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Grade 3 or 4 adverse events possibly related to refametinib or sorafenib, occurring in {greater than or equal to}2 patients in either cohort

Overview of dose-limiting toxicities and adverse events leading to discontinuation and relationship to study treatment

Refametinib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

Incidence of treatment-emergent adverse events, all grades, occurring in {greater than or equal to}20% of patients in either cohort

CTC enumeration and pERK analysis in course 1

pERK levels in hair follicles by dose level and course

Supplementary Figure 1. CONSORT diagram

Supplementary Tables. Supplementary Table 1. Pre-defined dose modification levels for sorafenib and refametinib Supplementary Table 2. Single-dose refametinib and its metabolite M17 geometric mean (% coefficient of variation) pharmacokinetic parameters on cycle 1 day −3 Supplementary Table 3. Multiple-dose refametinib and its metabolite M17, and sorafenib and its metabolite M2, geometric mean (% coefficient of variation) pharmacokinetic parameters on cycle 2 day 1 Supplementary Table 4. Incidence of treatment-emergent adverse events (occurring in {greater than or equal to}25% of patients), by CTCAE grade Supplementary Table 5. Incidence of adverse events related to refametinib and sorafenib (occurring in {greater than or equal to}15% of patients), by CTCAE grade Supplementary Table 6. Incidence of treatment-emergent serious adverse events (occurring in {greater than or equal to}2 patients), by CTCAE grades 2-5 Supplementary Table 7. Incidence of treatment-emergent serious adverse events (occurring in {greater than or equal to}2 patients) of CTCAE grades 3-5, related to both study drugs

Refametinib geometric mean (% coefficient of variation) single-dose pharmacokinetic data on day 1 of course 1

Sorafenib geometric mean (% coefficient of variation) multiple-dose pharmacokinetic data on day 1 of course 2

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177).Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability.Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients.Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AACR.

ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naive asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223. Patients were randomized to radium-223 (55 kBq/kg) or placebo once every 4 weeks (max. 6 cycles), and also received oral abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily during and after radium-223/placebo treatment, until a symptomatic skeletal event (SSE). The primary endpoint was SSE-free survival (SSE-FS); overall survival (OS) was a secondary endpoint. Of 806 patients randomized in ERA 223, 114 patients (57 per arm) were enrolled in Japan. SSE-FS was not improved significantly in the radium-223 arm [25.5 months, 95% CI 20.6–not estimated (NE)] compared with the placebo arm (28.7 months, 95% CI 19.7–NE) (HR = 0.907, 95% CI 0.501–1.642). OS and other secondary endpoints were not improved significantly in the radium-223 arm. The incidence of fracture was 23% and 11% in the radium-223 and placebo arms, respectively. The incidence of death was 32% and 36%, respectively. In the Japanese ERA 223 subgroup, concurrent treatment with AAP and radium-223 did not significantly improve SSE-FS and increased the incidence of fracture, similar to outcomes achieved in the overall population, while an increased incidence of death was not evident. The combination of radium-223 with AAP is not recommended in Japanese patients with asymptomatic or mildly symptomatic mCRPC and bone metastases. Clinical trial registration no: NCT02043678.

Aim Radium-223, a targeted alpha therapy, is approved widely for the treatment of patients with metastatic castrate-resistant prostate cancer, based on a pivotal phase 3 study in predominantly white patients. We investigated the efficacy and safety of radium-223 in Asian patients with castrate-resistant prostate cancer and metastatic bone disease. Methods This multicenter, prospective, single-arm, open-label phase 3 trial evaluated the efficacy and safety of the standard radium-223 regimen (55 kBq/kg every 4 weeks for six cycles) in patients from Asian countries. The primary endpoints were the safety and overall survival. Results A total of 226 patients were enrolled and received at least one dose of radium-223. Median overall survival was 14.0 months (95% confidence interval [CI], 11.2-17.4). Median time to total alkaline phosphatase and prostate-specific antigen progression were 7.5 (95% CI, 6.8-7.7) and 3.6 (95% CI, 3.1-3.7) months, respectively. Median skeletal-related event-free survival was 26.0 months (95% CI, 12.6-not reached). Grade ≥3 treatment-emergent adverse events were reported in 103 (46%) of 226 patients, with anemia being the most common event (34 [15%] patients). Grade ≥3 drug-related treatment-emergent adverse events occurred in 39 (17%) of 226 patients. Serious treatment-emergent adverse events were reported in 65 (29%) of 226 patients. Seven (3%) patients had an adverse event leading to death; none were considered to be related to radium-223. Conclusion The results of this study support the use of the standard radium-223 regimen for the treatment of Asian patients with castrate-resistant prostate cancer and symptomatic bone metastases.

TPS5093 Background: Men with mCRPC often receive sequential NAH (abiraterone and enzalutamide) despite reported cross-resistance, indicating a need for further life-prolonging options for progressive disease after prior NAH. Ra-223 is a targeted alpha therapy approved for mCRPC with symptomatic bone metastases based on the phase 3 ALSYMPCA study, in which it demonstrated significantly increased overall survival (OS), reduced symptomatic skeletal event (SSE) risk, improved quality of life, and reduced treatment-emergent adverse event rates vs placebo. As life-prolonging therapy is increasingly used in hormone-sensitive settings, this study has been designed to assess Ra-223 outcomes in patients with mCRPC that progressed after prior treatment with NAH and docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC) or mCRPC. Methods: This study is conducted in accordance with the Declaration of Helsinki, international ethical and good clinical practice guidelines, and local laws and regulations, with institutional review board/ethics committee approval at each site and written informed consent from patients before participation. This trial is registered with EudraCT: 2019-000476-42. Participants must be ≥18 years old, with an Eastern Cooperative Oncology Group performance status of 0/1; they must have mCRPC that progressed on/after ≥3 months of NAH for mHSPC or mCRPC and ≥2 cycles of docetaxel unless they refused or were ineligible, with ≥2 bone metastases on bone scan, no visceral metastases, and a worst pain score ≥1 on the Brief Pain Inventory-Short Form. Patients are randomized 1:1 to Ra-223 or NAH: Ra-223 55 kBq/kg intravenously every 4 weeks for 6 cycles or until disease progression, death, or withdrawal of consent if earlier; or abiraterone 1000 mg + prednisone 10 mg daily (if prior enzalutamide) or enzalutamide 160 mg daily (if prior abiraterone) until disease progression, death, or withdrawal of consent. NAH dosing may be modified to manage adverse events. Patients must use luteinizing hormone-releasing hormone analogs, if not surgically castrated, and bone health agents (bisphosphonates or denosumab) throughout the study. The primary endpoint is OS. Secondary endpoints are time to first SSE, radiologic progression-free survival, time to pain progression, adverse events, fracture incidence, and time to deterioration in quality of life (FACT-P total score). Using a test with a two-sided alpha of 0.05, 90% power, and randomization ratio of 1:1, approximately 508 events are required to detect a 33% increase in OS with Ra-223 vs NAH, assuming a median OS of 10 months with NAH. The expected study duration is 55 months, with a target of 696 patients to be randomized. The first patient was enrolled on November 9, 2020; 5 patients have been randomized and 2 have started treatment to date. Clinical trial information: 2019-000476-42.

BACKGROUND: Abiraterone acetate plus prednisone or prednisolone improves progression-free survival and overall survival in patients with metastatic castration-resistant prostate cancer. Radium-223 improves overall survival and delays the onset of symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases. We assessed concurrent treatment with abiraterone acetate plus prednisone or prednisolone and radium-223 in such patients. METHODS: We did a randomised, double-blind, placebo-controlled, phase 3 trial at 165 oncology and urology centres in 19 countries. Eligible patients were aged 18 years or older, and had histologically confirmed, progressive, chemotherapy-naive, asymptomatic or mildly symptomatic castration-resistant prostate cancer and bone metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 6 months, and adequate haematological, renal, and liver function. Participants were randomly assigned (1:1) according to a permuted block design (block size 4) via interactive response technology to receive up to six intravenous injections of radium-223 (55 kBq/kg) or matching placebo once every 4 weeks. All patients were also scheduled to receive oral abiraterone acetate 1000 mg once daily plus oral prednisone or prednisolone 5 mg twice daily during and after radium-223 or placebo treatment. The primary endpoint was symptomatic skeletal event-free survival, which was assessed in the intention-to-treat population. Safety analyses were done in all patients who received at least one dose of any study drug. This trial is registered with ClinicalTrials.gov, number NCT02043678. Enrolment has been completed, and follow-up is ongoing. FINDINGS: Between March 30, 2014, and Aug 12, 2016, 806 patients were randomly assigned to receive radium-223 (n=401) or placebo (n=405) in addition to abiraterone acetate plus prednisone or prednisolone. The study was unblinded prematurely, on Nov 17, 2017, after more fractures and deaths were noted in the radium-223 group than in the placebo group (in an unplanned ad-hoc analysis), but all patients had completed radium-223 or placebo before this date. At the primary analysis (data cutoff Feb 15, 2018), 196 (49%) of 401 patients in radium-223 group had had at least one symptomatic skeletal event or died, compared with 190 (47%) of 405 patients in the placebo group (median follow-up 21·2 months [IQR 17·0-25·8]). Median symptomatic skeletal event-free survival was 22·3 months (95% CI 20·4-24·8) in the radium-223 group and 26·0 months (21·8-28·3) in the placebo group (hazard ratio 1·122 [95% CI 0·917-1·374]; p=0·2636). Fractures (any grade) occurred in 112 (29%) of 392 patients in the radium-223 group and 45 (11%) of 394 patients in the placebo group. The most common grade 3-4 treatment-emergent adverse events were hypertension (43 [11%] patients in the radium-223 group vs 52 [13%] patients in the placebo group), fractures (36 [9%] vs 12 [3%]) and increased alanine aminotransferase concentrations (34 [9%] vs 28 [7%]). Serious treatment-emergent adverse events occurred in 160 (41%) patients in the radium-223 group and 155 (39%) in the placebo group. Treatment-related deaths occurred in two (1%) patients in the radium-223 group (acute myocardial infarction and interstitial lung disease) and one (

Purpose: Refametinib, an oral MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in patients with RAS-mutated hepatocellular carcinoma (HCC). Two phase II studies evaluated the efficacy of refametinib monotherapy and refametinib plus sorafenib in patients with RAS-mutant unresectable or metastatic HCC. Patients and Methods: Eligible patients with RAS mutations of cell-free circulating tumor DNA (ctDNA) determined by beads, emulsion, amplification, and magnetics technology received twice-daily refametinib 50 mg ± sorafenib 400 mg. Potential biomarkers were assessed in ctDNA via next-generation sequencing (NGS). Results: Of 1,318 patients screened, 59 (4.4%) had a RAS mutation, of whom 16 received refametinib and 16 received refametinib plus sorafenib. With refametinib monotherapy, the objective response rate (ORR) was 0%, the disease control rate (DCR) was 56.3%, overall survival (OS) was 5.8 months, and progression-free survival (PFS) was 1.9 months. With refametinib plus sorafenib, the ORR was 6.3%, the DCR was 43.8%, OS was 12.7 months, and PFS was 1.5 months. In both studies, time to progression was 2.8 months. Treatment-emergent toxicities included fatigue, hypertension, and acneiform rash. Twenty-seven patients had ctDNA samples available for NGS. The most frequently detected mutations were in TERT (63.0%), TP53 (48.1%), and β-catenin (CTNNB1; 37.0%). Conclusions: Prospective testing for RAS family mutations using ctDNA was a feasible, noninvasive approach for large-scale mutational testing in patients with HCC. A median OS of 12.7 months with refametinib plus sorafenib in this small population of RAS-mutant patients may indicate a synergistic effect between sorafenib and refametinib—this preliminary finding should be further explored. Clin Cancer Res; 24(19); 4650–61. ©2018 AACR.

Purpose: To assess the safety and tolerability of the small-molecule allosteric MEK inhibitor refametinib combined with sorafenib, in patients with advanced solid malignancies. Experimental Design: This phase I dose-escalation study included an expansion phase at the maximum tolerated dose (MTD). Patients received refametinib/sorafenib twice daily for 28 days, from a dose of refametinib 5 mg plus sorafenib 200 mg to a dose of refametinib 50 mg plus sorafenib 400 mg. Plasma levels of refametinib, refametinib metabolite M17, and sorafenib were measured for pharmacokinetic assessments. Tumors were biopsied at the MTD for analysis of MEK pathway mutations and ERK phosphorylation. Results: Thirty-two patients were enrolled in the dose-escalation cohort. The MTD was refametinib 50 mg twice daily plus sorafenib 400 mg twice daily. The most common treatment-related toxicities were diarrhea and fatigue. Refametinib was readily absorbed following oral administration (plasma half-life of ∼16 hours at the MTD), and pharmacokinetic parameters displayed near-dose proportionality, with less than 2-fold accumulation after multiple dosing. Another 30 patients were enrolled in the MTD cohort; 19 had hepatocellular carcinoma. The combination was associated with significantly reduced ERK phosphorylation in 5 out of 6 patients biopsied, with the greatest reductions in those with KRAS or BRAF mutations. Disease was stabilized in approximately half of patients, and 1 patient with colorectal cancer achieved a partial response at the MTD lasting approximately 1 year. Conclusions: In this phase I study, refametinib plus sorafenib was well tolerated, with good oral absorption, near-dose proportionality, and target inhibition in a range of tumor types. Clin Cancer Res; 22(10); 2368–76. ©2015 AACR.

Purpose: There is an unmet need for treatment options in hepatocellular carcinoma (HCC). Sorafenib is currently the only approved systemic treatment for HCC. Refametinib, an oral, allosteric MEK inhibitor, has demonstrated antitumor activity in combination with sorafenib in vitro and in vivo. A phase II study evaluated efficacy and safety of refametinib plus sorafenib in Asian patients with HCC (NCT01204177). Experimental Design: Eligible patients received twice-daily refametinib 50 mg plus twice-daily sorafenib 200 mg (morning)/400 mg (evening), with dose escalation to sorafenib 400 mg twice daily from cycle 2 if no grade ≥2 hand-foot skin reaction, fatigue, or gastrointestinal toxicity occurred. Primary efficacy endpoint: disease control rate. Secondary endpoints: time to progression, overall survival, pharmacokinetic assessment, biomarker analysis, safety, and tolerability. Results: Of 95 enrolled patients, 70 received study treatment. Most patients had liver cirrhosis (82.9%) and hepatitis B viral infection (75.7%). Disease control rate was 44.8% (primary efficacy analysis; n = 58). Median time to progression was 122 days, median overall survival was 290 days (n = 70). Best clinical responders had RAS mutations; majority of poor responders had wild-type RAS. Most frequent drug-related adverse events were diarrhea, rash, aspartate aminotransferase elevation, vomiting, and nausea. Dose modifications due to adverse events were necessary in almost all patients. Conclusions: Refametinib plus sorafenib showed antitumor activity in patients with HCC and was tolerated at reduced doses by most patients. Frequent dose modifications due to grade 3 adverse events may have contributed to limited treatment effect. Patients with RAS mutations appear to benefit from refametinib/sorafenib combination. Clin Cancer Res; 20(23); 5976–85. ©2014 AACR.

ABSTRACT: Aims: To assess the utility of dynamic contrast-enhanced MRI parameters in the demonstration of early antiangiogenic effects and as prognostic biomarkers in second-line treatment of advanced-stage non-small-cell lung cancer with vatalanib. Patients & methods: The transfer constant (Ktrans) and the initial area under the contrast concentration–time curve at 60 s (AUC60) were assessed in 46 patients. Changes were compared with response evaluation from computed tomography imaging and Response Evaluation Criteria In Solid Tumors guidelines. Results: Statistically significant mean reductions in Ktrans (38.4%; p < 0.0001) and AUC60 (24.9%; p < 0.0001) were found at day 2. After 12 weeks, 16 patients (35%) demonstrated stable disease and 30 (65%) demonstrated progressive disease. No statistically significant differences in day 2 Ktrans and AUC60 reductions between stable disease and progressive disease patients were found. Conclusion: Dynamic contrast-enhanced MRI can demonstrate a statistically significant reduction in vascular parameters of non-small-cell lung cancer, but does not predict patient outcome.

Background The objective of this multicenter, prospective uncontrolled phase II trial was to determine efficacy, safety and tolerability of vatalanib, an oral angiogenesis inhibitor targeting all known vascular endothelial growth factor receptors, in the second-line treatment of non-small-cell lung cancer (NSCLC). Patients and methods Patients with stage IIIB/IV NSCLC-proven tumor progression during or after one platinum-based chemotherapy regimen received a fixed dose of 1250 mg vatalanib either once-daily dosing (QD) or two divided daily dosing (TDD: 500 mg a.m. + 750 mg p.m.) until disease progression or unacceptable toxicity. Primary end point was the disease control rate (DCR) at 12 weeks. Results Fifty-four and 58 patients were enrolled to the QD and TDD arms. DCR at 12 weeks was 35% in the QD and 37% in the TDD arm. The best overall response included one (2%) patient with confirmed partial response with QD and three (5%) with TDD. Median progression-free survival and overall survival were 2.1/7.3 months in the QD arm and 2.8/9.0 months with TDD arm. This therapy showed a moderate toxicity profile for the majority of patients. Conclusions In the chosen patient population, vatalanib QD and TDD dosing demonstrated potential benefits in tumor size reduction, DCR, and survival.

Systemic treatment of metastatic melanoma is of low efficacy, and new therapeutic strategies are needed. Histone deacetylase inhibitors are supposed to restore the expression of tumor suppressor genes and induce tumor cell differentiation, growth arrest, and apoptosis. This study was aimed to evaluate the efficacy, safety, and pharmacokinetics of the histone deacetylase inhibitor pyridylmethyl-N-{4-[(2-aminophenyl)-carbamoyl]-benzyl}-carbamate (MS-275) in patients with pretreated metastatic melanoma. Patients with unresectable AJCC stage IV melanoma refractory to at least one earlier systemic therapy were randomized to receive MS-275 3 mg biweekly (days 1+15, arm A) or 7 mg weekly (days 1+8+15, arm B), in 4-week cycles. The primary study endpoint was objective tumor response, secondary endpoints were safety and time-to-progression. On the basis of Simon's two-stage design, the study initially allowed an entry of 14 patients per arm; if there was at least one responder, additional 33 patients were to be enrolled. Among 28 patients enrolled, no objective response was detected. Four (29%) patients in arm A and three (21%) patients in arm B showed disease stabilizations. Median time-to-progression was comparable in both arms with 55.5 versus 51.5 days, respectively; median overall survival was 8.84 months. Toxicity was mild to moderate with nausea (39%) and hypophosphatemia (29%) as the most frequently reported events. No treatment-related serious adverse events occurred. Single-agent treatment with MS-275 was well-tolerated and showed long-term tumor stabilizations, but no objective responses in pretreated metastatic melanoma. Further evaluation of MS-275 in combination schedules is warranted.

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: In a retrospective analysis performed in a phase II study evaluating efficacy and safety of the MEK-inhibitor refametinib plus sorafenib in Asian patients with HCC (Lim et al., Clin Cancer Res, in press), patients with mutant RAS appeared to exhibit a particularly robust clinical response to refametinib plus sorafenib compared to patients with wild-type RAS. To further investigate clinical activity of refametinib as monotherapy or in combination with sorafenib in HCC patients with mutant RAS, two Ph II studies for patients with unresectable HCC have been initiated; refametinib monotherapy ([NCT01915589][1]) and refametinib plus sorafenib combination therapy ([NCT01915602][2]). Since RAS mutations are very rare events in HCC and biopsies are not routinely taken in patients with underlying liver cirrhosis, only liquid biopsies seemed feasible for prospective patient selection. Therefore, Sysmex Inostics’ BEAMing (Beads, Emulsions, Amplification, and Magnetics) technology based on cell-free circulating DNA in plasma is used to select patients for KRAS/NRAS Mutation status prior to enrollment. Patients are eligible if they exhibit any one or multiple of 13 KRAS/NRAS mutations. Results: Between Sep 2013 and Nov 2014 more than 1000 plasma samples from patients with unresectable HCC enrolled in the refametinib monotherapy study or the refametinib plus sorafenib combination study, have been tested at a CLIA certified laboratory in Baltimore, MD. The turnaround time from shipping the plasma sample from the clinical trial site to the results reporting was 6-10 days. Out of 1004 samples from 116 trial sites in 18 countries, 47 (4.7%) have been reported to harbor a KRAS and / or a NRAS mut. The following mutations have been reported: KRAS\_G12A, KRAS\_G12C, KRAS\_G12D, KRAS\_G12R, KRAS_ G12S, KRAS\_G12V, KRAS\_G13D, NRAS\_Q61K, NRAS\_Q61L, NRAS\_Q61H, NRAS\_Q61R. The frequency of the mutant allele ranged from 0.02% to 9.75%. No obvious differences in the incidence of any of the mutations with regards to geography, demographic factors are other baseline characteristics have been observed. Conclusion: To our knowledge this is the largest dataset of KRAS and NRAS mutations in HCC. The observed prevalence of RAS mutations of approximately 5% across both trials is well in line with published data including the COSMIC database. Our data support that prospective selection of patients with HCC for KRAS or NRAS mutation is feasible with a turn-around time of 1-2 weeks depending on geographical region. These data further support the broad utility of such approaches for large randomized prospective studies in patients with specific tumor genetic profiles. The clinical outcome of the 2 clinical studies will help understand whether KRAS or NRAS can potentially be a predictive marker for response to refametinib in patients with HCC. Citation Format: Heiko Krissel, Andrea Hennig, Danny Zhang, Rodrigo Ito, Christine Gonschorek, Fabricio Souza, Martina Poethig, Kathleen Schostack, Joachim Reischl, Philipp Angenendt, Barrett H. Childs, Michael Teufel. Liquid biopsies to prospectively select patients with KRAS or NRAS mutant hepatocellular carcinoma (HCC) in two phase II studies with Refametinib. [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 5252. doi:10.1158/1538-7445.AM2015-5252 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01915589&atom=%2Fcanres%2F75%2F15_Supplement%2F5252.atom [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01915602&atom=%2Fcanres%2F75%2F15_Supplement%2F5252.atom

Background: Per COSMIC database, RAS mutations are uncommon events in hepatocellular carcinoma (HCC). Refametinib (BAY 86-9766) is a potent (IC50=17-60 nM) allosteric dual MEK 1/2 inhibitor, which exhibits high selectivity for MEK as compared to other kinases as well as strong preclinical synergy in combination with sorafenib, suggesting it may have potential utility in treating HCC patients. As part of a phase II study that evaluated the efficacy and safety of refametinib plus sorafenib in Asian patients with HCC, a biomarker analysis was performed using plasma DNA to investigate a possible correlation between mutational status and clinical outcome. Methods: Refametinib was tested in a kinase panel of 205 enzymes at 10 μM and in a variety of cancer cell lines for antiproliferative effects. In vivo refametinib was tested for tumor growth inhibition in monotherapy or in combination with sorafenib mouse xenograft HCC models. Mutational analysis of clinical plasma specimens was performed by Inostics GmbH (Hamburg, Germany) using BEAMing (Beads, Emulsions, Amplification, and Magnetics) technology on DNA isolated from plasma samples collected at baseline. Mutational status was correlated with clinical outcome using descriptive analyses. Plasma from 69 patients was evaluated for the following mutations: KRAS (G12A, C, D, R, S, V; G13D; Q61H; A146T); NRAS (Q61H, K, L, R) and BRAF (V600E). Results: Based on it allosteric binding mode refametinib shows more than 100-fold selectivity for MEK. There was strong antiproliferative activity of BAY 86-9766 in HCC cell lines being most active in an NRAS amplified model (HepG2). In the orthotopic HBV-driven human Hep3B xenograft model, BAY 86-9766 (25 mg/kg) monotherapy was more effective than sorafenib at its maximally tolerated dose (30 mg/kg) in prolonging survival and exhibited strong synergism in improving this endpoint when combined with sorafenib. Based on the BEAMing data, the frequency of HCC patients with mutant RAS identified in our study (5.8%) was similar to the frequency of RAS mutations reported in HCC patients (5%) (COSMIC). A RAS mutation was identified in 4 patients, 3 of whom were still receiving study treatment at the cut-off date used for the final data analysis. These 3 patients had achieved confirmed PR, with duration of responses ranging from 128 to 382 days. The fourth patient with a RAS mutation discontinued study treatment after 41 days on therapy due to PD. No mutations in BRAF were identified in these 69 samples. Conclusions: In this exploratory retrospective study, HCC patients with mutant RAS exhibited a particularly robust clinical response to refametinib plus sorafenib compared to patients with wild-type RAS. Further investigation is required to assess the clinical activity of this drug combination in HCC patients with mutant RAS. Accordingly, we have initiated two single-arm phase 2 studies in patients with prospectively identified, BEAMing-confirmed RAS-mutated HCC; sorafenib and refametinib in first-line (NCT01915602), and refametinib as first- or second-line monotherapy (NCT01915589). Citation Format: Ho Yeong Lim, Heiko Krissel, Michael Teufel, Florian Puehler, Joachim Reischl, Frank Diehl, Barrett H. Childs, Josep M. Llovet. RAS mutations detected by cell-free plasma DNA (BEAMing) assay may portend a favorable response to refametinib +/- sorafenib in hepatocellular carcinoma. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B42. doi: 10.1158/1557-3125.RASONC14-B42

TPS4163 Background: Sorafenib is the accepted first-line systemic therapy for HCC, but no standard option is available for patients with tumor progression following sorafenib. An open-label phase II study suggested that REG, a multikinase inhibitor, had an acceptable safety profile and showed evidence of antitumor activity in patients with progressive HCC (Bolondi et al. Eur J Cancer 2011; 47 [Suppl 1]: abstract 6.576): disease control was achieved in 26/36 patients (72%) and median time to progression (TTP) was 4.3 months; median overall survival (OS) was 13.8 months. On the basis of these promising data, a phase III trial was designed. Methods: This randomized, double-blind, placebo (PBO)-controlled, multinational study (ClinicalTrials.gov identifier NCT01774344) will assess the efficacy and tolerability of REG vs PBO in patients with HCC that has progressed following sorafenib treatment (target n=530). Inclusion criteria include Barcelona Clinic Liver Cancer stage B or C disease, Child–Pugh A liver function, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1. Patients who discontinued sorafenib ≥8 weeks before study entry or who received other previous systemic therapy for HCC will be excluded. Patients will be randomized in a 2:1 ratio to receive REG 160 mg or matching PBO OD for weeks 1–3 of each 4-week cycle; all patients will also receive best supportive care. Treatment will continue until disease progression, death, intolerable toxicity, or patient/investigator decision to stop. Doses of study drug may be delayed or reduced to manage clinically significant drug-related toxicities. The primary endpoint is OS; secondary endpoints are TTP, progression-free survival, tumor response, and safety. Analysis will be according to randomized group, stratified by geographic region (Asia vs rest of world), ECOG PS (0 vs 1), alfa-fetoprotein level (

4103 Background: Sorafenib (S) is the only approved systemic treatment for unresectable HCC. Nevertheless, there remains an unmet medical need for more effective treatment options for this disease. BAY 86-9766 (B) is an oral, allosteric inhibitor of MEK, a key component of the MAP kinase pathway. This study evaluated the efficacy and safety of a combination therapy with B plus S in patients (pts) with HCC. Methods: This is a single arm, open-label, phase 2 study. Eligible were pts with unresectable HCC, Child-Pugh Class A, performance status (PS) 0-1, and no prior systemic anticancer therapy for HCC. Pts started Cycle 1 (21 days) with B 50 mg bid orally plus S 600 mg daily (200 mg AM, 400 mg PM) orally. If there was no hand-foot skin reaction, fatigue, or gastrointestinal toxicity ≥ grade 2, S was escalated to 400 mg bid from Cycle 2 on. Treatment continued until progression or withdrawal criteria were met. Tumor assessment was performed every 6 weeks during treatment. Safety was evaluated every week for the first 6 weeks and every 3 weeks thereafter. Results: Seventy pts from Asia started study treatment. Pts were predominantly male (86%); median age was 56 years; 54% had PS of 0 and 46% PS of 1. The vast majority had liver cirrhosis (83%) and infection with HBV (76%) or HCV (17%). Sixty-five were evaluable for efficacy per protocol. Three pts (5%) had confirmed partial response and 25 pts (38%) had prolonged stable disease (≥10 weeks), with a disease control rate of 43%. Median time-to-progression was 4.1 months. Survival data are not mature, yet. The most frequent drug-related adverse events (AEs) were rash (60%), diarrhea (59%), AST elevation (43%), vomiting (30%), nausea (29%), ALT elevation (26%), and anorexia (26%). There were 4 Grade 5 related AEs (hepatic failure, sepsis/hepatic encephalopathy, tumor lysis syndrome, and unknown cause, respectively). Dose modifications due to AEs were necessary in almost all pts. The median daily dose was 64.2 mg for B and 443.3 mg for S, respectively. Conclusions: B in combination with S showed antitumor activity in pts with HCC. However, frequent dose modifications due to AEs might have limited the treatment effect of this combination.

7541 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival (OS). PTK/ZK is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R 1–3). Methods: A prospective, single-arm, multi-center, proof-of-principle phase II study to investigate efficacy and safety of PTK/ZK in pretreated pts with stage IIIB/IV NSCLC. Only one platinum-based chemotherapy regimen was allowed as first-line treatment. 55 pts each were planned to receive a fixed dose of 1,250 mg PTK/ZK once daily (qd) or twice daily (500 mg a.m. + 750 mg p.m.) (bid) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation was based on RECIST. A disease stabilization of at least 12 weeks was defined as clinically relevant drug activity. Additional biomarker evaluation included DCE-MRI and serum proteomics. Results: Enrolment is completed with 54 pts starting qd and 58 pts starting bid treatment. Most frequent adverse events in both cohorts were nausea (44%), vomiting (40%), and dizziness (34%). Three possibly related deaths were observed, 2 due to pulmonary hemorrhage and 1 due to pulmonary embolism. Best response by RECIST for the qd cohort (n=54) include 1 pt with a confirmed partial response (cPR) (2%), 32 pts (59%) with stable disease (SD) at week 4, hereof 18 pts (33%) for at least 12 weeks, and 21 pts (39%) with progressive disease (PD); for the bid cohort (n=57) 4 pts with cPR (7%), 18 pts (32%) with SD (=12 weeks), 19 pts (33%) not yet evaluated, and 16 pts (28%) with PD. Progression free survival (PFS)/OS were 2.4/7.0 months (mo) for the qd vs. 3.7/6.8 mo for the bid cohort. Conclusions: These results suggest that both qd and bid second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In this unfavorable pt population a considerably high rate of disease control could be achieved. Four pts with PR out of 38 evaluated pts in the bid cohort might indicate additional benefit of bid dosing. Final data of the primary endpoint (efficacy) for both cohorts will be presented at the meeting. [Table: see text]

7676 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R) in NSCLC-tumors is linked to poor prognosis and shorter overall survival. PTK/ZK (PTK/ZK) is a novel, oral, anti-angiogenic compound blocking all currently known VEGF receptors (VEGF-R1–3). DCE-MRI measures early changes in tumour-associated vasculature in response to treatment and has been successfully used as a biomarker for biological activity of PTK/ZK in liver metastases from colorectal cancer. Methods: This is a prospective, multi- centre, phase-II study of PTK/ZK in pretreated patients with advanced stage NSCLC. 54 patients (pts) received 1,250 mg PTK/ZK once daily (qd), followed by 58 patients receiving 1,250 mg (500 am + 750 mg pm) PTK/ZK twice daily (bid). Response evaluation was based on RECIST. Disease stabilization of at least 12 weeks based on CT/MRI-imaging was defined as clinically relevant drug activity. DCE-MRI was performed 2- 4 hours after PTK/ZK administration, on day 2 and at day 28. Contrast enhancement for the whole tumour was assessed by calculating the transfer constant (Ktrans) using a two-compartment model. Results: DCE-MRI was performed successfully in 35 pts in the qd cohort on day 2 and 29 pts in the qd cohort at day 28. There was a statistically significant mean reduction in Ktrans at day 2 of 35.2 % (ptrans at day 2 (39.4% and 37.1%, respectively). However, the difference between SD and PD was not statistically significant. Data for the bid cohort will be presented at the meeting. Conclusions: PTK/ZK causes statistically significant reduction in tumour vascular parameters of lung tumours. Ktrans has previously been shown to correlate with clinical outcome. However, for the qd cohort, no correlation could be demonstrated. This may be due to the limitation of the sample size as well as the heterogeneity of the targeted lesions selected for this study. [Table: see text]

7195 Background: Overexpression of vascular endothelial growth factor receptor (VEGF-R 1–3) in NSCLC is associated with poor prognosis and shorter overall survival. PTK787/ZK 222584 (PTK/ZK), a novel, oral, anti-angiogenic compound blocks tyrosine kinase signaling from all VEGF receptors. Methods: A prospective, single-arm, multi-center, proof-of-principle phase-II study to investigate both efficacy and safety of PTK/ ZK in patients with stage IIIB/IV NSCLC who received prior first line treatment with a platinum based chemotherapy regimen. All pts were relapsed/refractory as determined by available imaging. All pts were planned to receive 1,250 mg of PTK/ZK once daily (qd) for continuous treatment until disease progression or unacceptable toxicities. Response evaluation is based on RECIST criteria. Disease stabilization of at least 12 weeks based on CT/MRI-imaging was defined as clinically relevant drug activity. All pts had dynamic contrast enhanced MRI investigations for additional efficacy analysis and serum asservations for serum proteomic analysis. Results: To date, 56 pts have been enrolled. PTK/ZK is generally well tolerated. Most frequent adverse events (AEs) are nausea and vomiting. One pt developed interstitial lung disease (ILD) and in one pt with tracheal stent a fatal lung bleeding occurred. No other unexpected serious AEs have been reported. Maximum response for 48 evaluated pts include one pt with a partial response (PR) (2%), 27 pts with stable disease (SD) (56%), (disease control rate 58%), and 20 pts with progressive disease (PD) (42%). The pt with PR has responded for over 20 weeks. 15 pts have SD for at least 12 weeks; 5 pts of these had SD for at least 28 weeks. Conclusions: These preliminary results suggest that second-line treatment with single-agent PTK/ZK is generally safe and well tolerated. In pts with refractory disease in stage IIIB/IV NSCLC, a considerably high rate of disease control could be achieved in this study. The study is currently recruiting for twice daily (bid) treatment. [Table: see text]