uncertain. Pharmacokinetic analyses showed that TVB-2640 had a similar half-life whether given alone or in combo with paclitaxel. Clearance rates were similar on days 1 and 8 (or day 15 for combo). Multiple pharmacodynamic markers demonstrated potent inhibition of FASN and lipogenesis in pts. With respect to clinical activity, overall, 5 confirmed RECIST partial responses (cPR) were seen. Among pts with NSCLC, 18 of 31 were KRASmut, and KRASmut pts achieved longer progression-free survival on TVB-2640 monotherapy, with 60% of KRASmut pts vs. 0% of KRASwt pts on study > 12 wks. Among 18 KRASmut pts, 11 achieved prolonged SD (≥16 wks), including 6 mono pts (SD=19-46 wks) and 5 combo pts (SD=23-54 wks), whereas no KRASwt pts achieved prolonged SD. One NSCLC combo pt achieved cPR at wk 12 and remained on study for 39 wks. Of 14 breast cancer pts, 3 pts achieved cPR and 8 pts achieved prolonged SD (≥16 wks), despite extensive previous treatment, including taxane resistance. One ongoing breast cancer pt with SD, entering her 78th wk of treatment, discontinued paclitaxel at wk 35 and remains on monotherapy . One pt with peritoneal carcinoma (combo) achieved cPR and a 58% decrease in CA125. Reductions in CA125 were seen in 5 out of 12 ovarian cancer pts, who were typically heavily pretreated and taxane-resistant. Summary TVB-2640 demonstrated antitumor activity, including objective responses when combined with weekly paclitaxel, as well as prolonged SD as monotherapy or in combination with paclitaxel. Further studies are planned to evaluate the efficacy of TVB-2640 in NSCLC and breast cancer pts. Citation Format: Gerald Falchook, Manish Patel, Jeffrey Infante, Hendrik-Tobias Arkenau, Emma Dean, Andrew Brenner, Erkut Borazanci, Juanita Lopez, Kathleen Moore, Peter Schmid, Arthur Frankel, Suzanne Jones, William McCulloch, George Kemble, Howard Burris. First in human study of the first-in-class fatty acid synthase (FASN) inhibitor TVB-2640 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT153. doi:10.1158/1538-7445.AM2017-CT153

Abstract B18: Improving pancreatic cancer risk prediction through early detection

Introduction: It is estimated that by 2030 pancreatic cancer will be the second leading cause of cancer deaths in the US. Currently, only 9% of newly diagnosed pancreatic cancer is localized and 5-year survival is 7%. Due to most pancreatic cancers (PC) presenting at a later stage with poor overall survival, early detection methods must be implemented to improve treatment outcomes. Yet, effective early screening guidelines do not exist for pancreatic cancer. Our Early Detection Program (EDP) provides personalized early detection including risk assessment, screening, and genetic testing. We aim to evaluate risk assessment criteria, establish a database to delineate a pattern of characteristics, and utilize a biospecimen repository and molecular based technologies to map novel biomarkers for early detection. Methods: This is a prospective study for individuals with a family history or a germline mutation consistent with risk for developing PC. Patients are eligible based on risk assessment criteria and stratified into 3 groups as defined by best available evidence based upon the CAPS Consortium and a prior prospective screening study. Patients are assessed at initial visit, have yearly screenings, and each case is discussed at a multi-disciplinary pancreatic tumor board. At the initial visit, patients undergo a thorough history and physical exam, genetic testing for germline mutations, routine blood tests along with Ca19-9 tumor marker and if indicated, MRI/MRCP abdomen, GI consult and EUS. Patients defined as average risk have one family member diagnosed with PC above the age of 55 years. Those at moderate risk are individuals with two or more first, second, third degree relatives with PC or one first degree relative with PC diagnosed Results: Since the inception of the EDP (IRB approved November 2015), there have been no PC cases identified. Current participants include individuals age 34 to 79 with a mean age of 59. According to the current risk criteria 22% have a low PC risk, 26% have a moderate risk, and 52% have a high PC risk. All were advised a genetic assessment. Of the current sample, 36% were male and 64% were female, 55% used tobacco in the past, and 9% currently use tobacco. The BMI average is 26.85 (overweight), 2 participants have Type 2 diabetes, and several have had other types of cancer such as: 5% breast, 2% colon, 2% ovarian, 1% thyroid, and 38% had basal cell skin cancer. 26% had germline mutations and 10% with intraductal papillary mucinous neoplasm (IPMN). Initial results reveal there is a level of anxiety associated with PC risk and some indicate their chance to develop cancer is high (M = 5.05, SD = 1.80). Compared to other people, participants stated their chance of getting cancer sometime in their life is a little higher (M = 4.10, SD = .85), and their ability to exercise control over their cancer risk was moderate (M = 2.6, SD .93). Conclusions: Although the EDP is still recruiting patients, the effectiveness of our screening for PC has revealed some encouraging outcomes. Next-generation sequencing (NGS) and molecular based technologies will be explored for mapping novel biomarkers for early detection in a clinical study. The Institute is expanding to also include those at risk for breast and ovarian cancer. We will be evaluating risk assessment criteria and also current anxiety scales. A product of this study will be the development of a valid and reliable EDP index (EDP-I) anxiety instrument. Citation Format: Courtney Snyder, Susan G. Haag, Nickie Adams, Jade Hess, Breann Paskett, Erkut Borazanci. Improving pancreatic cancer risk prediction through early detection. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr B18.

Abstract B42: Ibrutinib in combination with durvalumab (MEDI4736) in patients with relapsed or refractory HER2-positive or triple-negative breast cancer: A phase 1b/2 multicenter study

Abstracts: AACR Special Conference: Advances in Breast Cancer; October 17-20, 2015; Bellevue, WA Purpose: HER2+ and triple-negative (TN) breast cancers (BC) are associated with an aggressive course and poor prognosis, with currently available treatments yielding low response rates and decreased progression-free survival (PFS) due to a high relapse rate, rapid disease progression, and development of resistance. Hence, novel agents with efficacy and a tolerable safety profile are needed for this challenging patient (pt) population. Ibrutinib is a first-in-class, oral inhibitor of Brutons tyrosine kinase (BTK), which is a crucial signaling molecule in the B-cell receptor pathway. It has demonstrated robust clinical activity in B-cell malignancies. In preclinical studies, ibrutinib inhibited tyrosine phosphorylation of ErbB and ErbB2 in HER2- positive BC cell lines, thereby suppressing AKT and MAPK signaling (Elias, 2013; Grabinski, 2014). Programmed death-ligand 1 (PD-L1) is a molecule associated with inhibition of antitumor T cell immunity (Zou, 2008; Keir, 2008), and is highly expressed in TNBC (Tessari, 2014; Mittendorf, 2014). Durvalumab (MEDI4736) is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 (IC50 of 0.1nM) and CD80/B7.1 (IC50 of 0.04 nM) (Ibrahim, 2015). Durvalumab has shown promising clinical activity with an acceptable safety profile across multiple solid tumors (Fury, 2014; Segal, 2014; Antonia, 2014). The combination of an anti–PD-L1 antibody and ibrutinib suppressed tumor growth in mouse models of solid tumors, and led to enhanced antitumor T-cell immune responses (Sagiv-Barfi, 2015). Based on these encouraging preclinical data, the PCYC-1135 trial ([NCT02403271][1]) was initiated to test the safety and efficacy of ibrutinib plus durvalumab in pts with relapsed/refractory (R/R) Stage III/IV BC (both HER2+ and TNBC), as well as non-small cell lung cancer (NSCLC), and pancreatic cancer. This abstract focuses on the BC cohort enrolling in the trial. Methods: A total of 130–160 pts (BC, NSCLC, and pancreatic) will be enrolled in this Phase 1b/2 study. Key eligibility criteria for the BC cohort include pathologically confirmed BC (HER2+ or TN), R/R disease (Stage III or IV) failing at least 2 prior therapies, measurable lesion by RECIST 1.1, and adequate hematologic, hepatic, and renal function. Key exclusion criteria include central nervous system involvement, antitumor therapy within 21 days of study initiation, prior treatment with ibrutinib or other BTK inhibitors, and/or anti-PD1, anti–PD-L1, anti–PD-L2, anti–CD137 or anti–CTLA-4 antibody, a history of allogeneic organ transplant, or treatment with a strong cytochrome P4503A inhibitor. The primary objectives are safety, tolerability, and efficacy as assessed by overall response rate. Secondary endpoints are disease control rate, duration of response, PFS, overall survival, and pharmacokinetics and pharmacodynamic assessments of the combination. The Phase 1b will assess dose-limiting toxicities (DLTs) and will determine the recommended phase 2 dose (RP2D) of ibrutinib plus durvalumab. The starting dose level of ibrutinib is 560 mg daily, with the potential for subsequent dose level reductions if DLTs occur, in combination with durvalumab 10 mg/kg IV every 2 weeks in 28-day cycles until DLT or disease progression. Enrollment in phase 2 will commence at the RP2D, accruing a total of 130–160 pts (Phase 1b + Phase 2). Ibrutinib and durvalumab will be administered until unacceptable toxicity or disease progression. Enrollment began in March 2015. Citation Format: Drew W. Rasco, Erkut Borazanci, Martin Guiterrez, David Hong, Ahmed Tawashi, Jennifer Lin, Isaiah W. Dimery, Mark Fosdale. Ibrutinib in combination with durvalumab (MEDI4736) in patients with relapsed or refractory HER2-positive or triple-negative breast cancer: A phase 1b/2 multicenter study. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research; Oct 17-20, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(2_Suppl):Abstract nr B42. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02403271&atom=%2Fmolcanres%2F14%2F2_Supplement%2FB42.atom

Abstract CT024: First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors

Background: DS-6051b is an orally available small molecule receptor tyrosine kinase inhibitor with high affinity for the ROS1 and NTRK receptors. Non-clinical pharmacology studies demonstrated activity of DS-6051b against tumors harboring ROS1 or NTRK fusion genes in cell culture and xenograft models. The objectives of this first in human (FIH) study are to assess safety and tolerability of DS-6051b in cancer subjects and identify the maximum tolerated dose (MTD) and the tentative RP2D. Pharmacokinetics (PK), QT prolongation, and tumor responses are also assessed in this study (Clinical Trial Information: NCT02279433). Methods: Dose escalation initially followed an accelerated titration design enrolling a single subject at each dose level, and then adopted the modified continuous reassessment method using a Bayesian logistic regression model and escalation with overdose control. Adult subjects with advanced solid tumors harboring ROS1 or NTRK1-3 fusion genes; or with neuroendocrine carcinoma; or with advanced solid tumors with tumor-induced pain are eligible for the study. DS-6051b is orally administered once-daily in 21-day cycles. Tumor assessments are performed every 3 cycles using RECIST 1.1 criteria. Plasma PK samples and time-matched ECG data are collected at multiple time points. Results: A total of 22 subjects have been enrolled at 50, 100, 200, 400, 800, and 1200 mg once daily (QD) dose levels. Enrolled population included 11 subjects with neuroendocrine carcinomas, 9 subjects with advanced solid tumors with tumor-induced pain, 1 subject with ROS1 fusion-positive NSCLC liver metastases, and 1 subject with leiomyosarcoma with a ROS1 point mutation. Two dose-limiting toxicities occurred in subjects who received 1200 mg QD, consisting of grade 3 transaminase elevations. The MTD is 800 mg QD. The most frequent (?20%) TEAEs were diarrhea, nausea, vomiting, dehydration, dizziness, dysgeusia, and fatigue, which were predominantly grade ?2. Cmax and AUC increased with the dose. Plasma terminal half-life was 11-24 hours. Steady state AUC was approximately 3 to 4-fold higher than that of Cycle 1 Day 1. Two subjects showed partial response: One with neuroendocrine carcinoma, who received 800 mg QD (33% decrease in tumor size), and one with ROS1 fusion-positive NSCLC liver metastases, who received 1200 mg QD (44% decrease in tumor size). Notably, the latter subject had progressed on crizotinib (best objective response stable disease) and ceritinib (progressive disease). Conclusions: DS-6051b has been well tolerated up to 800 mg QD in subjects with advanced solid tumors. The observed efficacy signals in two subjects with partial response warrant further evaluation. This trial is now selectively accruing subjects with ROS1 fusion-positive tumors. Citation Format: Kyriakos P. Papadopoulos, Erkut Borazanci, Daniel Von Hoff, Leena Gandhi, Amita Patnaik, Masaya Tachibana, Hamim Zahir, Roohi Gajee, Terri Goldberg, Giorgio Senaldi, Sai-Hong Ou. First-in-human phase 1 dose-escalation study of DS-6051b, an oral ROS1 and NTRK inhibitor, in subjects with advanced solid tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT024.