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.

482 Background: Tumor suppressor proteins (TSPs) are inactivated by their export from the nucleus by Exportin1 (XPO1/CRM1). The oral selective inhibitor of nuclear export selinexor (KPT-330)restores the nuclear localization and function of TSPs and shows a broad anti-tumor activity in animal models. Here we report on the treatment of a subset of patients (pts) with metastatic colorectal cancer (CRC) in a phase I trial of selinexor. Methods: Objectives were to determine the recommended phase 2 dose, evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and tumor response (RECIST 1.1) of selinexor administered in two different schedules with 8 or 10 doses in a 28-day cycle. An expansion cohort of 15 pts with CRC was planned. Results: Twenty-seven pts with CRC were treated across eight doses (3-40 mg/m2) including 15 pts in the expansion cohort (30-35 mg/m2). Median age was 61 yrs and median number of prior regimens was 4. MTD of the 10-dose schedule was 30 mg/m2. MTD for the 8-dose schedule has not been reached. Thirteen pts experienced drug related gr 3-4 adverse events (AEs) including fatigue (n = 6), hyponatremia (n = 5), thrombocytopenia (n = 3), anorexia (n = 3), dehydration (n = 2), anemia (n = 2), hyperglycemia (n = 1), pulmonary embolism (n = 1), and hypotension (n = 1). The most common gr 1-2 drug related AEs were nausea (74 %), anorexia (67 %), fatigue (67 %), vomiting (59 %), dysgeusia (52 %), and weight loss (48 %). Cmax increased with dose to ≈ 1.4 µM with T½ of 4.0 – 7.4 hrs. Significant increases (2-20x) in PD marker XPO1 mRNA in circulating leukocytes were observed at all doses. Analysis of tumor biopsies confirmed nuclear localization of TSPs and induction of apoptosis following selinexor. CEA decreased in 4 of 12 pts. One pt had a partial response at 23 mg/m2, 6 patients had stable disease ≥8 weeks, and 3 patients had stable disease ≥24 weeks in 25 evaluable pts Conclusions: Preliminary signals of antitumor activity in CRC pts were observed. Selinexor is generally well tolerated and prolonged drug exposure is feasible. Selinexor induces Exportin in leucocytes and apoptosis in tumor biopsies with restoration of the nuclear location of TSPs. Clinical trial information: NCT01607905.

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 Brünner, 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.

Patients' decisions regarding participation in phase 1 trials are based on more than the information of the trial. The way patients express the information they have been given could be limited by the applied methods for evaluating this variable. While relatives are expected to be resources for patients entering a phase 1 trial, this topic has not been investigated.

PurposeThis study investigated the safety and clinical activity of lumretuzumab, a humanised antihuman epidermal growth factor receptor 3 (HER3) monoclonal antibody, in combination with carboplatin and paclitaxel in first-line treatment of patients with squamous non-small cell lung cancer (sqNSCLC). HER3 ligand heregulin and HER3 protein expression were evaluated as potential biomarkers of clinical activity.Patients and methodsThis open-label, phase Ib/II study enrolled patients receiving lumretuzumab at 800 mg (flat) in combination with carboplatin (area under the curve (AUC) 6 mg/mL×min) and paclitaxel (200 mg/m2) administered intravenously on a every 3-week schedule. Adverse event (AE) rates and tumour responses were determined. Heregulin messenger RNA (mRNA) and HER3 protein expression were investigated in archival tumour biopsies.ResultsAltogether, 12 patients received lumretuzumab in combination with carboplatin and paclitaxel. The most frequent AEs were gastrointestinal, haematological and nervous system toxicities, which were generally mild and manageable. Partial responses were observed in 3 of 12 patients lasting 81, 177 and 207 days. All responses were achieved in tumours expressing higher heregulin mRNA levels.ConclusionLumretuzumab in combination with carboplatin and paclitaxel was well tolerated. Objective responses were enriched in tumours expressing higher heregulin mRNA levels.

2556 Background: Agents that generate breaks in DNA are frequently used as cancer therapeutics. These agents induce different forms of DNA damage including double-strand breaks (DSBs), which are the most lethal if left unrepaired. M3814 targets tumor cell growth and survival by inhibiting DNA-PK, which is part of a critical DSB DNA damage repair mechanism. The purpose of the phase I, first in man trial was to evaluate the dose-limiting toxicity (DLT), establish a recommended phase II dose (RP2D), and assess the pharmacokinetic (PK) profile and single-agent clinical activity of M3814. Methods: Patients (pts) with potential aberrations in the DNA-damage and repair systemwere included. A standard 3+3 design was implemented with a starting dose of M3814 of 100 mg once daily, determined based on non-clinical safety. M3814 was given continuously and DLT was evaluated after 3 weeks. Throughout the trial rich PK sampling was taken. Tumor evaluation was performed every second cycle and treatment continued until progression, unacceptable toxicity, pt wish, or physician decision. Results: A total of 25 pts were enrolled at 6 dose levels (DL). Three pts were enrolled per DL, except at 300 and 400 mg BID where 9 and 4 pts were enrolled, respectively. At 300 mg BID one DLT (several low grade adverse events [AEs] lasting > 1 week) was seen. No DLTs were observed at 400 mg BID, which was declared as the RP2D; further dose escalation was not possible due to an impurity in the drug. An additional 6 pts were included at the RP2D. The most frequent AEs were nausea, vomiting, decreased appetite, constipation, diarrhea, pyrexia, fatigue, and rash, all seen in > 20% of pts. No pts discontinued due to AE and no grade 4 AEs were reported. Six pts (20%) had stable disease for at least 18 weeks; no pt had a partial remission. PK analysis demonstrated high variability of exposure with a tendency for skin rash in pts with the highest exposure. Conclusions: M3814 was found to be safe and tolerable at doses up to 400 mg BID, with limited single-agent activity in the studied population. Clinical evaluation of M3814 is ongoing in combination with radiotherapy as well as chemo-radiotherapy and planned in combination with chemotherapy. Clinical trial information: NCT02316197.

BACKGROUND: Selecting patients for early clinical trials is a challenging process and clinicians lack sufficient tools to predict overall survival (OS). Circulating cell-free DNA (cfDNA) has recently been shown to be a promising prognostic biomarker. The aim of this study was to investigate whether baseline cfDNA measurement could improve the prognostic information of the Royal Marsden Hospital (RMH) score. METHODS: Solid tumour patients referred for phase I trials were included in the Copenhagen Personalized Oncology (CoPPO) programme. Baseline characteristics were collected prospectively, including the RMH prognostic score, Eastern Cooperative Oncology Group (ECOG) performance status and concentration of cfDNA per millilitre plasma. Cox proportional hazards model was used to assess the prognostic value of baseline variables. RESULTS: Plasma cfDNA concentration was quantifiable in 302 patients out of a total of 419 included in the study period of 2 years and 5 months. The RMH score was confirmed to be associated with OS. Cell-free DNA was shown to be an independent prognostic marker of OS and improved the risk model, including RMH, performance status and age. Furthermore, both plasma cfDNA concentration and RMH score were associated with treatment allocation (p < 0.00001). CONCLUSION: Our model based on RMH score, age, ECOG performance status and cfDNA improved prediction of OS and constitutes a clinically valuable tool when selecting patients for early clinical trials. An interactive version of the prognostic model is published on http://bit.ly/phase1survival.

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