Michel Ducreux

Introduction: Poor outcome in pancreatic ductal adenocarcinoma (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which may compromise chemotherapy access to tumors. In animal models, PEGPH20 degrades HA in tumors. Key endpoint data from a Phase 2 study showed that PEGPH20 plus chemotherapy improved efficacy over chemotherapy alone in tumors retrospectively identified to accumulate HA (“HA-High”). The objectives of this Phase 3 study are to compare efficacy and safety of standard-dose nab-paclitaxel (NAB) and gemcitabine (GEM) combined with either PEGPH20 or placebo in patients with HA-High, previously untreated, Stage IV PDA. Primary endpoints are progression-free survival (PFS) and overall survival (OS). Secondary endpoints are objective response rate, duration of response, and safety.

10069 Background: A substantial proportion of breast, colo-rectal and prostate cancer patients (pts) can expect long term disease free survival after their primary treatment. Among those, fatigue commonly persists after diagnosis (dx) and can be debilitating. In this study, we evaluated the incidence of fatigue 2 years (y) after cancer dx and its association with health behaviors. Methods: We used a French population based cross-sectional study, which included a representative sample of pts from 12 cancer types (VICAN2). VICAN2 surveyed 4347 pts 2 y after dx. There is a 99% completion rate of fatigue related questions. For this study, we included 2017 pts with breast (1237), colo-rectal (348) and prostate (432) cancer without evidence of metastases at dx or relapse 2y after dx and with fatigue information. Severe fatigue was defined as average score of EORTC QLQC30 fatigue subscale ≥40 at 2y after dx. There were aOR] for severe fatigue, 95% confidence interval [95% CI]: 0.97, 0.96-0.98), gender (aOR, 95 CI male vs. female: 0.5, 0.3-0.8), comorbidities (aOR, 95 CI yes vs. no: 2.0, 1.6-2.4) and treatment type (aOR, 95 CI radiation vs. no: 1.5, 1.1-2.0). Conclusions: Fatigue continues to be a substantial problem for cancer survivors 2 y after dx. Some factors that may contribute to persistent fatigue (health behaviors) may be amenable to interventions.

TPS4148 Background: Patients (pts) with metastatic or locally advanced, non-resectable, Well-Differentiated Duodeno-Pancreatic (WDDP) NETs are treated following European guidelines. Pts with more aggressive disease, i.e. progressive and/or symptomatic metastases, significant hepatic invasion ( > 30-50%), and/or bone metastases, combination chemotherapy is considered; otherwise biotherapy (everolimus or sunitinib) is an option. The recommendations are to stop chemotherapy once disease control is obtained. The concept of maintenance therapy is well established in several cancer types. In this study we will evaluate the role of a somatostatin analogue (LAN) as maintenance in patients with stable/responding disease after 1L therapy (which may have been interrupted for tolerability issues) until progression. Somatostatin analogues are well tolerated and have demonstrated anti-proliferative effect making them ideal candidates for maintenance therapy. Methods: REMINET is an academic randomized, double-blind, placebo-controlled, phase II/III study. A total of 222 adults patients pts with a metastatic (synchronous or metachronous) or locally advanced, non-resectable, grade 1 or 2 WDDP NETs (WHO 2010 classification; Ki-67 ≤ 20%) and documented stable disease or objective response after 1L therapy at least 4 weeks prior to randomization, will be enrolled and randomly assigned in a 1:1 ratio to receive 120 mg LAN or placebo, every 28 days, until disease progression or unacceptable toxicity. Stratification factors: Centre, Grade 1 vs. 2, 1L treatment (chemotherapy vs. biotherapy). The primary endpoint of the phase III part is Progression-Free Survival (PFS) assessed by the investigators (RECIST v1.1). The aim of the phase II part is to demonstrate a 6-months PFS > 45% in LAN arm. Main secondary endpoints are PFS according to central review, overall survival, safety and quality of life. Frozen blood samples (-80°C) will be BioBanked for ancillary studies. The study is currently open in Europe. Status: A total of 13 patients are already randomized. Clinical trial information: NCT02288377.

4030 Background: Circulating tumor cells (CTC) with CellSearch Veridex, is a prognostic marker in breast, colon and prostate cancer approved by the Food and Drug Administration but is not validated in gastroesophageal adenocarcinomas (GEA). Objective: To evaluate the prognostic value of CTC in advanced GEA before and during treatment (Tx). Methods: 134 patients (pts) were enrolled in the biological substudy of the randomized trial PRODIGE 17 ACCORD 20 MEGA testing FOLFOX +/- panitumumab or rilotumumab in 1^st-line Tx of locally advanced or metastatic GEA. Blood samples were collected on CellSave tubes on day (D)0 and D28, after 2 cycles. CTC were detected with CellSearch Veridex. Prognostic value of CTC was analyzed using the Cox model. Results: Quantification of CTC at D0 and D28 was achieved for respectively 106 and 65 pts. The median of CTC at D0 was 1 [range: 0-415], with 40 (38%), 17 (16%), 10 (9%), and 39 (37%) pts with 0, 1, 2, or > 2 CTC, respectively. A CTC level at D0 ≥ 2 was significantly associated with worse PFS and OS. The number of CTC decreased under Tx regardless of Tx arm (p < 0.001). The persistence of CTC ≥ 2 at D28 was associated with even poorer PFS and OS as compared to D0. After adjustment on tumor location, histological type (diffuse vs intestinal), age, ECOG PS and the number of metastases (1 vs > 1), CTC ≥ 2 at D0 remained an independent prognostic factor for PFS (HR: 1.71; 95%CI, 1.06-2.77; p = 0.03) and OS (HR: 2.03; 95%CI, 1.19-3.48; p = 0.01). No interaction was found between CTC and Tx received. Conclusions: Quantification of CTC before Tx could be a useful prognostic tool in advanced GEA. A CTC threshold ≥ 2 seems to have better discriminant value than the presence or absence of CTC. CTC quantitation at D28 may help to adapt Tx early in non-responding pts. Clinical trial information: NCT01443065.

E15036 Background: Early tumor shrinkage has been associated with improved long-term outcome in patients (pts) with chemotherapy (chemo)-refractory LM-CRC. We examined the prognostic relevance of early tumor response after hepatic artery infusion of triplet chemotherapy combined with intravenous (IV) Cetuximab (Cet) in pts with unresectable LM-CRC. Methods: Pts received IV-Cet (500 mg/m2) and HAI of Irinotecan (180mg/m2), 5–Fluorouracil (2800 mg/m2), and Oxaliplatin (85mg/m2) every two weeks. Tumor response (RECIST) was based on CT scans ± MRI q3 courses. Pts were categorized as early-responders (CR or PR after 3 courses – at » 6 weeks), late responders (CR or PR > 3 courses) and non-responders (SD or PD). The rate of conversion to liver surgery (R0-R1), progression free survival (PFS) and overall survival (OS) were compared. Results: 57/64 registered pts (89%) received ³ 3 courses. They were assessed for response, which occurred early for 16/57 pts (28%), late for 10 pts (17.5%) or not at all for 31 pts (54.4%). The early-responders had similarly extensive disease as the other pts (median of 12 LM, median largest diameter = 37 mm, bilateral LM for 81% pts). Grade 3-4 diarrhea and asthenia were least in the early responders (6.3% vs 22.0%, and 0% vs 26.8%, p = 0.024, respectively).R0-R1 resection rate was twice as high in the early response group as compared to the other group (7/16; 48,8% vs 10/41; 24,4%, p = 0.10). PFS curves did not differ. In contrast. median OS was significantly longer in the 16 early-responders - 34.5 months [32.1 -36.9] - as compared to both the 41 non-early responders - 20.2 [13.6 – 26.8]; p = 0.010); and the 10 late responders - 12.0 [6.9 -17.2]; p = 0.001. Conclusions: Best clinical tolerability, LM conversion-to-resection, and survival outcomes were obtained in pts achieving an early tumor response on combined triplet hepatic artery infusion and IV Cet. The rapid disease-modifying effect of HAI is an important asset for curative intent medico-surgical strategies, and awaits prospective confirmation. Clinical trial information: NCT00852228.

E15003 Background: IAHCT is more and more recognized in the management of LMCRC. Regarding its anti-angiogenic effect bevacizumab (B) could be considered as a good candidate for IAH treatment. This phase II evaluate IAH administration of B in second line treatment of LMCRC combined with systemic treatment. We report here the results of the planned interim analysis on toxicity plus those on efficacy as the trial closed prematurely. Methods: Inclusion criteria: patients (pts) with LMCRC after failure to a 1st line of IV CT ; ECOG performance status (PS) 0 or 1; at least one liver lesion evaluable by RECIST; extra-hepatic disease acceptable when limited to one or two lung metastases or lymph nodes potentially accessible to a curative treatment. They had to receive IAH treatment with B, 7.5 mg/kg every 3 weeks, and systemic CT with capecitabine (2 g/m²/day (d) 14 d, followed by 7 d rest) + irinotecan (200 mg/m² every 21d) or oxaliplatin (130 mg/m² every 21 d) depending on the 1st line received. Results: Between June 2013 and February 2015, 10 pts from 5 centers were included: 6 men, 4 women (median age 61 years); ECOG PS0 (n = 7) and PS1 (n = 3); limited extra-hepatic disease in 4 pts. Median duration of 1st line treatment was 6 months. IAH catheter was implanted surgically in one pt and radiologically in 9. Pts had an average of 6 cycles of IAH B, 3 received oxaliplatin and 7 irinotecan concomitantly. There was one grade (G) 3 allergic reaction to IAH B, one G3 abdominal pain, one G3 mucositis, one G3 nausea and one G3 vomiting events. Related to the use of B, 2 G3 thromboembolic events and 3 G3 hypertension were observed. In the 9 evaluable pts, 2 had partial response (22%), 5 stable disease (56%) and 2 progressive disease (22%). The median progression-free and overall survival were 5.2 months 95%CI [1.6 – 6.2] and 13.5 months [4.8 – Not reached], respectively. Conclusions: IAH administration of bevacizumab in patients with LMCRC seems to be feasible with no major side effect. The efficacy reported did not suggest a major effect of this treatment that should rather be used in combination with IAH chemotherapy such as oxaliplatin. We thank the PHRC for its financial support. Clinical trial information: NCT01677884.