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The purpose of this study is to improve the mathematical problem solving ability of students who are taught by applying a problem based learning model that is taught by a direct learning model. Problem Based Learning (PBL) approach can be used as a solution in learning mathematics. The research method used is a quasi-experimental research in the form of a posttest and there is an experimental class and a control class. This research method is a meta-analysis with a sample of 5 articles in Sinta 3-6 accredited national journals from 2017 to 2021 with the research subject being junior high and high school education levels. Meta-analysis research shows that the effect of Problem Based Learning (PBL) learning approach is effective on problem solving abilities. The research data were collected through the provision of instruments in the form of a mathematical problem solving ability test in the form of description questions and observation sheets. The data analysis technique used descriptive statistics and inferential statistics. Based on the results of the study, it was concluded that there was a significant effect of the Problem Based Learning model on mathematical problem solving abilities.

PDF file - 30K, Estimated maximal concentration (Cmax) and total area under the concentration-time curve (AUClast) of total and free oxaliplatin with and without vismodegib

PDF file - 25K, A comparison of steady-state 5-FU concentrations with and without vismodegib co-treatment

PDF file - 33K, Estimated maximal concentration (Cmax) and total area under the concentration-time curve (AUClast) of irinotecan (and metabolites SN-38 and SN-38G) with and without vismodegib

PDF file - 25K, A comparison of serum concentrations of bevacizumab with and without vismodegib co-treatment

PDF file - 57K, A summary of primer/probes used for qRT-PCR profiling of Hh pathway genes

Purpose: Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC).Experimental design: Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions.Results: A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89–1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43–60) and 46% (90% CI: 37–55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab.Conclusions: Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy. Clin Cancer Res; 19(1); 258–67. ©2012 AACR.

PDF file - 24K, A comparison of vismodegib steady-state plasma concentrations (Css) between patients receiving FOLFOX and FOLFIRI

PDF file - 61K

This study aims to determine the effect of market orientation and environmental adaptability through product innovation on marketing performance. The samples studied were durian MSME actors (in the form of durian or durian processed) that were registered with the Banten Durian Entrepreneur Group (KPDB) with 70 businessmen in the Serang, Cilegon, Pandeglang and Lebak regions. Sources of research data are obtained from online questionnaires using google forms tools that are distributed via the whatsapp media group. Data processing uses the Structural Equation Model (SEM) approach with Smart PLS 3.0 Software. The results showed that market orientation and environmental adaptability didn’t have a positive effect on marketing performance, environmental adaptability didn’t have a positive effect on product innovation, market orientation have a positive effect on product innovation, and product innovation have a positive effect on marketing performance. From the results of this study indicate that MSEs have not been consistent in improving marketing performance, because durian is still classified as seasonal fruit and the price is high when it is out of season.

Purpose Notch signaling dysregulation is implicated in the development of pancreatic adenocarcinoma (PDAC). Tarextumab is a fully human IgG2 antibody that inhibits Notch2/3 receptors. Patients and methods Aphase 2, randomized, placebo-controlled, multicenter trial evaluated the activity of tarextumab in combination with nab-paclitaxel and gemcitabine in patients with metastatic PDAC. Patients were stratified based on ECOG performance score and Ca 19-9 level and randomized 1:1 to nab-paclitaxel, gemcitabine with either tarextumab or placebo. Based on preclinical and phase Ib results suggesting a positive correlation between Notch3 gene expression and tarextumab anti-tumor activity, patients were also divided into subgroups of low, intermediate, and high Notch3 gene expression. Primary endpoint was overall survival (OS) in all and in patients with the three Notch3 gene expression subgroups (≥25th, ≥50% and ≥75% percentiles); secondary end points included progression-free survival (PFS), 12-month OS, overall response rate (ORR), and safety and biomarker investigation. Results Median OS was 6.4 months in the tarextumab group vs 7.9 months in the placebo group (HR = 1.34 [95% CI = 0.95, 1.89], P = .0985). No difference observed in OS in the Notch3 gene expression subgroups. PFS in the tarextumab-treated group (3.7 months) was significantly shorter compared with the placebo group (5.5 months) (hazard ratio was 1.43 [95% CI = 1.01, 2.01]; P = .04). Grade 3 diarrhea and thrombocytopenia were more common in the tarextumab group. Conclusions The addition of tarextumab to nab-paclitaxel and gemcitabine did not improve OS, PFS, or ORR in first-line metastatic PDAC, and PFS was specifically statistically worse in the tarextumab-treated patients. Clinical trial registry no NCT01647828.

Summary Background VEGF and VEGF receptor 2 (VEGFR-2)-mediated signalling and angiogenesis can contribute to the pathogenesis and progression of gastric cancer. We aimed to assess whether the addition of ramucirumab, a VEGFR-2 antagonist monoclonal antibody, to first-line chemotherapy improves outcomes in patients with metastatic gastric or gastro-oesophageal junction adenocarcinoma. Methods For this double-blind, randomised, placebo-controlled, phase 3 trial done at 126 centres in 20 countries, we recruited patients aged 18 years or older with metastatic, HER2-negative gastric or gastro-oesophageal junction adenocarcinoma, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate organ function. Eligible patients were randomly assigned (1:1) with an interactive web response system to receive cisplatin (80 mg/m2, on the first day) plus capecitabine (1000 mg/m2, twice daily for 14 days), every 21 days, and either ramucirumab (8 mg/kg) or placebo on days 1 and 8, every 21 days. 5-Fluorouracil (800 mg/m2 intravenous infusion on days 1–5) was permitted in patients unable to take capecitabine. The primary endpoint was investigator-assessed progression-free survival, analysed by intention to treat in the first 508 patients. We did a sensitivity analysis of the primary endpoint, including a central review of CT scans. Overall survival was a key secondary endpoint. This study is registered with ClinicalTrials.gov, number NCT02314117. Findings Between Jan 28, 2015, and Sept 16, 2016, 645 patients were randomly assigned to receive ramucirumab plus fluoropyrimidine and cisplatin (n=326) or placebo plus fluoropyrimidine and cisplatin (n=319). Investigator-assessed progression-free survival was significantly longer in the ramucirumab group than the placebo group (hazard ratio [HR] 0·753, 95% CI 0·607–0·935, p=0·0106; median progression-free survival 5·7 months [5·5–6·5] vs 5·4 months [4·5–5·7]). A sensitivity analysis based on central independent review of the radiological images did not corroborate the investigator-assessed difference in progression-free survival (HR 0·961, 95% CI 0·768–1·203, p=0·74). There was no difference in overall survival between groups (0·962, 0·801–1·156, p=0·6757; median overall survival 11·2 months [9·9–11·9] in the ramucirumab group vs 10·7 months [9·5–11·9] in the placebo group). The most common grade 3–4 adverse events were neutropenia (85 [26%] of 323 patients in the ramucirumab group vs 85 [27%] of 315 in the placebo group), anaemia (39 [12%] vs 44 [14%]), and hypertension (32 [10%] vs 5 [2%]). The incidence of any-grade serious adverse events was 160 (50%) of 323 patients in the ramucirumab group and 149 (47%) of 315 patients in the placebo group. The most common serious adverse events were vomiting (14 [4%] in the ramucirumab group vs 21 [7%] in the placebo group) and diarrhoea (11 [3%] vs 19 [6%]). There were seven deaths in each group, either during study treatment or within 30 days of discontinuing study treatment, which were the result of treatment-related adverse events. In the ramucirumab group, these adverse events were acute kidney injury, cardiac arrest, gastric haemorrhage, peritonitis, pneumothorax, septic shock, and sudden death (n=1 of each). In the placebo group, these adverse events were cerebrovascular accident (n=1), multiple organ dysfunction syndrome (n=2), pulmonary embolism (n=2), sepsis (n=1), and small intestine perforation (n=1). Interpretation Although the primary analysis for progression-free survival was statistically significant, this outcome was not confirmed in a sensitivity analysis of progression-free survival by central independent review, and did not improve overall survival. Therefore, the addition of ramucirumab to cisplatin plus fluoropyrimidine chemotherapy is not recommended as first-line treatment for this patient population. Funding Eli Lilly and Company.

Roket merupakan sebuah peluru kendali atau suatu kendaraan terbang yang mendapatkan dorongan melalui reaksi roket secara cepat dengan bahan fluida dari keluaran mesin roket. Sistem Kendali Sirip Roket berbasis Mikrokontroller ATmega8 berguna untuk mengendalikan sirip roket khususnya bagian a i leron. D ibutuhkan komponen – komponen pendukung berupa Sensor Accelerometer, Sensor Gyroscope, ATmega8 dan Motor Servo. Alat pengendali sirip roket ini dapat digunakan untuk mengendalikan sirip roket bagian a i leron pada saat posisi roket tidak stabil atau terjadi gerakan naik turun pada saat setelah diluncurkan, sehingga dapat menghasilkan penerbangan yang maksimal dalam mencapai sasaran. Perancangan yang digunakan adalah jenis pengendalian dengan kontrol PID. PID ( Proportional Integral Derivative controller ) merupakan kontro l ler untuk menentukan presisi suatu sistem instrumentasi dengan karakteristik adanya umpan balik pada sistem tesebut. Pengontrol PID adalah pengontrol konvensional yang banyak dipakai dalam dunia industri. Karakteristik pengontrol PID sangat dipengaruhi oleh kontribusi besar dari ketiga parameter P, I dan D. Pemilihan konstanta Kp, Ki dan Kd akan mengakibatkan penonjolan sifat dari masing-masing elemen. Dalam perancangan sebuah sistem kendali menggunakan kontroller PID pada motor servo yang diharapkan mampu menggerakkan sirip naik dan sirip turun pada roket sehingga mampu menjaga kestabilan roket saat diluncurkan. Prosentase error pada proyek akhir ini adalah 0,5 %. Roket merupakan sebuah peluru kendali atau suatu kendaraan terbang yang mendapatkan dorongan melalui reaksi roket secara cepat dengan bahan fluida dari keluaran mesin roket. Sistem Kendali Sirip Roket berbasis Mikrokontroller ATmega8 berguna untuk mengendalikan sirip roket khususnya bagian a i leron. D ibutuhkan komponen – komponen pendukung berupa Sensor Accelerometer, Sensor Gyroscope, ATmega8 dan Motor Servo. Alat pengendali sirip roket ini dapat digunakan untuk mengendalikan sirip roket bagian a i leron pada saat posisi roket tidak stabil atau terjadi gerakan naik turun pada saat setelah diluncurkan, sehingga dapat menghasilkan penerbangan yang maksimal dalam mencapai sasaran. Perancangan yang digunakan adalah jenis pengendalian dengan kontrol PID. PID ( Proportional Integral Derivative controller ) merupakan kontro l ler untuk menentukan presisi suatu sistem instrumentasi dengan karakteristik adanya umpan balik pada sistem tesebut. Pengontrol PID adalah pengontrol konvensional yang banyak dipakai dalam dunia industri. Karakteristik pengontrol PID sangat dipengaruhi oleh kontribusi besar dari ketiga parameter P, I dan D. Pemilihan konstanta Kp, Ki dan Kd akan mengakibatkan penonjolan sifat dari masing-masing elemen. Dalam perancangan sebuah sistem kendali menggunakan kontroller PID pada motor servo yang diharapkan mampu menggerakkan sirip naik dan sirip turun pada roket sehingga mampu menjaga kestabilan roket saat diluncurkan. Prosentase error pada proyek akhir ini adalah 0,5 %.

Background Dysregulated hepatocyte growth factor/mesenchymal-epithelial transition (MET) signaling is associated with poor prognosis and resistance to vascular endothelial growth factor inhibition in metastatic colorectal cancer (mCRC). We report outcomes from a double-blind, multicenter phase II trial of the MET inhibitor onartuzumab in combination with mFOLFOX-6 and bevacizumab for mCRC (GO27827; NCT01418222). Materials and methods Patients were randomized 1:1 to receive onartuzumab (10 mg/kg intravenously [IV]) or placebo plus mFOLFOX-6 and bevacizumab (5 mg/kg IV). Oxaliplatin was given for 8-12 cycles; other agents were continued until disease progression, unacceptable toxicity, or death. The primary endpoint was progression-free survival (PFS) in the intent-to-treat (ITT) and MET immunohistochemistry (IHC) expression-positive populations. Results Between September 2011 and November 2012, 194 patients were enrolled. In September 2013, an interim analysis recommended stopping onartuzumab treatment due to lack of efficacy. At the time of the final analysis in February 2014, no significant improvement in PFS was seen with onartuzumab versus placebo in either the ITT or MET IHC-positive populations. An improvement in PFS was noted in the MET IHC-negative population. Neither overall survival nor response rate was improved with onartuzumab. The incidence of fatigue, peripheral edema, and deep vein thrombosis was increased with onartuzumab relative to placebo. Conclusion Onartuzumab combined with mFOLFOX-6 and bevacizumab did not significantly improve efficacy outcomes in either the ITT or MET IHC-positive populations. MET expression by IHC was not a predictive biomarker in this setting. The Oncologist 2017;22:264-271 IMPLICATIONS FOR PRACTICE: The addition of onartuzumab to mFOLFOX-6 plus bevacizumab did not improve outcomes in patients with previously untreated metastatic colorectal cancer in this randomized, phase II study. Although initial results with onartuzumab were promising, a number of phase II/III clinical trials have reported a lack of improvement in efficacy with onartuzumab combined with standard-of-care therapies in several tumor types. Furthermore, negative study data have been published for rilotumumab and ficlatuzumab, both of which block hepatocyte growth factor binding to the mesenchymal-epithelial transition (MET) receptor. MET immunohistochemistry was not a predictive biomarker. It remains to be seen if other biomarkers or small molecule inhibitors may be more appropriate for inhibiting this oncogenic pathway.

Background The first-in-class antibody-drug conjugate TAK-264 (formerly MLN0264) consists of an antibody targeting guanylyl cyclase C (GCC) conjugated to monomethyl auristatin E (MMAE) via a peptide linker. This phase II study evaluated the efficacy and safety of TAK-264 in patients with adenocarcinoma of the stomach or gastroesophageal junction expressing GCC, who had progressed on ≥1 line of prior therapy. Methods This study used a two-stage design, with an interim analysis conducted after stage I to determine whether to continue to stage II or discontinue on the grounds of futility. Adult patients with gastric and gastroesophageal junction adenocarcinoma expressing low, intermediate, or high GCC levels received TAK-264 1.8 mg/kg as a 30-min intravenous infusion once every 21 days, for up to 1 year. The primary endpoint was objective response rate. Radiographic assessments of tumor burden were performed every 2 cycles (6 weeks). Results A total of 38 patients participated in the study. Patients received a median of 2 (range 1-14) cycles; 8 (21%) received at least 6 cycles. The most common adverse events were nausea (53%), fatigue (32%), and decreased appetite (29%). Grade ≥3 events including anemia, diarrhea, and neutropenia were seen in 14 (37%) patients. Systemic exposure to TAK-264 was maintained throughout each treatment cycle. Two patients (6%) with intermediate GCC expression had objective responses. Conclusions TAK-264 demonstrated a manageable safety profile in this patient population. The stage I interim analysis did not support continuation to stage II of the study.

Mothers with positive HIV status risk to failure in role adaptation, which causes confusion in carrying out multiple roles, which results in the inaccuracy of parents in implementing parenting styles for their children. The purpose of this study was to explore in depth the meaning of the experience of mothers with HIV / AIDS as a parent in implementing parenting. The method used in this research is a qualitative method using a descriptive phenomenology approach. While the data collection method used is by using in-depth interviews until 40-60 minutes. The participants were five people who were registered as patients at the Poli Flamboyan RSUD Kota Cilegon. We used phenomenological data analysis with Collaizi’s approach. The researcher applied the ethical principles in the form of Respect for Autonomy and self-determination, Confidentiality and anonymity, and Protection from discomfort and harm. The results obtained five themes which significantly describes wail of the wife with HIV / AIDS status, unbelieve in HIV / AIDS status, fear of being stigmatized, the impact of HIV on the adoption of parenting styles and feelings of failure to become mothers. There needs to be education or counseling for parents with HIV / AIDS regarding choosing the implementation of parenting for children along with the Peer Support Group (KDS) program for people with HIV / AIDS to increase the spirit of ODHA to continue their life. Keywords: HIV/AIDS, Mother, Parenting

This phase II trial examined the addition of ramucirumab, a vascular endothelial growth factor receptor-2 monoclonal antibody, to mFOLFOX6 as front-line therapy for patients with advanced gastric/GEJ or esophageal adenocarcinoma. A survival benefit was not observed in the ITT population, but an exploratory analysis suggested a potential benefit for ramucirumab in the gastric/GEJ cancer subgroup. Background We report the first randomized, Phase II trial of ramucirumab, an anti-vascular endothelial growth factor receptor-2 monoclonal antibody, as front-line therapy in patients with advanced adenocarcinoma of the esophagus or gastric/gastroesophageal junction (GEJ). Patients and methods Patients from the USA with advanced esophageal, gastric, or GEJ adenocarcinoma randomly received (1:1) mFOLFOX6 plus ramucirumab (8 mg/kg) or mFOLFOX6 plus placebo every 2 weeks. The primary end point was progression-free survival (PFS) with 80% power to detect a hazard ratio (HR) of 0.71 (one-sided α = 0.15). Secondary end points included evaluation of response and overall survival (OS); an exploratory ramucirumab exposure–response analysis was undertaken. Results Of 168 randomized patients, 52% of tumors were located in the stomach/GEJ and 48% in the esophagus. The trial did not meet the primary end point of PFS [6.4 versus 6.7 months, HR 0.98 (95% confidence interval 0.69–1.37)] or the secondary end point of OS (11.7 versus 11.5 months) in the intent-to-treat (ITT) population. Objective response rates (45.2% versus 46.4%) were similar between arms. Most Grade ≥3 toxicities did not differ significantly between arms, yet premature discontinuation of FOLFOX and ramucirumab (for reasons other than progressive disease) was more common among ramucirumab- versus placebo-treated patients. In an exploratory analysis that censored for premature discontinuation, the HR for PFS favored the ramucirumab arm (HR 0.76), particularly in patients with gastric/GEJ cancer. An exploratory exposure–response analysis indicated that patients with higher ramucirumab exposure had longer OS. Conclusion The addition of ramucirumab to front-line mFOLFOX6 did not improve PFS in the ITT population. Clinicaltrials.gov identifier NCT01246960.

Objective: To evaluate the feasibility and efficacy of sequential neoadjuvant chemotherapy, chemoradiation, and surgery in patients with locally advanced esophageal cancer. Patients and Methods: There were 29 patients who received paclitaxel 150 mg/m 2 and gemcitabine 3000 mg/m 2 2 weeks apart. Two weeks later, patients received cisplatin 75 mg/m 2 and 5-fluorouracil (5-FU) 1000 mg/m 2 /d continuous infusion for 4 days with concurrent radiotherapy in 15 fractions to a total dose of 4000 cGy. After 6 weeks, cisplatin and 5-FU were repeated at the above doses. After 4 to 6 weeks, patients were restaged and underwent surgical resection. Results: All 29 patients completed the prescribed gemcitabine, paclitaxel, and radiation therapy. Febrile neutropenia occurred in 1 patient and 4 patients received growth factor support. After neoadjuvant treatment, 1 patient refused surgery, 23 underwent R0 resection (82%), while 5 developed progressive disease. Four patients developed anastomotic leaks (17%). Four patients had complete pathologic responses (14%) and 4 (14%) had only residual microscopic disease. Nine patients remain alive at a median follow-up of 48 months. Three-year survival for the entire cohort was 36%. Conclusion: This regimen was associated with a high rate of compliance and induction therapy had an acceptable toxicity profile. The R0 resection rate and 3-year survival data are similar to recently reported studies. While active, gemcitabine and paclitaxel induction therapy was associated with an increased rate of postoperative complications, but no increase in survival. Patterns of failure continue to demonstrate the need for regimens incorporating greater emphasis on systemic therapy for locally advanced esophageal cancer.

Purpose: To investigate the combination of liposomal doxorubicin/pazopanib in advanced relapsed/refractory ovarian cancer. Patients and Methods: Twenty-two patients received liposomal doxorubicin/pazopanib. Initial doses (liposomal doxorubicin, 40 mg/m2 monthly; pazopanib, 400 mg daily) were too toxic; three subsequent groups received lower doses/altered schedules. Results: The maximum tolerated doses (MTD) were liposomal doxorubicin, 30 mg/m2, and pazopanib, 400 mg daily. Severe toxicity included neutropenia (18%), rash/desquamation (14%), hypertension (9%), and hand–foot syndrome (9%). Five of the eight patients treated with MTD had grade 3 toxicity during the first two cycles. Dose reductions were frequently required. Conclusions: Further development of the liposomal doxorubicin/pazopanib combination is not recommended.

279 Background: Tarextumab (TRXT), fully human IgG2 antibody inhibits signaling of Notch2/ 3 receptors. Tumor regression seen in Notch3 (N3) expressing pt-derived pancreatic cancer xenografts when TRXT combined with Nab-P+Gem. Phase 2, randomized, placebo-controlled trial conducted to evaluate efficacy, safety of combination in mPC. Methods: Pts randomized 1:1 to TRXT or placebo (PL). TRXT given IV at 15 mg/kg q 2wks (D 1, 15), nab-P 125 mg/m2, GEM 1000mg/m2 on D1, 8, 15 q 28 days. Tissue for N3 gene expression determination was required. Primary endpoints: overall survival (OS) in all and in 3 subgroups determined by Notch 3 gene expression. Secondary: safety, progression-free survival (PFS) and overall response rate (ORR). Results: N = 177 pts randomized. Performance status (0 or 1), CA19-9 stratum (0 – ULN, > ULN – 59ULN, ≥ 59ULN) balanced. Clinical trial information: NCT01647828. . Conclusions: Addition of TRXT to Nab-P+Gem did not improve OS in 1st line mPC. A potential detrimental effect on PFS and ORR was seen in subjects with N3 < 25%ile.[Table: see text]

TPS475 Background: Nivo, an antibody against PD-1, is approved for unresectable or metastatic melanoma and metastatic squamous non-small cell lung cancer (NSCLC) after initial standard therapies. nab-P does not require immunosuppressive steroid premedication and is approved for treatment of metastatic breast cancer (MBC) after initial chemotherapy (CT) including an anthracycline, and for advanced NSCLC (+ carboplatin), and metastatic PC (+ Gem). This 6-arm, multicenter phase I trial will evaluate the safety of Nivo with nab-P— based therapy in MBC, advanced NSCLC, and advanced PC. The study design for the pancreatic portion (arm A: nab-P + Nivo; arm B: nab-P + Gem + Nivo) is described below. Methods: This 2-part study will identify dose-limiting toxicities (DLTs) in Part 1 and assess safety and explore antitumor activity in Parts 1 and 2 (Table). If Arm A, Part 1, is deemed safe (≤ 1 DLT in up to 6 pts), then Arm B, Part 1, will initiate enrollment. Regimens in Part 1 may be expanded in Part 2. Enrollment in Arm A, Part 1, is ongoing. ClinicalTrials.gov: NCT02309177. Clinical trial information: NCT02309177. [Table: see text]

663 Background: In mCRC, MET overexpression has been associated with poor prognosis and resistance to anti-VEGF therapy. We initiated a phase II study to evaluate the combination of onartuzumab (O), a ligand-blocking monoclonal antibody directed against the MET receptor, plus bevacizumab and FOLFOX, in first-line mCRC (GO27827; NCT01418222). Methods: This double-blind, randomized, multicenter phase II study randomized patients 1:1 to receive O (10 mg/kg iv) or placebo (P), plus mFOLFOX6 and bevacizumab (5 mg/kg iv). Stratification was by prior adjuvant therapy. All treatments were given on day 1–3 of a 2-week cycle. Oxaliplatin was given for up to 8–12 cycles; all other agents were continued until progression, unacceptable toxicity or death. Primary endpoint was progression-free survival (PFS) in ITT and MET+ subgroup by immunohistochemistry (IHC). MET status was determined by central laboratory IHC evaluation, with scores of 2+ or 3+ considered MET+. Results: From September 2011 to November 2012, 194 patients were enrolled. A recommendation was made to stop O after an interim efficacy and safety analysis in September 2013, due to lack of efficacy. The final analysis (cut-off Feb 2014) found that O did not improve PFS vs. P in the ITT (HR 0.75 [0.52–1.08]; p=0.12) or MET IHC+ populations (n=79; HR 1.03 [0.56–1.89]; p=0.93), although improvement was noted in the MET IHC− population (n=108; HR 0.60 [0.37–0.97]; p=0.03). Neither overall survival (OS) nor response rate (RR) was improved with O vs. P in any of the groups (OS HR 0.96 [0.61–1.50], p=0.85 for ITT; OS HR 1.24 [0.63–2.43], p=0.54 for MET IHC+; OS HR 0.83 [0.44–1.56], p=0.56 for MET IHC−; RR 57.3% vs. 57.7% for ITT, 43.2% vs. 57.1% for MET IHC+, 66.1% vs. 60.8% for MET IHC−). More edema (65.7% vs. 12.9%) and venous thromboembolic events (30.3% vs. 16.1%) were seen with O vs. P, respectively. Grade ≥3 events were similar (86.9% vs. 84.9%) and events leading to discontinuation were increased (48.5% vs. 37.6%) with O vs. P. Conclusions: Adding onartuzumab to FOLFOX/bevacizumab did not prolong PFS in first-line unselected or MET IHC+ mCRC. A trend towards PFS benefit was seen in those with MET IHC− mCRC, contrary to prior reports in other tumor types. Clinical trial information: NCT01418222.

4004 Background: RAM, an anti-VEGFR2 monoclonal antibody, improved overall survival (OS) in 2 phase 3 trials in patients (pts) with previously treated gastric/gastroesophageal junction (GEJ) AC. We...

LBA3501 Background: Perifosine (P) is an oral, synthetic alkylphospholipid that inhibits or modifies signal transduction pathways including AKT, NFkB and JNK. A randomized phase II study examined P-CAP vs. CAP in pts with 2nd or 3rd line mCRC. This study showed improvement in mTTP (HR 0.254 [0.117, 0.555]) and mOS (HR 0.370 [0.180,0.763]). Based on these results, a randomized phase III study of P-CAP vs. CAP with a primary endpoint of overall survival (OS) in pts with refractory mCRC was initiated. Methods: The study was a prospective, randomized, double-blind, placebo-controlled randomized phase III trial. Eligible pts had mCRC which was refractory to all standard therapies. Pts randomized 1:1 to Arm A = P-CAP (P 50 mg PO QD + CAP 1000 mg/m2PO BID d1-14) or Arm B = CAP (placebo + CAP 1000 mg/m2 PO BID d 1-14). Cycles were 21 days. Baseline tumor block collection and a biomarker cohort of pts with pre- and on-treatment tumor and blood samples were performed. Results: Between 3/31/10 and 8/12/11, 468 pts were randomized, 234 pts were in each arm. Baseline demographics were balanced between the arms: age < 65y (A: 65%, B: 58.5%), male (A: 57.7%, B: 53.0%), ECOG PS 0 (A: 39.7%, B: 39.7%), K-ras mutant (A: 50.4%, B: 51.3%), and median number of prior therapies (A: 4, B: 4). As of 3/19/12, median follow up was 6.6 months. Median overall survival: Arm A = 6.4 mo, Arm B = 6.8 mo, HR 1.111 [0.905,1.365], p = 0.315. Median overall survival for K-ras WT pts: Arm A = 6.6 mo, Arm B = 6.8 mo, HR 1.020 [0.763,1.365], p = 0.894; K-ras mutant pts: Arm A = 5.4 mo, Arm B = 6.9 mo HR 1.192 [0.890,1.596], p = 0.238. Conclusions: Despite promising randomized phase II data, this phase III study shows no benefit in overall survival adding perifosine to capecitabine in the refractory colorectal cancer setting. Response rate, progression free survival, and safety data will be presented. Biomarker analysis is pending to see if subgroups of patients may have potential benefit.

4127 Background: Targeted agents are used to treat well-differentiated NET. Octreotide binds somatostatin receptors and improves time to progression (TTP) of carcinoid tumors, and VEGF pathway targeting improves TTP of pancreatic NET. HER2 overexpression is reported in NET, and pertuzumab blocks HER2 receptor dimerization. This phase II trial combined bevacizumab, pertuzumab, and octreotide LAR for pts with advanced NET. Methods: Pts with advanced well-differentiated NET were enrolled. Pts had ECOG 0-1, and normal end-organ function, including left ventricular ejection fraction (LVEF) ≥50%. Pts received bevacizumab 15 mg/kg IV, pertuzumab 420 mg IV (following an 840 mg loading dose) day 1 of a 21 day cycle, and octreotide LAR 30 mg IM every 28 days. Primary endpoint was objective response rate (ORR). Results: Between 6/10 and 4/11, 43 pts enrolled. 22 M/21 F, med age 62 (33-88), 32 (74%) carcinoid, 11 (26%) PNET. 26% had prior sandostatin, 72% prior surgery, 19% prior radiation, 23% with > 2 previous systemic therapies. Treatment-related grade 3 toxicities included: hypertension (28%), LVEF dysfunction (9%) (reversible with trial drug hold), and diarrhea (7%). No grade 4 toxicity was reported. Median treatment duration was 38 weeks (range: 0 – 76). Chromogranin A values were elevated in 27 pts; 59% had decreases during treatment. Seven pts (16%) achieved objective response [CR: 1 carcinoid (2%), PR: 6 (4 carcinoid, 2 PNET) (14%)]. ORR for carcinoid pts was 15.6%. Median PFS for the entire group was 8.2 months (95% CI: 6.3 – NA). PFS for carcinoid pts was 8.5 months (95% CI: 6.3 – NA); PFS for PNET pts was 6.4 months (95% CI: 3.9 – NA). Median OS has not been reached at 14.3 months followup. Conclusions: The ORR of the combination of bevacizumab, pertuzumab, and octreotide LAR in NET pts was encouraging. Particularly the response rate in carcinoid pts appears higher than historical data, warranting further investigation of this regimen in these pts.

3530 Background: GDC-0449 is an HPI that has shown clinical activity in advanced basal cell carcinoma and preclinical activity in CRC. Methods: 199 previously untreated mCRC patients (pts), receive...