Morten Mau-Soerensen

First-in-Class, First-in-Human Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Patients With Advanced Solid Tumors

Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.

444OPHASE IB TRIAL TRIAL OF RG7116, A GLYCOENGINEERED MONOCLONAL ANTIBODY TARGETING HER3, IN COMBINATION WITH CETUXIMAB OR ERLOTINIB IN PATIENTS WITH ADVANCED/METASTATIC TUMORS OF EPITHELIAL CELL ORIGIN EXPRESSING HER3 PROTEIN

ABSTRACT Aim: To evaluate the safety profile of RG7116 in combination with cetuximab or erlotinib. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. RG7116 plus cetuximab (400u2003mg/m2 followed by 250u2003mg/m2 qw IV) and RG7116 plus erlotinib (150u2003mg/day p.o.) combinations were evaluated in a dose escalation study with “3 + 3” design at a starting dose of 400u2003mg IV of RG7116 in a q2w regimen. Results: Twenty-seven pts were enrolled in 5 cohorts (400 to 2000u2003mg) in the cetuximab arm. One dose-limiting toxicity (DLT) of grade 3 dehydration was reported in the 800-mg cohort. Twenty-seven pts were enrolled in 4 cohorts (400 to 2000u2003mg) in the erlotinib arm. One DLT was reported in the 1600-mg cohort (grade 3 diarrhea and grade 3 hypokalemia) and one DLT was reported in the 2000-mg cohort (grade 3 blood bilirubin increase). No maximum tolerated dose was reached. The most frequently reported adverse events of any grade were diarrhea (78%) and rash (59%) for the cetuximab arm and diarrhea (82%) and decreased appetite (48%) for the erlotinib arm. In the erlotinib arm treatment-related grade 3 diarrhea was observed more frequently at higher doses of RG7116 (400u2003mg: 0%; 800u2003mg: 17%; 1600u2003mg: 43%; 2000u2003mg: 33%). Overall, infusion-related reactions related to RG7116 occurred in 11% of pts. Two of these were grade 3 (4%). The pharmacokinetic profile of RG7116 in combination with cetuximab and erlotinib was comparable to that in the monotherapy setting (Meulendijks et al. J Clin Oncol 31, 2013 suppl; abstr 2522). HER3 membranous protein down-regulation was observed from 400u2003mg onwards in on-treatment tumor and skin tissue. In the cetuximab arm, two pts with colorectal carcinoma had a confirmed partial response (PR). In the erlotinib arm, one patient with ovarian carcinoma had a confirmed PR. Metabolic PR on FDG-PET occurred in 42% of pts in the cetuximab arm and in 28% of pts in the erlotinib arm. Conclusions: RG7116 combination with cetuximab or erlotinib was well tolerated, and demonstrated preliminary signs of clinical activity. Disclosure: U.N. Lassen: discloses Research grants from Roche; A. Cervantes Ruiperez: discloses Research grants, advisory boards and lectures for Roche; C. Adessi, A. Keelara, F. Michielin, B. Bossenmaier, G. Meneses-Lorente, I. James, W. Jacob and M. Weisser: Employee of Roche. All other authors have declared no conflicts of interest.

Abstract A116: Targeting the Wnt-5a signaling pathway as a novel anti-metastatic therapy

Most current anti-cancer therapeutic drugs are targeting the proliferation and/or survival of cancer cells while very few drugs are aimed at specifically targeting the dissemination process. Several reports have demonstrated that low-levels or lack of Wnt-5a protein expression in primary breast-, colon-, and prostate cancer tissues correlates with shortened patient recurrence-free survival and overall survival pointing to a biological role of Wnt5a signaling in the dissemination process of cancer cells. The Wnt5a ligand mediates its effects vid interaction with G-protein coupled Frizzled receptors and tyrosine-kinase coupled receptors such as ROR1 and ROR2. Therefore, we developed two peptides, one being a Wnt-5a agonist (Foxy-5) and one being a Wnt-5a antagonist (Box-5). The Foxy-5 is a formylated Wnt5a-derived hexapeptide that mimics the ability of the Wnt-5a molecule to impair cancer cell migration in vitro and significantly reduces the formation of distant metastases in vivo in mouse models of breast- and prostate cancer. In addition, a 4-week toxicology study in rats and dogs with a final dose well exceeding the dose previously used in the mouse models showed no drug-induced toxic reactions.Based on all these pre-clinical data we initiated a clinical phase 1 study with the primary objective to evaluate the safety and tolerability of Foxy-5. All eligible patients are pre-screened for Wnt-5a immunoreactivity in archival tumor tissue and from dose level 7 and onwards only patients with negative or low level Wnt5a expressing metastatic breast-, colon-, or prostate cancer are enrolled in the study. This study has currently recruited cohorts 1-7 without reaching MTD and the final recruitment for the last dose level (dose level 8) is ongoing. Clinical trial information: NCT02020291. This study will be finalized during early fall 2015 and followed by a phase 1b study which will continue dose escalation but with a specific focus on determining the Biological Active Dose (BAD) since Foxy-5 does not possess anti-proliferative activities and is therefore not expected to induce tumor regression. In contrast to breast, colon and prostate cancer, Wnt5a signaling promotes tumor progression in vitro in melanoma and gastric cancer. The antagonistic Wnt5a-derived peptide Box5 possesses the capacity to impair Wnt5a signaling and migration in melanoma cells. We are now performing additional pre-clinical experiments to enable us to test the in vivo effects of Box5 in a melanoma animal model. Future clinical development plans include a phase II study enrolling patients with stage III colorectal cancer and then add Foxy-5 to standard 5FU plus oxaliplatin adjuvant treatment. Citation Format: Tommy Andersson, Lena Axelsson, Purusottam Mohapatra, Chandra Prasad, Peter Grundtvig Soerensen, Morten Mau-Soerensen, Ulrik Lassen, Tine Molvadgaard, Ulla Buhl, Nils Brunner, Dorte Nielsen. Targeting the Wnt-5a signaling pathway as a novel anti-metastatic therapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A116.

Abstract 3701: Phase II study of BIBF1120 in recurrent glioblastoma multiforme

Background: BIBF 1120, a potent, orally available triple angiokinase inhibitor targeting VEGFR 1-3, PDGFR- α/-α, and FGFR 1-3, has shown promising clinical activity with a good safety profile in patients with advanced non-small cell lung cancer or ovarian cancer. The specific and simultaneous abrogation of these three pathways results in effective growth inhibition of both endothelial and perivascular cells. This may be more effective than inhibition of endothelial cell growth via the VEGF pathway alone. In addition, signalling via FGF-receptors has been identified as a possible escape mechanism for tumour angiogenesis when the VEGF pathway is disrupted. Recurrent glioblastomas (GBM) have an extremely poor prognosis and consequently new and innovative therapies are still needed. Accordingly, the purpose of this study was to assess the efficacy and safety of BIBF 1120 in two parallel groups of patients with recurrent GBM after radiotherapy and temozolomide (STD) or the same regimen and subsequent bevacizumab based therapy (BEV). Methods: Patients were included in one of two parallel groups depending of prior exposure to bevacizumab (STD or BEV). Inclusion critieria included recurrent GBM, PS 0-1, normal organ function, available archival tissue blocks, and measurable disease according to RANO guidelines. A total of 32 patients were to be enrolled in each group in a two-stage design including a stopping rule if less than 4/16 patient responded. BIBF-1120 was administered orally 200 mg bid, with weekly plasma sampling for the first 4 weeks and MRI assessement every 8 weeks. Primary endpoint was objective response rate. Secondary endpoints were safety, PFS and plasma and tissue biomarkers. Results: The study was prematurely stopped for after inclusion of 13 patients in the STD arm and 12 patients in the BEV arm. No objective responses were seen in either arm. One patient in the BEV arm has had stable disease for 8 months while the remainder of the patients in both arms progressed within the first 4 cycles. BIBF-1120 was very well tolerated with no observed grade III or IV adverse events. Most frequent adverse events were grade I-II hypertension, diarrhoea and fatigue, with a frequency of Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3701. doi:1538-7445.AM2012-3701

Patient information in phase 1 trials: A systematic review

To review what is known about cancer patients decisions to enter a phase 1 trial and how they and their relatives perceive the information they receive when they are invited to participate.

Actionable targets in recurrent bile duct and pancreatic cancer in a prospective cohort of patients evaluated by whole exome sequencing and SNP array analysis.

e23256Background: No standard therapy exists for recurrent bile duct cancer. In this study, we characterized actionable targets in patients with recurrent bile duct- and pancreatic cancer included ...

Dynamics of mutant BRAF V600E in free circulating DNA (fcDNA) of non-melanoma cancer patients (pts) in response to treatment with BRAF and MEK/EGFR inhibitors.

11531Background: Therapies targeting mutant BRAF V600E have changed practice in the treatment of metastatic melanoma and are currently tested in other malignancies. Treatment response can be monito...