Neuroendocrine carcinoma of the cervix (NECC) is a rare variant of cervical cancer. The prognosis of women with NECC is poor and there is no standardized therapy for this type of malignancy based on controlled trials. We performed a systematic literature search of the databases PubMed and Cochrane Central Register of Controlled Trials to identify clinical trials describing the management and outcome of women with NECC. Three thousand five hundred thirty-eight cases of NECC in 112 studies were identified. The pooled proportion of NECC among women with cervical cancer was 2303/163470 (1.41%). Small cell NECC, large cell NECC, and other histological subtypes were identified in 80.4, 12.0, and 7.6% of cases, respectively. Early and late stage disease presentation were evenly distributed with 1463 (50.6%) and 1428 (49.4%) cases, respectively. Tumors expressed synaptophysin (424/538 cases; 79%), neuron-specific enolase (196/285 cases; 69%), chromogranin (323/486 cases; 66%), and CD56 (162/267; 61%). The most common primary treatment was radical surgery combined with chemotherapy either as neoadjuvant or adjuvant chemotherapy, described in 42/48 studies. Radiotherapy-based primary treatment schemes in the form of radiotherapy, radiochemotherapy, or radiotherapy with concomitant or followed by chemotherapy were also commonly used (15/48 studies). There is no standard chemotherapy regimen for NECC, but cisplatin/carboplatin and etoposide (EP) was the most commonly used treatment scheme (24/40 studies). Overall, the prognosis of women with NECC was poor with a mean recurrence-free survival of 16 months and a mean overall survival of 40 months. Immune checkpoint inhibitors and targeted agents were reported as being active in three case reports. NECC is a rare variant of cervical cancer with a poor prognosis. Multimodality treatment with radical surgery and neoadjuvant/adjuvant chemotherapy with cisplatin and etoposide with or without radiotherapy is the mainstay of treatment for early stage disease while chemotherapy with cisplatin and etoposide or topotecan, paclitaxel, and bevacizumab is appropriate for women with locally advanced or recurrent NECC. Immune checkpoint inhibitors may be beneficial, but controlled evidence for their efficacy is lacking.

This randomized study was designed to investigate the superiority of gemcitabine (gem) plus nimotuzumab (nimo), an anti-epidermal growth factor receptor monoclonal antibody, compared with gem plus placebo as first-line therapy in patients with advanced pancreatic cancer. Patients with previously untreated, unresectable, locally advanced or metastatic pancreatic cancer were randomly assigned to receive gem: 1000 mg/m², 30-min i.v. once weekly (d1, 8, 15; q29) and nimo: fixed dose of 400 mg once weekly as a 30-min infusion, or gem plus placebo, until progression or unacceptable toxicity. The primary end point was overall survival (OS), secondary end points included time to progression, overall response rate, safety and quality of life. A total of 192 patients were randomized, with 186 of them being assessable for efficacy and safety (average age 63.6 years). One-year OS/progression-free survival (PFS) was 34%/22% for gem plus nimo compared with 19%/10% for gem plus placebo (HR = 0.69; P = 0.03/HR = 0.68; P = 0.02). Median OS/PFS was 8.6/5.1 months for gem plus nimo versus 6.0/3.4 mo in the gem plus placebo group (HR = 0.69; P = 0.0341/HR = 0.68; P = 0.0163), with very few grade 3/4 toxicities. KRAS wildtype patients experienced a significantly better OS than those with KRAS mutations (11.6 versus 5.6 months, P = 0.03). This randomized study showed that nimo in combination with gem is safe and well tolerated. The 1-year OS and PFS rates for the entire population were significantly improved. Especially, those patients with KRAS wildtype seem to benefit. The study was registered as protocol ID OSAG101-PCS07, NCT00561990 and EudraCT 2007-000338-38.

Background: Atu027 is a liposomally formulated short interfering RNA with anti-metastatic activity, which silences the expression of protein kinase N3 (PKN3) in the vascular endothelium. This trial was designed to assess the safety, pharmacokinetics and efficacy of Atu027 in combination with gemcitabine in advanced pancreatic carcinoma (APC). Methods: In total, 23 patients (pts) with inoperable APC were randomly assigned to gemcitabine combined with two different Atu027 schedules (0.235 mg/kg once weekly vs. 0.235 mg/kg twice weekly). ClinicalTrials.gov Identifier: NCT01808638. Results: The treatment was well-tolerated. There were Grade 3 adverse events (AEs) in 9/11 pts (arm 1) and 11/12 pts (arm 2), while Grade 4 AEs were reported for two pts in each arm. The AEs were mainly laboratory abnormalities without clinical significance. The median progression-free survival reached statistical significance in patients who had metastatic disease (1.6 vs. 2.9 months, p = 0.025). Disease control during treatment was achieved in 4/11 pts (arm 1) and in 7/12 pts (arm 2). Pts in arm 1 experienced stable global health status while pts in arm 2 reported improvement. Conclusions: Combining Atu027 with gemcitabine is safe and well tolerated. In pts with metastatic APC, twice-weekly Atu027 is associated with significantly improved outcomes. Our clinical results support the significant involvement of the vascular endothelium in the spread of cancer, and thus the further investigation of its target role.

3585 Background: Regorafenib is an oral multikinase inhibitor of angiogenic (VEGFR1-3, TIE2), stromal (PDGFR-β, FGFR), and oncogenic kinases (KIT, RET, B-RAF). Regorafenib resulted in a 74% disease control rate (PR+SD) in a phase I study in patients (pts) with refractory metastatic colorectal cancer (CRC). A phase III monotherapy trial in relapsing CRC pts is ongoing. Methods: The phase Ib study 11656 investigated the safety, PK, and efficacy of sequentially administered regorafenib in combination with mFOLFOX6 (FOLFOX) or FOLFIRI (oxaliplatin 85 mg/m² or irinotecan 180 mg/m², 400 mg/m² D/L-folinic acid, 400 mg/m² 5 FU bolus followed by 5 FU 2400 mg/m² for 46 h) every 2 wks as 1st or 2nd line treatment for CRC. Regorafenib 160 mg was given once daily on days 4-10 and 18-24 of every 4 wk cycle. Tumor response was evaluated per RECIST 1.0. Results: 45 pts (FOLFOX: n=25 , FOLFIRI: n=20) were enrolled. 12 pts were ongoing at data cutoff Dec 2010. Demographic variables were similar in both groups. The median treatment duration was 107 days in the FOLFOX and 112 days in the FOLFIRI group. The primary reason for discontinuation was PD (n=10), AE (n=12), consent withdrawn/other (n=8), metastasectomy surgery (n=3).The incidence of treatment related AEs is presented in the table below. Regorafenib had no significant effect on the PK of platinum and 5-FU, whereas exposure of SN-38 increased by 32%. Of the 21 pts in the FOLFOX group who were evaluable for efficacy, 4 achieved PR, 15 SD and 2 PD as best response. Of the 17 evaluable pts in the FOLFIRI group, 4 achieved PR, 11 SD and 2 PD. Conclusions: Regorafenib, when administered sequentially with standard chemotherapy, has shown acceptable tolerability and promising activity in 1st and 2nd line pts with CRC. Regorafenib increased the exposure to SN-38 in the FOLFIRI group, but was not associated with a reduced tolerability. Regorafenib combined with mFOLFOX6 or FOLFIRI will be evaluated in phase II CRC trials.

E13079 Background: High levels of VEGF protein correlate with a poor prognosis translating into poor OS of cancer patients. Bevacizumab in combination with paclitaxel significantly prolongs PFS and increases the objective RR in patients with breast cancer. Serum levels of VEGF increase, in a dose-dependent manner, with all oral TKIs inhibiting VEGFR-2; this reflects a potential escape mechanism of the tumor, consequently overcoming antiangiogenic TKI activity. Combination of sorafenib plus bevacizumab has impressive clinical activity in patients with mRCC, potentially due to overcoming such escape mechanisms. Methods: Titration of the minimal effective (MED) or maximum tolerable dose (MTD) of bevacizumab in combination with regular dosed weekly paclitaxel (90 mg/m² d1,8,15 q4wks) and continuous oral sorafenib (200 mg bid), that is sufficient to suppress the increase of VEGF levels. A total of 3-6 pts have been or will be treated per dose level with 0 mg, 1 mg, 2 mg, 3 mg and 5 mg bevacizumab q2wks, respectively. Blood levels of VEGF are assessed at baseline, and 8 h post-dose of first sorafenib on days 1 and 15 before the initial dose of bevacizumab, and thereafter before every bevacizumab infusion. Results: Currently 12 pts with various solid tumors were enrolled with bevacizumab doses of 0 mg (n=4), 1 mg (n=6), and 2 mg (n=2). Drug-related adverse events (AEs) observed so far were predominantly hand-foot- syndrome (HFS) (6 pts; CTC 3: 3pts), rash (CTC3: 1pt), stomatitis (3 pts; CTC3: 1 pt), PNP (2 pts; CTC3: 1 pt), diarrhea (CTC 3: 2 pts), granulocytopenia (CTC4: 1 pt), hoarseness (2 pts; CTC3: 1 pt). Treatment-related AEs leading to dose reduction, interruption or discontinuation were HFS (2 pts) and PNP (1 pt). So far, toxicities were not related to the dose of bevacizumab. Currently 9 pts are evaluable for response according to RECIST (ongoing SD: 8 pts, PD: 1 pt). Preliminary VEGF-data support the biological activity of the treatment. Conclusions: The combination of paclitaxel with sorafenib and bevacizumab is potentially highly efficacious, but toxicities might require special precautions. MED or MTD of bevacizumab in this combination have not been reached yet. No significant financial relationships to disclose.