Mark Voskoboynik

Combination therapies for the treatment of advanced melanoma: A review of current evidence

The treatment of advanced melanoma has been revolutionised in recent years with the advent of a range of new therapies. BRAF inhibitors, such as vemurafenib, have demonstrated improvements in the overall survival of patients with advanced melanoma that harbour a BRAF V600 mutation. Alongside these targeted therapies, novel immune-checkpoint inhibitors, such as ipilimumab, have also been developed and have produced similarly improved outcomes for patients. For the first time in the history of melanoma, monotherapy with each of these drugs has produced improvements in the overall survival of patients with advanced disease. Building on this initial success, there has been intense interest in developing combination therapies predominantly with either dual blockade of the MAPK oncogenic pathway or dual immune-checkpoint blockade. The current evidence for the use of these combination therapies will be presented here.

'Charting a new course for prostate cancer' - currying favor for docetaxel in hormone-sensitive metastatic prostate cancer.

Docetaxel has an established role in the treatment of metastatic castrate-resistant prostate cancer. A number of recent treatments have been shown to improve the survival outcomes for this group of patients and many with improved toxicity profiles, bringing the role of docetaxel into question. We discuss the results and implications of the CHAARTED study that demonstrated a significant improvement in overall survival with docetaxel in metastatic hormone-sensitive prostate cancer.

SELECT-3: a phase I study of selumetinib in combination with platinum-doublet chemotherapy for advanced NSCLC in the first-line setting.

Background:We investigated selumetinib (AZD6244, ARRY-142886), an oral, potent, and highly selective, allosteric MEK1/2 inhibitor, plus platinum-doublet chemotherapy for patients with advanced/metastatic non-small cell lung cancer.Methods:In this Phase I, open-label study (NCT01809210), treatment-naïve patients received selumetinib (50, 75, 100 mg BID PO) plus standard doses of gemcitabine or pemetrexed plus cisplatin or carboplatin. Primary objectives were safety, tolerability, and determination of recommended Phase II doses.Results:Fifty-five patients received treatment: selumetinib 50 or 75 mg plus gemcitabine/cisplatin (n=10); selumetinib 50 mg plus gemcitabine/carboplatin (n=9); selumetinib 50, 75 or 100 mg plus pemetrexed/carboplatin (n=21); selumetinib 75 mg plus pemetrexed/cisplatin (n=15). Most frequent adverse events (AEs) were fatigue, nausea, diarrhoea and vomiting. Grade ⩾3 selumetinib-related AEs were reported in 30 (55%) patients. Dose-limiting toxicities (all n=1) were Grade 4 anaemia (selumetinib 75 mg plus gemcitabine/cisplatin), Grade 4 thrombocytopenia/epistaxis and Grade 4 thrombocytopenia (selumetinib 50 mg plus gemcitabine/carboplatin), Grade 4 febrile neutropenia (selumetinib 100 mg plus pemetrexed/carboplatin), and Grade 3 lethargy (selumetinib 75 mg plus pemetrexed/cisplatin). Partial responses were confirmed in 11 (20%) and unconfirmed in 9 (16%) patients.Conclusions:Standard doses of pemetrexed/carboplatin or pemetrexed/cisplatin were tolerated with selumetinib 75 mg BID. The selumetinib plus gemcitabine-containing regimens were not tolerated.

1242PA PHASE I STUDY OF THE MEK1/2 INHIBITOR SELUMETINIB IN COMBINATION WITH FIRST-LINE CHEMOTHERAPY REGIMENS FOR NSCLC

ABSTRACT Aim: Selumetinib (AZD6244, ARRY-142886) is an orally available MEK1/2 inhibitor with activity in combination with docetaxel in the second-line setting for KRAS mutation-positive advanced NSCLC. This Phase I study assessed the safety, tolerability, recommended Phase II combination dose (RP2D), pharmacokinetics (PK) and preliminary efficacy of selumetinib in combination with first-line chemotherapy regimens in unselected patients (pts) with advanced/metastatic NSCLC. Methods: This open-label, multicentre study (NCT01809210) enrolled pts into dose-finding cohorts of orally administered selumetinib (50 mg bid [sel50] to 75 mg bid [sel75]) in combination with standard doses of gemcitabine (gem) or pemetrexed (pem) plus cisplatin (cis) or carboplatin (carb). Each dose cohort consisted of at least 3 and up to 6 evaluable pts. On completion of chemotherapy, pts had the option of maintenance selumetinib. Results: As of 20 April 2014, 17 pts were evaluable (8 female; median age 63; 8 adenocarcinoma, 8 squamous, 1 non-squamous histology) to the following treatment cohorts: gem + cis + sel50, n = 3; gem + cis + sel75, n = 1; gem + carb + sel50, n = 7; pem + carb + sel50, n = 2; pem + carb + sel75, n = 4. Median total selumetinib exposure was 78 days (range 16–224). The majority of adverse events (AEs) were CTCAE Grade 1 or 2. Selumetinib-related AEs of Grade ≥3 were seen in 7 pts: gem + cis + sel50, 0/3; gem + cis + sel75, 0/1; gem + carb + sel50, 6/7; pem + carb + sel50, 1/2; pem + carb + sel75, 0/4. One DLT of thrombocytopenia was observed in the gem + carb + sel50 cohort. Combination therapy did not appear to show any marked effect on the PK profile of selumetinib. Across all cohorts, partial responses were seen in 6/17 (35%) pts evaluable for response, and 4/17 (24%) had stable disease. Conclusions: The AE profile of selumetinib in combination with these chemotherapy regimens for NSCLC was consistent with the known profiles. Two tolerated dose regimens have been confirmed: gem + cis + sel50 and pem + carb + sel50. The activity of platinum-based regimens seems to be preserved in this unselected population. Dose escalation and expansion is ongoing; updated data including the RP2D and PK will be presented. Disclosure: F. Blackhall: Research funding: AstraZeneca; R. Califano: Consultancy/honoraria: Roche, Lilly, Boehringer Ingelheim, Pfizer; D. Ghiorghiu: Employment and stock ownership: AstraZeneca; A. Dymond: Employment and stock ownership: AstraZeneca; I. Smith: Employment and stock ownership: AstraZeneca R. Plummer: Consultancy agreement (no remuneration to date): AstraZeneca. Institutional trial costs. All other authors have declared no conflicts of interest.

First-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640 as monotherapy or in combination - final results of dose escalation.

Introduction FASN inhibition is a novel approach to cancer treatment involving the 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 demonstrates in vitro and in vivo anti-tumor effects. We previously reported (EORTC-NCI-AACR 2014: 3 LBA, AACR/ASCO 2015: CT203/ TPS2615) on the design of this trial (NCT02223247) and now report on the final results of the dose escalation phase. Methods Patients from 7 US and 4 UK sites with adequate bone marrow, hepatic and renal function were enrolled. Patients with significant cardiovascular or ophthalmological disease and any conditions that might interfere with oral absorption were excluded. In addition to standard safety assessments and pharmacokinetic (PK) sampling, ophthalmological examinations and 24-hour Holter monitoring for QTc assessments were performed. Blood and tumor tissue (archival and/or fresh) for various pharmacodynamic (PD) assessments were obtained. Results Thirty-one patients were enrolled in 6 monotherapy cohorts (60 mg/m2 to 250 mg flat dose) and 13 patients were enrolled in 2 combination cohorts (200 and 250 mg flat dose) in combination with weekly paclitaxel (80 mg/m2, days 1, 8 and 15 q 28 days). Plasma TVB-2640 drug levels increased with dose, with a half-life of approximately 15 hr. The MTD was declared at 100 mg/m2 for both schedules. DLTs observed in both mono- and combination patients were reversible and consisted of corneal edema (Grade 3, n = 2), keratitis and iritis (Grade 2 and 3, n = 1 each), probably a consequence of disrupted tear film lipid metabolism, and palmar-plantar erythrodysesthesia or skin peeling (Grade 3, n = 3 and Grade 1, n = 1). Other toxicities were mild (≤ Grade 2) and only minor GI symptoms were observed; alopecia was reported by 63% of patients overall. No enhancement of known paclitaxel toxicity was observed when given in combination with TVB-2640. Of the 7 NSCLC patients accrued so far, 1 achieved SD for 17 weeks with monotherapy and 2 patients treated in combination with paclitaxel had SD for 24 and 21 weeks respectively. One of three breast cancer patients (histology: triple negative) treated in combination had SD for 20 weeks. One confirmed PR was seen in a combination-treated patient who had peritoneal serous carcinoma with a 42% reduction in tumor load and 58% reduction in CA-125 levels. PD biomarkers have been identified in tumor and in serum. In all four patients with paired tumor biopsies, decreased pAKT S473 was observed after 1 cycle compared to pretreatment biopsies. Global metabolic profiling of serum showed increased levels of malonyl carnitine, a malonyl coA derivative, and decreased tripalmitin, a palmitate derivative, in 9 of 10 patients tested, after 8 days of TVB-2640 treatment. These changes are consistent with FASN inhibition. Summary Continuously administered, oral TVB-2640 demonstrated a tolerated dose and schedule with a manageable toxicity profile in association with encouraging signs of preliminary activity both as monotherapy and in combination with paclitaxel. PD analyses reveal engagement of the target in both tumor and surrogate tissue. Further exploration of biological activity in various specific tumor types is now underway in expansion cohorts at the MTD using both schedules. Citation Format: Andrew Brenner, Jeffrey Infante, Manish Patel, Hendrik-Tobias Arkenau, Mark Voskoboynik, Erkut Borazanci, Gerald Falchook, L.R. Molife, Shubham Pant, Emma Dean, Lorraine Pelosof, Suzanne Jones, Chris Rubino, William McCulloch, Valentina Zhukova-Harrill, George Kemble, Marie O9Farrell, Howard A. Burris, III. First-in-human study of the first-in-class fatty acid synthase (FASN) inhibitor, TVB-2640 as monotherapy or in combination - final results of dose escalation. [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 A54.