Untreated Metastatic Pancreatic Cancer Research Articles

Abstract 4658: Genome wide CRISPR/Cas9 library screening identifies aurora kinase A as a regulator of elraglusib sensitivity in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with a dismal 5-year survival rate, highlighting the urgent need to improve drug response and overcome primary or acquired (secondary) resistance to conventional chemotherapy. Glycogen synthase kinase 3β (GSK-3β) is a target in PDAC and the GSK-3 inhibitor, elraglusib, has been shown to improve chemosensitivity of PDAC and survival in preclinical cancer models. In addition, data from phase II clinical trials in patients with previously untreated metastatic pancreatic cancer is demonstrating preliminary evidence of clinical benefit in patients receiving a combination of gemcitabine/nab-paclitaxel. While this early evidence is highly encouraging, the biological determinants of elraglusib response are unknown. Using genome wide CRISPR/Cas9 library screening, we identify aurora kinase A (AURKA), an oncogenic kinase with major roles in mitosis, as a critical regulator for elraglusib sensitivity. Elraglusib treatment activates AURKA by inducing a G2/M cell cycle arrest. We show that knocking out AURKA reduces the phosphorylation of polo like kinase 1 (PLK1), arresting cells in mitosis, and leading to mitotic catastrophe and significant apoptosis after elraglusib treatment. Strikingly, the AURKA inhibitor, alisertib, works synergistically with elraglusib to inhibit PDAC cell line growth and induce apoptosis. In summary, our results demonstrate that targeting AURKA is an effective approach to sensitize PDAC tumors to elraglusib. Citation Format: Li Ding, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Daniel Schmitt, Andrew Mazar, Hu Li, Daniel Billadeau. Genome wide CRISPR/Cas9 library screening identifies aurora kinase A as a regulator of elraglusib sensitivity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4658.

Abstract CT246: Phase 1b/2 study of giloralimab in combination with modified FOLFIRINOX with or without budigalimab in patients with untreated metastatic pancreatic cancer

Abstract Background: The 5-year survival rate for metastatic pancreatic cancer is ~3%, indicating an urgent need for novel therapies. Combination therapy with modified FOLFIRINOX (leucovorin, irinotecan, 5-fluorouracil, and oxaliplatin) and immunotherapy has been proposed for first-line metastatic pancreatic cancer to improve tolerability and clinical efficacy, respectively (NCCN, Pancreatic. 2021; Vonderheide, Annu. Rev. Med. 2020). The present study evaluates the safety, pharmacokinetics, and preliminary antitumor activity of modified FOLFIRINOX + giloralimab (CD40 agonist) with or without budigalimab (anti-PD-1) in patients with untreated metastatic pancreatic cancer. Methods: Multicenter, randomized phase 1b/2 study (NCT04807972) in patients (18-75 years) with untreated metastatic pancreatic cancer. The phase 1b (dose escalation) examines the safety dose level of giloralimab in a triplet of modified FOLFIRINOX + giloralimab + budigalimab using a Bayesian optimal interval [BOIN] design. BOIN design is utilized to guide giloralimab escalation decisions. In phase 2 (dose expansion), patients are randomized 1:1:1 to receive treatment with modified FOLFIRINOX (cohort A), modified FOLFIRINOX + giloralimab (cohort B), or modified FOLFIRINOX + giloralimab + budigalimab (cohort C). Randomization is stratified according to Eastern Cooperative Oncology Group performance status. Primary objectives are to assess the safety and tolerability of modified FOLFIRINOX + giloralimab + budigalimab (phase 1b) and to evaluate overall survival in patients treated with modified FOLFIRINOX + giloralimab with or without budigalimab (versus those receiving modified FOLFIRINOX alone; phase 2). Secondary objectives include characterizing the pharmacokinetics of giloralimab and budigalimab in combination with modified FOLFIRINOX, assessing the efficacy of modified FOLFIRINOX + giloralimab with or without budigalimab, and evaluating the safety/tolerability of modified FOLFIRINOX + giloralimab with or without budigalimab. Patients will receive giloralimab and budigalimab intravenously in combination with modified FOLFIRINOX in a 28-day cycle. Dose-limiting toxicities are assessed during the first cycle of dosing. Adverse events are evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events. Blood samples for pharmacokinetic analysis are collected at designated time points throughout the study. Responses are assessed by Response Evaluation Criteria in Solid Tumors version 1.1. Survival outcomes are described using the Kaplan-Meier method. Approximately 129 patients are planned to be included. Enrollment started in June 2021, with 7 patients enrolled as of November 2021. Citation Format: Dung T. Le, Marcia Cruz-Correa, David L. Bajor, Rocio Garcia-Carbonero, Marion Harris, Roberto Pazo-Cid, Hedy Kindler, Nelson Yee, Suneel Kamath, Maulik Patel, Hua Fang, William Henner, Patrick Hardesty, Martha Blaney, Michael McDevitt, Talia Golan. Phase 1b/2 study of giloralimab in combination with modified FOLFIRINOX with or without budigalimab in patients with untreated metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT246.

Abstract PO-015: A phase Ib/II trial of high dose ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with previously untreated metastatic pancreatic cancer (MPC)

Abstract Background: Increasing evidence suggests that high concentrations of AA (vitamin C) can decrease the growth of aggressive tumors, including Ras-mutant tumors. Based on the unmet need in MPC, its high frequency of Ras mutations, and prior work combining PP +C +G in pts with MPC (response rate of 70.5%, median survival 16.4 mos), we explored the addition of AA to that regimen. Pre and post treatment biopsies for biomarkers and digital spacial profiling are also being performed. Methods: This pilot trial utilized a 3 + 3 design for dose escalation of AA. Eligibility criteria included untreated stage IV MPC, ECOG 0-1, and measurable disease. Excluded were pts with a G6PD deficiency, renal oxalate stones, or need of capillary blood glucose monitoring as AA causes false low readings. The primary objective of the phase 1b was to determine the maximum tolerated dose (MTD) of AA in combination with PP +C +G in pts with MPC. Exploratory objectives included analysis of tumor texture on radiologic scans as an imaging biomarker for response; correlation between peak plasma levels of AA and response to treatment; potential biomarkers in the tumor including tumor immune cell infiltration, stromal activation, stem call enumeration; change in numbers of circulating tumor stem cells and macrophage lineage changes. Results: As of 7/2021, the phase Ib enrollment in this study has been completed. Six pts were treated in the cohort of AA 25 gm/m2, 4 pts at AA 37.5 gm/m2, and 7 pts at 56.25 gm/m2. The majority of all reported AEs were grades 1-2. The most common AEs related to study treatment were: platelet count decrease (70.6%), diarrhea (70.6%), hypomagnesemia (52.9%), dysgeusia (47.1%), peripheral sensory neuropathy (47.1%), nausea (35.3%), fatigue (35.3%), neutrophil count decreased (35.3%), and hypokalemia (35.3%). Of the 17 pts enrolled, 15 were evaluable. Response by RECIST 1.1 is 11 PR (73.3%), 2 SD (13.3%), 2 PD (13.3%). Evaluation of median PFS and OS is ongoing. Conclusions: This study has a high response rate of 73%. Most pts in all AA dosing cohorts experienced a brisk response to therapy. AA did not appear to add toxicities compared to historical AE data of PP +C +G and was well tolerated in all dose cohorts. The MTD of AA was not reached in the 56.25 gm/m2 cohort. The protocol allowed for an additional dose escalation of AA to 75 gm/m2. However, all pts in the 56.25 gm/m2 cohort achieved our goal of peak plasma AA levels of > 20 mM so the study was closed to enrollment. Quality of life measures, tumor tissue and blood sample analyses are underway. Supported by SU2C, Cancer Research UK, Lustgarten Foundation, Destroy Pancreatic Cancer & the Young family. Citation Format: Gayle S. Jameson, Erkut H. Borazanci, Daniel D. Von Hoff, Joshua D. Rabinowitz, Michael S. Gordon, Sarah D. LeGrand, Courtney Snyder, Karen Ansaldo, Denise J. Roe, Haiyong Han. A phase Ib/II trial of high dose ascorbic acid (AA) + paclitaxel protein bound (PP) + cisplatin (C) + gemcitabine (G) in patients (pts) with previously untreated metastatic pancreatic cancer (MPC) [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-015.

A phase II study of FOLFIRINOX with primary prophylactic pegfilgrastim for chemotherapy-na\xefve Japanese patients with metastatic pancreatic cancer

BackgroundAlthough FOLFIRINOX is currently one of the standard therapies for chemotherapy-naïve patients with metastatic pancreatic cancer (MPC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to evaluate the safety and efficacy of primary prophylactic pegfilgrastim with FOLFIRINOX in Japanese MPC patients.MethodsFOLFIRINOX (intravenous oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, levofolinate 200 mg/m2, 5-fluorouracil (5-FU) bolus 400 mg/m2 and 5-FU 46 h infusion 2400 mg/m2) and pegfilgrastim 3.6 mg on day 4 or 5, every 2 weeks was administered to previously untreated MPC patients. The primary endpoint was the incidence of FN during the first 3 cycles. The planned sample size was 35 patients, but the trial was predefined to discontinue enrollment for safety if 4 patients developed FN.ResultsAt the enrollment of 22 patients, 4 patients developed FN in the first cycle, resulting in an incidence of FN of 18% {95% confidence interval [CI], 0.5–40.3%}, and enrollment was discontinued early. The incidence of grade 3 or higher neutropenia was 36.4%. Median relative dose intensities during the initial 3 cycles of oxaliplatin, irinotecan, bolus 5-FU, infusional 5-FU, and levofolinate maintained high (100%, 89.0%, 100%, 66.0%, and 100%, respectively). Response rate and median overall survival were 54.5% (95% CI 32.7–74.9) and 15.7 months (95% CI 7.9–18.8), respectively.ConclusionsThis phase II study could not demonstrate any reduction in the incidence of FN, nevertheless some patients experience benefits for efficacy by maintaining dose intensity using prophylactic pegfilgrastim.Trial registrationhttp://www.umin.ac.jp/ctr/index-j.htm, UMIN000017538. Date of registration: May/13/2015

Phase I/II trial of sequential treatment of nab-paclitaxel in combination with gemcitabine followed by modified FOLFOX chemotherapy in patients with untreated metastatic exocrine pancreatic cancer: Phase I results

BackgroundAlthough occasioned through different mechanisms, the potential neurotoxicity and also haematological toxicity of nab-paclitaxel and oxaliplatin-based chemotherapy regimen were studied in this trial, which aimed to determine the maximum-tolerated dose (MTD) and to evaluate safety and efficacy of the combination in a sequential regimen of nab-paclitaxel, gemcitabine (GEM) and modified FOLFOX (mFOLFOX) in untreated patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Materials and methodsTreatment consisted of nab-paclitaxel (125/100 mg/m2) plus GEM (1000/800 mg/m2) on days 1, 8 and 15, followed by mFOLFOX (oxaliplatin [85/75/65 mg/m2], 5-FU bolus [400/300/200 mg/m2], 5-FU infusion [2400/2000/1600 mg/m2]) on day 28, of a 42-day cycle. Patients were enrolled at the highest dose level with a subsequent 3 + 3 dose de-escalation plan. ResultsEleven patients (median age = 61, 64% with performance status [PS] = 1) were eligible. All patients received the highest dose level. No de-escalation was needed. A dose-limiting toxicity was reported, an upper gastrointestinal haemorrhage. The MTD was nab-paclitaxel 125 mg/m2, GEM 1000 mg/m2, oxaliplatin 85 mg/m2, 5-FU bolus 400 mg/m2 and 5-FU infusion 2400 mg/m2. Common all-grade toxicities were neutropenia (73%), anaemia (55%), thrombocytopenia (55%) and asthenia (55%). Other relevant toxicities were paraesthesia (46%), nausea (36%), dysesthesia (27%) and pyrexia (27%). Objective response rate was 50% and disease control rate was 80%. ConclusionsThe regimen of nab-paclitaxel plus GEM followed by mFOLFOX showed favourable safety and tolerability profiles with significant anti-tumor activity. More data are being achieved in a randomised phase II trial, to confirm efficacy rates and dismiss long-term neurotoxicity concerns regarding the sequencing of nab-paclitaxel and oxaliplatin.

Integration of geriatric assessment into routine oncologic care and advances in geriatric oncology: A young International Society of Geriatric Oncology Report of the 2020 American Society of Clinical Oncology (ASCO) annual meeting

Integration of geriatric assessment into routine oncologic care and advances in geriatric oncology: A young International Society of Geriatric Oncology Report of the 2020 American Society of Clinical Oncology (ASCO) annual meeting

HGCSG 1803: Single-arm phase II study evaluating efficacy of oxaliplatin, irinotecan and S-1 combination therapy (OX-IRIS) in metastatic pancreatic cancer as first-line treatment.

TPS4668 Background: Combination chemotherapy with oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX) showed improved survival compared to gemcitabine monotherapy for patients with metastatic pancreatic cancer and has become the one of the standard regimens. Despite of its clinical benefit, FOLFIRNIOX needs continuous infusion of 5-FU for 46 hours, which impairs quality of life. In other gastrointestinal cancer, infuser pomp free regimens, in which oral 5-FU drug replace the continuous infusion of 5-FU, have developed as alternative regimen. Therefore, we planned to develop new combination chemotherapy with oxaliplatin, irinotecan and S-1 (OX-IRIS) for advanced pancreatic cancer. We previously conducted the phase Ⅰ study for assessing the safety and determining the recommended dose of OX-IRIS regimen. Methods: To evaluate efficacy and safety of OX-IRIS, HGCSG1803 study staeted as a multicenter, non-randomized, single arm, prospective, phase II study in December 2019. The patients with untreated metastatic or relapsed pancreatic cancer are eligible for this study. OX-IRIS is administered as follows; a 30-min intravenous infusion (IV) of antiemetic, a 2-h IV of oxaliplatin at 85 mg/m2, a 1.5-h IV of irinotecan at 150 mg/m2 on day 1 and day 15 of each 4-week cycle, and S-1 (40 mg/m2) was taken orally twice daily, from after dinner on day 1 to after breakfast on day 15, followed by a 14-day rest, and to be repeated every 2 weeks until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint is response rate, and the secondary endpoints are overall survival, progression-free survival, safety, and dose intensity for each drug. A total of 40 cases are planned for registration from 18 institutions in Japan within 2.5 years. Clinical trial information: jRCTs011190008 .

691P - Integrated population pharmacokinetic modelling of liposomal irinotecan in patients with various tumour types, including untreated metastatic pancreatic cancer (mPC)

BackgroundLiposomal irinotecan (nal-IRI) is a liposomal formulation of irinotecan which prolongs circulation of irinotecan and its active metabolite SN-38. This analysis describes the population pharmacokinetics (PK) of nal-IRI in patients with various tumour types, including untreated mPC. MethodsPlasma concentration data for total irinotecan (tIRI) and SN-38 from an open-label, phase 2 study of nal-IRI plus 5-fluorouracil/leucovorin and oxaliplatin in patients with untreated mPC (NCT02551991; N=48) were pooled with data from six other nal-IRI studies (five phase 1/2, one phase 3) in various tumour types. Data from overall 440 patients were used in the population PK model for tIRI and SN-38 after nal-IRI administration. PK parameters were estimated with non-linear mixed effects modelling. The adequacy of the model was assessed based on the uncertainty of parameter estimates, and on advanced evaluation methods such as visual predictive check. Potential covariates such as patient demographics and genotype were investigated to examine inter-individual variability. ResultstIRI is described by a two-compartment model with first-order elimination. SN-38 is formed directly by a first-order constant from the central compartment of nal-IRI or after using a transit compartment. In the pooled population (N=440), clearance was 0.1L/h and 150L/h for tIRI and SN-38, respectively. Central and peripheral volumes of distributions for tIRI were 4L and 0.4L, respectively. Consistent with previous data, tIRI clearance was 80% higher in patients of Asian ethnicity (n=154/440) than other populations. Increasing bilirubin levels were associated with lower SN-38 clearance, and tIRI and SN-38 clearances were 20% lower in females than males. The UGT1A128 7/7 homozygous genotype (6% of the study population) had no statistically significant impact on SN-38 clearance. Model evaluation was satisfactory for both tIRI and SN-38. ConclusionsThe PK of nal-IRI and SN-38 in patients with mPC is well described by the population model. The results suggest that UGT status has no impact on the PK of nal-IRI. Editorial acknowledgementOxford PharmaGenesis, Oxford, UK for providing editorial support, which was sponsored by Ipsen, Abingdon, UK. Legal entity responsible for the studyIpsen. FundingIpsen. DisclosureT. Macarulla: Honoraria (institution): Shire Pharmaceuticals; Honoraria (institution): Roche; Honoraria (institution): Tesaro; Honoraria (institution): Baxter; Honoraria (institution), Travel / Accommodation / Expenses: Sanofi; Honoraria (institution): Celgene; Honoraria (institution): QED Therapeutics; Honoraria (institution): Genzyme Europe; Honoraria (institution): Baxalta; Honoraria (institution), Travel / Accommodation / Expenses: Bayer; Honoraria (institution): Incyte; Honoraria (institution): Genzyme; Travel / Accommodation / Expenses: Merck; Travel / Accommodation / Expenses: H3 Biomedicine. K. Brendel: Full / Part-time employment: Ipsen. Z.A. Wainberg: Advisory / Consultancy: Lilly; Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Ipsen. F. Dayyani: Advisory / Consultancy: Array; Advisory / Consultancy, Speaker Bureau / Expert testimony: Eisai; Advisory / Consultancy, Speaker Bureau / Expert testimony: Genentech; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Amgen; Speaker Bureau / Expert testimony: Sirtex. B. Zhang: Full / Part-time employment: Ipsen. B. Belanger: Full / Parttime employment: Ipsen. Y. Moore: Full / Part-time employment: Ipsen. A. Pedret-Dunn: Full / Parttime employment: Ipsen. F. Maxwell: Full / Part-time employment: Ipsen. A. Dean: Advisory / Consultancy, Non-paid: Shire; Advisory / Consultancy, Non-paid: Specialised Therapeutics Australia; Travel / Accommodation / Expenses, Grant: Amgen. All other authors have declared no conflicts of interest.

A phase 1b dose escalation study of Wnt pathway inhibitor vantictumab in combination with nab-paclitaxel and gemcitabine in patients with previously untreated metastatic pancreatic cancer

SummaryVantictumab is a fully human monoclonal antibody that inhibits Wnt pathway signaling through binding FZD1, 2, 5, 7, and 8 receptors. This phase Ib study evaluated vantictumab in combination with nab-paclitaxel and gemcitabine in patients with untreated metastatic pancreatic adenocarcinoma. Patients received vantictumab at escalating doses in combination with standard dosing of nab-paclitaxel and gemcitabine according to a 3 + 3 design. A total of 31 patients were treated in 5 dosing cohorts. Fragility fractures attributed to vantictumab occurred in 2 patients in Cohort 2 (7 mg/kg every 2 weeks), and this maximum administered dose (MAD) on study was considered unsafe. The dosing schedule was revised to every 4 weeks for Cohorts 3 through 5, with additional bone safety parameters added. Sequential dosing of vantictumab followed by nab-paclitaxel and gemcitabine was also explored. No fragility fractures attributed to vantictumab occurred in these cohorts; pathologic fracture not attributed to vantictumab was documented in 2 patients. The study was ultimately terminated due to concerns around bone-related safety, and thus the maximum tolerated dose (MTD) of the combination was not determined. The MAD of vantictumab according to the revised dosing schedule was 5 mg/kg (n = 16).

P-215 - Progression-free survival is a predictor of survival in patients with untreated metastatic pancreatic cancer: A systematic literature review

P-215 - Progression-free survival is a predictor of survival in patients with untreated metastatic pancreatic cancer: A systematic literature review

A systematic review examining the relationship between progression-free survival and overall survival in adults with untreated metastatic pancreatic cancer.

e15724 Background: The majority of pancreatic cancers are diagnosed in advanced stages with a median survival of 3 to 5 months. From 2005 to 2012, the US Food and Drug Administration approved 41 oncology drugs; surrogate endpoints were used in 84% of the trials providing the basis of approval. The aim of this systematic review was to evaluate the relationship between PFS/TTP and OS in metastatic pancreatic cancer. Methods: A systematic literature review used the Centre for Reviews and Dissemination principles to identify studies that reported median PFS or TTP and OS. We searched Medline, Medline In-Process, and Embase, with the following additional limits: English language and published 1/1990 to 7/ 2016. Selection criteria, defined a priori, included chemo, immuno or targeted therapy, randomized controlled studies (Phase 2 or 3) in patients with metastatic pancreatic cancer. Studies were assessed for quality using the Cochrane Risk of Bias tool and the Jadad scale. Studies were excluded if full-text articles were not available, and if patients received chemotherapy plus radiotherapy or surgery. Correlation analyses and weighted linear regression were used to assess the association between median PFS/TTP and median OS. The distributions of median PFS/TTP and OS were examined using scatterplots. Results: 1,691 studies were identified. After screening by title and abstract, 212 full articles were assessed, of which 28 studies (evaluating 6,734 patients) met the selection criteria. The mean median PFS/TTP and OS were, respectively, 3.82 months (range 1.2 to 6.8 months), and 7.06 months (range 2.5 to 11.9 months). The correlation coefficient was 0.837; 95% CI (0.734-0.903) indicating a very strong positive correlation between median OS and median PFS/TTP. Regression analysis indicated that median PFS/TTP was a highly significant predictor of median OS = 2.177 + 1.247 * median PFS/TTP (p < 0.001). Conclusions: The analysis demonstrates a very strong positive correlation of median PFS/TTP with median OS for the treatment of metastatic pancreatic cancer, which reinforces the hypothesis that PFS or TTP is a useful surrogate endpoint for OS in this cancer setting.

Results of a randomized phase II trial of an anti-notch 2/3, tarextumab (OMP-59R5, TRXT, anti-Notch2/3), in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

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]

Gemcitabine and S-1 as first-line chemotherapy in patients with metastatic or advanced pancreatic cancer.

492 Background: Gemcitabine and S-1 are both effective antitumor chemotherapeutic agents for pancreatic cancer. We evaluate the efficacy and safety of the combination of gemcitabine (GEM) and S-1 (GS) as first-line chemotherapy in Chinese patients with metastatic or advanced pancreatic cancer. Methods: Patients with previously untreated metastatic or advanced pancreatic cancer who had measurable lesion(s) were enrolled. Gemcitabine was administered intravenously at a dose of 1,000 mg/m (2) during 30 min on days 1 and 8 and oral S-1 was given twice daily (BSA < 1.25 m(2), 80 mg/day; 1.25 ≤ BSA < 1.50 m(2), 100 mg/day; 1.50 m(2) ≤ BSA, 120 mg/day) on days 1-14 followed by a drug-free interval of 1 week every 21-day cycle. Results: Twenty-five patients were enrolled between 2012 and 2014. The assessed overall response rate was 24 % partial response in 6 patients, 56 % stable disease in 14 patients, and 20 % progressive disease in 5 patients. Sixteen patients (64 %) received second-line chemotherapy. The estimated median progression-free survival and median overall survival times were, respectively, 5.6 months (95 % CI 4.1-6.7 months) and 10.2 months (95 % CI 6.5-14.2 months). The major hematological toxicities were included grade 3/4 leucocytopenia in 8 patients (32 %), grade 3/4 neutropenia in 13 patients (52 %), and one patients (4 %) suffered grade 1 febrile neutropenia. The common grade 3/4 non-hematological toxicity was Anorexia, rash and fatigue, held the proportion of 12%, 16% and 12%, respectively. Conclusions: Gemcitabine and S-1 (GS) combination therapy showed promising activity with acceptable toxicities as first-line chemotherapy in Chinese patients with metastatic or advanced pancreatic cancer.

Development of peripheral neuropathy and its association with survival during treatment with nab-paclitaxel plus gemcitabine for patients with metastatic adenocarcinoma of the pancreas: A subset analysis from a randomised phase III trial (MPACT)

BackgroundIn a phase III trial in patients with metastatic pancreatic cancer (MPC), nab-paclitaxel plus gemcitabine (nab-P/Gem) demonstrated greater efficacy but higher rates of peripheral neuropathy (PN) versus Gem. This exploratory analysis aimed to characterise the frequency, duration, and severity of PN with nab-P/Gem in the MPACT study. Patients and methodsPatients with previously untreated MPC received nab-P/Gem or Gem. PN was evaluated using a broad-spectrum group of Standardised Medical Dictionary for Regulatory Activities Queries (SMQ) and graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0. A case report form was completed by physicians on day 1 of each cycle (also graded by NCI CTCAE version 3.0). ResultsIn the nab-P/Gem arm, 227/421 patients (54%) experienced any-grade PN and 70 (17%) experienced grade III PN. No grade IV PN was reported. Most early-onset PN events were grade I, and treatment-related grade III PN occurred in 7% of patients who received up to three cycles of nab-P. Of those who developed grade III PN with nab-P/Gem treatment, 30 (43%) improved to grade ≤I (median time to improvement = 29 days) and 31 (44%) resumed therapy. Development of PN was associated with efficacy; median overall survival in patients with grade III versus 0 PN was 14.9 versus 5.9 months (hazard ratio, 0.33; P < .0001). Conclusionsnab-P/Gem was associated with grade III PN in a small percentage of patients. PN development was associated with longer treatment duration and improved survival. Grade III PN was reversible to grade ≤I in many patients (median ≈ 1 month) NCT00844649.

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer

Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m(2) weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m(2) via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m(2) weekly for 3 weeks in a 4-week cycle (GEM). A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85-1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68-1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Abstract B97: A phase II trial of low-dose multiagent chemotherapy with gemcitabine, taxotere, xeloda, and cisplatin (GTX-C) in subjects with metastatic pancreatic cancer

Abstract Background: Triplet chemotherapy has been shown to delay the emergence of resistance and extend survival in patients with metastatic pancreatic adenocarcinoma. Four drug regimens, even at low doses, may further improve survival by simultaneously targeting multiple oncogenic pathways. Methods: A phase II study of GTX-C (capecitabine 500 mg bid on days 1-14, and the combination of gemcitabine 500 mg/m2 (10 mg/m2/min), taxotere 20 mg/m2 and cisplatin 20 mg/m2 on days 4 and 11) was initiated in newly diagnosed untreated metastatic pancreatic cancer patients. The primary endpoint was progression-free survival rate at 6 months and designed such that the regimen would be considered active if the 6-month PFS rate was &amp;gt;75% and inactive if &amp;lt; 50%. Results: Twenty-eight patients were enrolled. All patients were ECOG 0-1. Eighty-six percent of patients had evidence of liver metastases and 25% had biliary stents in place at time of study initiation. Median CA19-9 was 6,159 U/mL (37-154,323 U/mL). Median length of follow-up was 10.1 months. Grade 3/4 related adverse events included: nausea/vomiting (7%), transaminitis (10%), anemia (14%), thrombocytopenia (24%), and neutropenia (55%). However, febrile neutropenia occurred in only 3 patients (10%) and not until cycles 6, 14, and 15. PFS rate at 6 months was 74.2% (95% CI: 53.3% - 86.8%). The partial response (PR) rate was 50%, stable disease (SD) rate was 39% and the disease control rate (DCR) was 89%. CA19-9 declines of &amp;gt;80% occurred in 77% of patients with measurable levels. Estimated median PFS was 8.4 months (95% CI: 6.1-10.6 months) and OS was 12.9 months (95% CI: 10.0-NA months) as of 11/14/2013. Ten additional patients have been enrolled onto an expansion cohort in which the period off between cycles has been changed from 7 to 14 days. Conclusions: GTX-C is highly active and well-tolerated in patients with metastatic pancreatic cancer and should be tested in a larger, comparative study. Clinical trial information: NCT01459614. Citation Format: Dung Le, Daniel Laheru, Luis A. Diaz, Jr. A phase II trial of low-dose multiagent chemotherapy with gemcitabine, taxotere, xeloda, and cisplatin (GTX-C) in subjects with metastatic pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B97.

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

4117 Background: Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Methods: Patients with metastatic adenocarcinoma of the pancreas were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m2 via 2-hr continuous IV (CIV) infusions given twice weekly for 3 weeks of a 4-week cycle (RIG+GEM) versus gemcitabine 1000mg/m2 weekly for 3 weeks in a 4-week cycle (GEM). Results: A total of 160 patients were enrolled globally and randomly assigned to RIG+GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG+GEM group vs. 6% in the GEM group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The primary outcome of the study, median overall survival (OS), was 6.1 months for RIG+GEM versus 6.4 months for GEM (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median progression-free survival (PFS) was 3.4 months for both groups (HR = 0.96; 95% CI, 0.68-1.36). The partial response rate by Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1 was 19% versus 13% for RIG+GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40/47, 85%). Other mutations detected included TP53 (13 cases) and PIK3CA(1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of RIG+GEM failed to demonstrate an improvement in survival or response compared to GEM in metastatic pancreatic adenocarcinoma. Rigosertib had a similar safety profile to that observed in other trials of the IV formulation. Clinical trial information: NCT01360853.

Final results of phase Ib of anticancer stem cell antibody tarextumab (OMP-59R5, TRXT, anti-Notch 2/3) in combination with nab-paclitaxel and gemcitabine (Nab-P+Gem) in patients (pts) with untreated metastatic pancreatic cancer (mPC).

278 Background: Tarextumab (TRXT), fully human IgG2 antibody, inhibits signaling Notch 2, 3 receptors. Tumor regression seen in Notch 3 patient-derived PC xenografts when TRXT added to Nab-P+Gem. The maximum tolerated dose (MTD) of single agent TRXT was 7.5mg/kg every other week (Smith, EORTC 2012); the main dose limiting toxicity (DLT) was Grade 3 diarrhea. This study evaluates MTD, pharmacokinetics (PK), pharmacodynamics (PD) and early efficacy of TRXT + Nab-P+Gem in mPC. Methods: Cohorts of 3-6 pts treated at 6 dose levels of TRXT. TRXT IV Days 1 + 15 with GEM 1000mg/m2 alone (first two cohorts) or nab-P 125 mg/m2 and GEM 1000mg/m2on Days 1, 8, 15 of every 28-day cycle. Biomarker analysis of surrogate tissue and tumor undertaken. Results: By 08/22/14, N= 40 treated. TRXT 15 mg/kg selected as Phase 2 dose. 1 DLT Grade 3 diarrhea in 15 mg/kg cohort. Frequently reported (≥15%) TRXT adverse events(AEs) were: diarrhea(60%), fatigue(43%), anemia(28%), decreased appetite (18%) and nausea(15%); most grade 1 or 2 and managed supportively. Other AEs (≥ 30%) were: cytopenia, alopecia, vomitng and peripheral edema. GEM or Nab-P+Gem did not alter PK of TRXT. Notch pathway-related genes, HEYL, HES2, NOTCH2 and cancer stem cell markers were altered in hair follicles at TRXT &gt; 7.5 mg/kg combined with Nab-P+Gem. Plasma, blood RNA biomarkers were also modulated by TRXT + Nab-P+Gem. Conclusions: TRXT + Nab-P+ Gem is well tolerated. 15 mg/kg is the selected Phase 2 dose of TRXT. Encouraging anti-tumor activity was observed. Final safety, efficacy, PK and PD results in surrogate and serial tumor tissues will be presented. The Phase 2 randomized, placebo-controlled ALPINE study is underway. Clinical trial information: NCT01647828. [Table: see text]

A phase II/III randomized study to compare the efficacy and safety of rigosertib plus gemcitabine versus gemcitabine alone in patients with previously untreated metastatic pancreatic cancer.

342 Background: Rigosertib (ON 01910.Na), a dual non-ATP inhibitor of polo-like kinase 1 (Plk1) and phosphoinositide 3-kinase (PI3K) pathways, was assessed in patients with treatment-naïve metastatic pancreatic adenocarcinoma. Methods: Patients with metastatic adenocarcinoma of the pancreas were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800mg/m2 via 2-hr CIV infusions given twice weekly for 3 weeks of a 4-week cycle versus gemcitabine 1000mg/m2 weekly for 3 weeks in a 4-week cycle. Results: A total of 160 patients were enrolled globally and randomly assigned to rigosertib plus gemcitabine (106 patients) or gemcitabine (54). The most common grade 3 or higher adverse events were neutropenia (8% in the rigosertib plus gemcitabine group vs. 6% in the gemcitabine group), hyponatremia (17% vs. 4%), and anemia (8% vs. 4%). The primary outcome of the study, median OS, was 6.1 months in the gemcitabine plus rigosertib arm versus 6.4 months with gemcitabine alone (hazard ratio (HR), 1.24; 95% confidence interval [CI], 0.85-1.81). The median PFS was 3.4 months for both groups (HR, 0.96; 95% CI, 0.68-1.36). The overall best response between arms were partial response rates of 19% versus 13% and stable disease in 50% versus 56% in the gemcitabine plus rigosertib versus gemcitabine alone, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40/47, 85%), which included c.35G&gt;T, p.G12V (12 cases), c.35G&gt;A, p.G12D (21 cases), c.34G&gt;C, p.G12R (4 cases), c.34G&gt;T, p.G12C (1 case) and c.183C&gt;A, p.Q61H (2 cases). Other mutations detected included TP53 (13 cases) and PIK3CA(1 case). No correlation between mutational status and efficacy was detected. Conclusions: The combination of rigosertib plus gemcitabine failed to demonstrate an improvement in survival or response compared to gemcitabine alone in metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01360853.

Tumor reduction in pancreatic versus metastatic sites in a randomized phase III study (MPACT) of weekly nab-paclitaxel (nab-P) plus gemcitabine (Gem) versus Gem alone.

382 Background: nab-P + Gem was superior to Gem alone in MPACT, a phase III metastatic pancreatic cancer (PC) trial, for all endpoints examined. An updated analysis verified the superior overall survival of nab-P + Gem vs Gem alone (median 8.7 vs 6.6 months; hazard ratio 0.72; P &lt; 0.001). Whether antitumor agents may have differential activity on pancreatic vs metastatic lesions in PC has not been definitively addressed. This prespecified analysis examined the activity of nab-P + Gem vs Gem alone in reducing tumor size in pancreatic and metastatic lesions. Methods: Previously untreated metastatic PC pts (N = 861) were randomized 1:1 to receive nab-P 125 mg/m2 + Gem 1000 mg/m2 days 1, 8, and 15 every 4 weeks or Gem alone 1000 mg/m2weekly for 7 weeks followed by 1 week of rest (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycles ≥ 2). Most pts (99%) underwent spiral CT imaging, allowing precise tumor measurement. Changes in the sum of target tumor diameter from baseline to postbaseline nadir were evaluated separately for pancreatic and metastatic lesions by independent radiological review. Results: Baseline sizes of pancreatic and metastatic tumors were comparable between treatment arms (Table). nab-P + Gem elicited an approximately 3-fold greater median percentage decrease vs Gem alone in pancreatic (−22.15% vs −7.02%) and metastatic (−24.27% vs −8.74%) tumor size, agreeing with the 3-fold higher overall response rate of target lesions by RECIST. Tumor shrinkage was similar between pancreatic and metastatic lesions. Conclusions: nab-P + Gem was associated with a greater reduction in tumor size of both primary and metastatic lesions compared with Gem alone. Clinical trial information: NCT00844649. [Table: see text]