Refractory Metastatic Pancreatic Cancer Research Articles

Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials.

CT041 is a chimeric antigen receptor (CAR)-modified T-cell therapy that specifically targets claudin18.2 in solid tumors. Here, we report the pooled analysis results of two exploratory clinical trials to evaluate CT041 in patients with previously treated pancreatic cancer (PC). These two multicenter, open-label phase I/Ib trials (CT041-CG4006, CT041-ST-01) have a similar target population and evaluation schedule. The primary objective was to assess the safety and tolerability of CT041, whereas secondary objectives included efficacy, pharmacokinetics, and immunogenicity. The combined cohort comprised 24 patients with advanced PC. Among them, five patients (20.8%) had previously received one line of therapy, whereas 19 (79.2%) received ≥2 lines of therapy. The most common treatment-emergent adverse events of grade 3 or more were preconditioning-related hematologic toxicities. Cytokine release syndrome (CRS) and GI disorders were most reported grade 1 or 2 adverse events. The overall response rate and disease control rate were 16.7% and 70.8%. The median progression-free survival (mPFS) after infusion was 3.3 months (95% CI, 1.8 to 6.2), and the median overall survival (mOS) was 10.0 months (95% CI, 5.5 to 17.6). The median duration of response (mDoR)was 9.5 months (95% CI, 2.6 to Not reached), with a DoR rate at 12 months of 50% (95% CI, 5.8 to 84.5). The mPFS (6.0 v 1.0 months, P < .001) and mOS (17.6 v 4.0 months, P < .001) were prolonged in patients achieving partial response/stable disease than the progressive disease group. CA19-9 levels had reduced by at least 30% in 17 (70.8%) patients. In patients with metastatic PC after progression on previous therapy, CT041 demonstrated a tolerable safety profile and encouraging anticancer efficacy signals. Response benefit observed here needs to be ascertained in the future.

Abstract CT218: Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer

Abstract Background: Triptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. Preclinical investigations indicate significant activity against super enhancer targets. In the phase I clinical trial of Minnelide™ activity in highly refractory metastatic pancreatic carcinoma was observed. Hence, we undertook this study in patients with chemotherapy refractory metastatic PDAC. Our aims were to determine clinical anticancer effects, and to define effects of the drug on super enhancer expression and downstream effects. Methods: Eligibility criteria included stage IV PDAC progressing on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease by RECIST 1.1. Planned sample size was up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 was administered intravenously over 30 minutes on days 1-21, followed by a 7-day rest period in a 28-day cycle. Exploratory objectives included: analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, proteomics and metabolism. Results: 17 patients were treated. There were no RECIST responses or stable disease. However, evidence of activity was observed in 4 of 15 evaluable patients. This activity included progression after 117 days treatment in 1 patient and reductions in CT tumour size or FDG-PET uptake and/or significant decreases in circulating CA19.9 levels in 3 others. Minnelide was generally well tolerated. Treatment related toxicities &amp;gt; 3 were: neutropenia 4 patients and cerebellar ataxia 1 patient.Exploratory analyses included ATAC-Seq on paired biopsies where gene ontology analyses showed downregulation of genes negatively regulating cell cycle and upregulation of genes controlling cell cycle checkpoints. Other exploratory analyses will be presented. Conclusions: The study identified a tolerable drug dose and evidence of activity in a highly chemotherapy-refractory population which provides encouraging proof for the principle of targeting TFIIH in human PDAC. Supported by SU2C, Cancer Research UK, Lustgarten Foundation Citation Format: David Propper, Erkut Borazanci, Peter J. O'Dwyer, Daniel Von Hoff, Joseph Hartlebury, Corina E. Antal, Gerard I. Evan, HaiYong Han, Michael Downes, Ronald Evans, Joshua Rabinowitz, Emmanuel Petricoin, Ashok Saluja, Mohana Velagapudi, Hitendra Patel. Phase II open label trial of Minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT218.

Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer.

Interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway inhibition may overcome chemoresistance of metastatic pancreatic cancer (MPC). We sought to determine the safety and recommended dose of tocilizumab (TCZ), an IL-6 receptor monoclonal antibody, and biological correlates of tumor shrinkage in patients with gemcitabine (GEM)/nanoparticle albumin-bound paclitaxel (nab-PTX)-refractory MPC. This phase 1 study enrolled 10 patients with MPC who had progressed after GEM/nab-PTX. Patients initially received TCZ 8 mg/kg on Day 1 and nab-PTX 100 mg/m2 + GEM 750 mg/m2 on Days 2, 9, and 16. Before and at the end of Cycle 1, biopsy of liver metastases was performed 3-5 h after levofloxacin (LVFX) administration to measure LVFX infiltration into tumor tissue. No dose-limited toxicities occurred, and the recommended dosage of TCZ was determined to be 8 mg/kg. Treatment-emergent adverse events occurred in 80% of patients, of which decreased neutrophil count was the most common. Tumor reduction during Cycle 1 was observed in four patients, who were defined as responders. In paired-biopsy samples, responder-related biological activities were an increase of cleaved PARP expression of tumor nuclei (p = 0.01), a decrease of proliferative cancer-associated fibroblasts (CAFs) (p = 0.08), and an increase of LVFX infiltration in the tumor (p = 0.04). A decrease of phosphorylated STAT3 expression (p = 0.02) favored an increase in LVFX infiltration. In conclusion, TCZ + GEM/nab-PTX-rechallenge had a manageable safety profile and showed preliminary activity via inhibition of CAF and improved intratumoral drug infiltration in MPC.

Randomized phase 2 study of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy in patients with refractory metastatic pancreatic cancer (CHECKPAC).

554 Background: Pancreatic ductal adenocarcinoma remains one of the most lethal diseases. Investigating novel treatment strategies for patients with metastatic pancreatic cancer (mPC) is crucial. The purpose of this phase II trial study was to evaluate the clinical benefit of nivolumab with or without ipilimumab in combination with stereotactic body radiotherapy (SBRT) in patients with mPC. Methods: Between November 2016 and December 2019, patients with refractory mPC were randomly assigned 1:1 to SBRT of 15 Gy with nivolumab or nivolumab/ipilimumab stratified by performance status. Primary endpoint was clinical benefit rate (CBR) defined as proportion of patients with complete or partial response (PR) or stable disease, according to RECIST 1.1. Simon’s 2-stage phase II optimal design was used independently for both arms with CBR determining expansion to second stage. Secondary endpoints included safety, overall response rate, duration of response (DOR), progression free survival and overall survival (OS). Exploratory analyses included biomarkers related to immune response. Results: Eighty-four patients (41 SBRT/nivolumab and 43 SBRT/nivolumab/ipilimumab) received at least one dose of study treatment. CBR was 17.1% (95% CI, 8.0 to 30.6) for SBRT/nivolumab and 37.2% (95% CI, 24.0 to 52.1) for SBRT/nivolumab/ipilimumab. PR was observed in one patient in SBRT/nivolumab and lasted for 4.6 months. Six patients in SBRT/nivolumab/ipilimumab obtained a PR with a median DOR of 5.4 months (95% CI, 4.2 - not reached). All responders had mismatch repair proficient tumors. Grade 3 or higher treatment-related adverse events occurred in 10 (24.4%) patients in SBRT/nivolumab and in 13 (30.2%) patients in SBRT/nivolumab/ipilimumab. PD-L1 expression by tumor proportion score or combined positivity score of ≥1% was not associated with clinical benefit. On-treatment decrease in serum interleukin (IL)-6, IL-8 and CRP levels was associated with better OS. Conclusions: Clinical meaningful antitumor activity and a manageable safety profile were demonstrated after SBRT/nivolumab/ipilimumab in patients with refractory mPC. Clinical trial information: NCT02866383.

A phase II, open-label pilot study evaluating the safety and activity of Nal-IRI in combination with 5-FU and oxaliplatin in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI Study) (NCT03483038).

TPS790 Background: Neoadjuvant treatment for borderline resectable pancreatic cancer (PCa) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Irinotecan liposomal injection (Nal-IRI) is FDA approved with a well-tolerated safety profile in relapsed, refractory metastatic PCa. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with borderline resectable PCa without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board, adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive FOLFNal-IRINOX regimen as per Table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30 day postoperative complication rate. Clinical trial information: NCT03483038 . [Table: see text]

Abstract CT165: Phase II open label trial of minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer

Abstract BackgroundTriptolide and its water-soluble prodrug, Minnelide™, have shown promising activity against pancreatic ductal adenocarcinoma (PDAC) in both in vitro and in vivo experiments. Triptolide induces apoptosis in pancreatic cancer cells by different pathways, including caspase-dependent apoptotic death and caspase -independent autophagic death. It inhibits the activity of the TFIIH general transcription factor complex and modulates the transcriptional landscape of both the stroma and cancer cell compartments. In the epithelial tumour compartment, triptolide down-regulates key transcription factors such as c-MYC. In the phase I clinical trial of Minnelide™ significant activity in highly refractory metastatic pancreatic carcinoma was observed. Hence we undertook this study in patients with chemotherapy refractory metastatic PDAC. MethodsEligibility criteria include stage IV PDAC that has progressed on standard chemotherapy, Karnofsky performance status ≥ 70%, and measurable disease. Planned sample size is up to 35 patients with interim analysis after the first 18 evaluable patients, aiming for at least a 20% difference in DCR (10% v 30%). Minnelide™ 0.67 mg/m2 is administered intravenously over 30 minutes on days 1-21, followed by a 7 day rest period in a 28 day cycle. Exploratory objectives include: analysis of tumor texture on radiologic scans as a non-invasive biomarker for response, as well as analyses of paired tumour biopsies for changes in immune cell infiltration, stromal activation, chromatin accessibility, phopshoproteomics and metabolism. # NCT03117920The trial opened 4/2017 and as of 12/2018, 18 patients have been treated. Supported by SU2C, Cancer Research UK, Lustgarten Foundation Citation Format: David Propper, Haiyong Han, Daniel Von Hoff, Erkut Borazanci, Tannishtha Reya, Jonathan Ghergurovich, Irina Pshenichnaya, Corina Antal, Rachel Condjella, Shreya Sharma, Peter O'Dwyer, Trevor Littlewood, Hitendra Patel, Ashok Saluja, Mohana Velagapudi, Lifeng Yang, Michael Downes, Ronald Evans, Gerard Evan. Phase II open label trial of minnelide™ in patients with chemotherapy refractory metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT165.

A phase Ib dose-escalation and cohort-expansion study of safety and activity of the transforming growth factor (TGF) β receptor I kinase inhibitor galunisertib plus the anti-PD-L1 antibody durvalumab in metastatic pancreatic cancer.

4124 Background: Pancreatic cancer (PC) is characterized by a highly immunosuppressive microenvironment, and immune checkpoint inhibitors as monotherapy have been ineffective to date. TGFβ is commonly viewed as a powerful immunosuppressive cytokine, and inhibition of its signaling reverses this suppression and activates adaptive immune responses. A combination of TGFβ and PD-L1 inhibition may act synergistically to induce immune restoration and to improve antitumor responses. This Phase 1b study (NCT02734160) evaluated the combination of galunisertib plus durvalumab in recurrent or refractory metastatic PC. Methods: Eligible patients (pts) were ≥18 years old, had ECOG status ≤1, and had not received treatment with anti-PD-1, anti-PD-L1, or TGFβ R1 kinase inhibitors. The primary objective was to assess the safety and the recommended dose of galunisertib given 14 days on/14 days off in combination with durvalumab 1500 mg every 4 weeks. Four dose levels of galunisertib were tested in the dose escalation portion of the study: 50 mg QD, 50 mg BID, 80 mg BID and 150 mg BID, followed by the cohort expansion portion of the study at the recommended Phase 2 dose (RP2D). Secondary objectives included preliminary assessment of activity by response rate, (RECIST v1.1), median PFS (mPFS), and OS (mOS). Results: 42 pts (25F/17M) were treated in the study (median age 56.5 y; 71.4% had received ≥2 prior systemic regimens). There was no dose limiting toxicity and galunisertib 150 mg BID was chosen as the RP2D. In the 32 pts treated at this dose, Grade ≥3 related AEs included AST and GGT elevations (2 pts each), and ALT and alkaline phosphatase elevations, and neutropenia (1 pt each). One partial response and 7/32 stable diseases were observed (disease control rate 25%); mPFS was 1.9 months (95% CI: 1.5, 2.2) and mOS was NR (95% CI: 3.6, NR). Biomarker data will be presented at the meeting. Conclusions: The combination of galunisertib plus durvalumab had an acceptable tolerability and safety profile. The activity of this combination in second and third line PC patients warrants further consideration. Clinical trial information: NCT02734160.

A phase II, open-label pilot study evaluating the safety and activity of nal-IRI in combination with 5-FU and oxaliplatin in preoperative treatment of pancreatic adenocarcinoma (NEO-Nal-IRI study).

TPS476 Background: Neoadjuvant treatment for borderline resectable pancreatic cancer (PCa) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given neoadjuvantly. Irinotecan liposomal injection (Nal-IRI) is FDA approved with a very tolerable safety profile in refractory metastatic PCa. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen and demonstrate safe and effective delivery in the neoadjuvant setting. Methods: This phase II, open-label, single-arm study targets patients with borderline resectable PCa without metastatic disease. Other key eligibility criteria include age ≥ 18 years, measurable disease by RECIST v1.1, adequate cardiac, renal, hepatic function, and Eastern Cooperative Oncology Group performance status of 0 to 1. Patients receive FOLFNal-IRINOX regimen as per table every two weeks for four months followed by disease reassessment. Patients who remain surgical candidates will undergo surgical resection within four to eight weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in perioperative setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable patients to demonstrate a reduction in historical 30 day postoperative complication rate. FOLFNal-IRINOX regimen. Clinical trial information: NCT03483038. [Table: see text]

Phase 1b dose-escalation and cohort-expansion study of the safety, tolerability, and efficacy of a novel transforming growth factor-β receptor I kinase inhibitor (galunisertib [G]) administered in combination with the anti-PD-L1 antibody (durvalumab [D]) in recurrent or refractory metastatic pancreatic cancer.

TPS501 Background: Transforming growth factor-β (TGF-β) can suppress adaptive and innate anti-tumor immune responses. G (LY2157299) is an oral small molecule inhibitor of TGF-β receptor I kinase that down-regulates phosphorylation of SMAD2, abrogating activation of the canonical pathway. Programmed cell death-ligand 1 (PD-L1) is upregulated in a broad range of cancers including pancreatic; expression of PD-L1 helps tumors evade immune system detection through binding to PD-1 on cytotoxic T lymphocytes. D (MEDI4736) is an anti-PD-L1 monoclonal antibody that blocks PD-L1/PD-1 interactions. Blockade of both TGF-β and PD-L1 pathways could reverse immunosuppression associated with these molecules by activating adaptive and innate anti-tumor immune responses. Methods: This two part phase 1b open-label study will enroll patients (pts) with recurrent or refractory metastatic pancreatic cancer. Part 1 is a 3+3 dose-escalation assessment of the safety and tolerability of G (4 escalating doses) and D (constant dose). After dose-limiting toxicity evaluation, cohort expansion with approximately 25 pts at the dose determined in the dose escalation portion will occur. Eligible pts have recurrent or refractory metastatic pancreatic cancer ( ≤ 2 prior systemic regimens) regardless of PD-L1 status; ECOG PS 0-1. Pts who have received prior therapy targeting T-cell costimulation or checkpoint pathways, or have received a TGF-β R1 kinase inhibitor are not eligible. Pretreatment and on-treatment biopsies will be obtained. The primary objective is to assess safety and tolerability of G in combination with D by identifying dose-limiting toxicities and to assess safety of the combination at the dose-escalation-established dose. Secondary objectives are pharmacokinetics; immunogenicity; preliminary anti-tumor activity; overall survival. Exploratory objectives are to examine biomarkers relevant to G, D, and the disease state. Enrollment began on 15-June-2016; as of 13-Sep-2016, 1 pt entered treatment. Clinical trial information: NCT02734160.

692P - Regorafenib in patients with refractory metastatic pancreatic cancer. An open-label phase II study (RESOUND)

692P - Regorafenib in patients with refractory metastatic pancreatic cancer. An open-label phase II study (RESOUND)

Safety and antitumor activity of chimeric antigen receptor modified T cells in patients with chemotherapy refractory metastatic pancreatic cancer.

3007 Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an immunosuppressive microenvironment with a scarcity of effector T cells. Adoptive T cell therapy to restore anti-tumor...

A phase II study of ganetespib (G) as second- or third-line therapy for metastatic pancreatic cancer (MPC).

297 Background: Heat shock protein 90 (HSP90) regulates folding, stability and function of signaling proteins such as EGFR, IGF-1R, c-Met, ERBB4, PDGFRα and c-Ret, several of which are key pathways for MPC pathogenesis. G prevents Hsp90 binding to client proteins leading to inactivation and degradation, disrupting signaling that promotes cancer progression. This phase II study is designed to evaluate the efficacy of G in patients (pts) with refractory MPC. Methods: Pts with MPC in the 2nd or 3rd line setting, with PS 0-1, received G 175 mg/m2intravenously once weekly for 3 weeks out of a 4 week cycle. Primary endpoint was disease control rate (DCR) at 8 weeks, with a goal of 70% DCR. Secondary endpoints were response rate (RR), overall survival (OS), and safety. 43 pts were planned for initial accrual. Simon’s optimal two-stage design was used to assess 8 week DCR. G was considered inactive if 8 or fewer pts among the first 15 treated had disease control after 8 weeks of treatment (tx). Results: Seventeen pts were enrolled, and 14 received G. Median age was 65 (range 33-77), 4 female and 10 male. Eight received 1 prior line of therapy, and 6 received 2 prior lines of therapy. Grade 3 related toxicities include abdominal pain (4), fatigue (4), diarrhea (4), hyponatremia (9), nausea (1) and vomiting (1). There were no Grade 4-5 related events. DCR at 8 weeks was 21%, and OS was 2.5 months. Three pts didn’t complete tx; 1 due to disease progression after first cycle, 1 due to tx related toxicity, and 1 withdrew after 2 tx’s. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions: Single agent G was tolerable with modest disease control when used as a single agent in refractory MPC. This disease is resistant to chemotherapy, and given the emerging data in both lung and breast cancer suggesting improved activity of G in combination with cytotoxic agents, studies combining this agent with chemotherapy in MPC are under development. Supported by Vanderbilt-Ingram Cancer Center CCSG (P30CA68485) and Synta. Clinical trial information: NCT01227018.

Abstract LB-221: Phase II study of therapy selected by molecular profiling in patients with previously treated metastatic pancreatic cancer. A study of the stand up to cancer (SU2C) consortium

Abstract Background: A significant number of patients with refractory metastatic pancreatic cancer (mPC) have an adequate performance status (PS) and able to pursue subsequent therapy. However the outcome of salvage therapy is poor, there is no standard therapy and selection is empiric. We designed a phase II study to evaluate the efficacy of therapy selected by molecular profiling for mPC patients. Methods: Eligible patients had evidence of mPC, had progressive disease following at least one systemic therapy and a metastatic lesion amenable to percutaneous biopsy. All patients were required to have a KPS of &amp;gt;70 and adequate bone marrow, kidney and liver function. The study required 35 evaluable patients, this design has a power of 86% for detecting a true one year survival rate of &amp;gt; 20% versus the null hypothesis survival rate of &amp;lt; 5%. Patients underwent a percutaneous biopsy, sample was fresh frozen, divided into 3 and sent for IHC, CGH and microarray (MA). Treatment selection was based on the Target Now® IHC assay (Caris Life Sciences, Irving, TX). For CGH analysis, flow sorted nuclei of diploid and aneuploid tumor cell populations were processed and hybridized to 400,000 feature CGH arrays. MA was matched to the NCI-60 cell line expression and the Pan-Xeno bank at Johns Hopkins University for drug sensitivity. Results: Forty nine subjects were accrued between August 2010-January 2012. There were no major complications due to biopsy. Fourteen patients did not start protocol therapy either due to insufficient tumor on biopsy or due to worsening cancer related symptoms after biopsy. The demographics of evaluable patients (n=34) are M/F (59%/41%), the majority had KPS of 70-80 and age range is 34-78 (median 62.5 years). Time from first diagnosis of mPC to biopsy ranged from 5.8-26.7 months (median 16.1 months). Patients had 1-6 prior regimens with a median of 2. The most common IHC targets were Topoisomerase 1 or 2 and Thymidylate synthase. Only commercially available agents were prescribed. Common regimens/ agents recommended were FOLFIRI, FOLFOX, irinotecan and doxorubicin. Conclusions: Study has completed accrual, one patient treated with FOLFIRI is a one year survivor. Genomic and pathway analysis is ongoing to understand response and molecular factors of patients with long term survival from first diagnosis. In most patients, molecular profiling resulted in at least 2 targets for therapy and a non cross resistant regimen could be implemented. (Supported by a SU2C- pancreatic dream team grant.) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-221. doi:1538-7445.AM2012-LB-221

A phase II study of S-1 in gemcitabine-refractory metastatic pancreatic cancer

Gemcitabine monotherapy or gemcitabine-containing combination chemotherapy is the standard first-line therapy for advanced pancreatic cancer. After disease progression, there is no standard regimen available. In a previous phase II trial, S-1 has been reported to show considerable efficacy, achieving a response rate of 37.5% in chemo-naïve patients with pancreatic cancer. This study evaluated the efficacy and toxicity of S-1 in patients with gemcitabine-refractory metastatic pancreatic cancer. Eligibility criteria were histologically proven pancreatic adenocarcinoma with confirmation of progressive disease while receiving gemcitabine-based first-line chemotherapy, 20-74 years of age, Karnofsky performance status of 80-100 points, with measurable metastatic lesions, adequate hematological, renal and liver functions, and written informed consent. S-1 was administered orally at 40 mg/m(2) twice daily for 28 days with a rest period of 14 days as one course. Administration was repeated until the appearance of disease progression or unacceptable toxicity. The primary endpoint of this study was an objective response, and secondary endpoints included toxicity, progression-free survival (PFS) and overall survival, as well as clinical benefit response in symptomatic patients. Forty patients from two institutions were enrolled between September 2004 and November 2005. The most common adverse reactions were fatigue and anorexia, although most of those adverse reactions were tolerable and reversible. One patient developed grade 3 pneumonitis without neutropenia and recovered with appropriate antibiotic treatment. Although no complete response was seen, partial response was obtained in six patients (15, 95% confidence interval, 3.9-26%). Stable disease was noted in 17 patients (43%), and progressive disease in 15 patients (38%). Out of 19 evaluable patients, a clinical benefit response was observed in four patients (21%). The median PFS was 2.0 months, and the median survival time was 4.5 months with a 1-year survival rate of 14.1%. S-1 as monotherapy had marginal anti-tumor activity with tolerable toxicity in patients with gemcitabine refractory metastatic pancreatic cancer.

A phase I clinical and pharmacokinetic study of weekly docetaxel followed by flavopiridol: promising activity in metastatic pancreatic cancer

4096 Background: Flavopiridol (F), a potent cyclin dependent kinase inhibitor, potentiates docetaxel (Doc) induced apoptosis at nanomolar concentrations (300 nm). Significant tumor regression has been seen in tumor xenografts when Doc is given 3–7 hours before F. Methods: In view of this finding, we designed an ongoing phase I trial in advanced solid tumors with fixed dose Doc (35 mg/m2 ), followed 4 hours later by escalating doses of F (20–80 mg/m2) administered weekly over one hour, for 3 weeks out of every 4. Standard phase I eligibility criteria apply. Prior Taxane therapy is allowed. Results: Median characteristics of 27 evaluable patients: age 57 (39–77), KPS 90% (70–90), 11 males/ 16 females, 2 prior regimens (range 0–8). The combination has been well-tolerated, with 1 dose limiting toxicity (DLT) occurring at 70 mg/m2 (grade 3 mucositis), and 1 DLT at 80 mg/m2 (grade 4 neutropenia). Pharmacokinetic (PK) studies demonstrate Cmax ranging from 1.342±0.646 μM (F 20 mg/m2) to 4.167±0.016 μM (F 60 mg/m2). Due to wide interpatient variability, no relationship between dose and Cmax has been seen. There is no appreciable difference in Cmax between cycles 1 and 2. We have observed 5 partial responses (PR) to treatment in pancreatic (2), breast (2), and ovarian (1) cancers. Stable disease (SD) has been seen in 10 patients, including 4 with pancreatic cancer previously treated with gemcitabine (3,4,6, and 2+ months). Conclusions: The combination is safe and effective with PK data exceeding the 300 nm of F needed to enhance apoptosis at all dose levels. Significant activity is seen in gemcitabine refractory metastatic pancreatic cancer (10 patients treated: 2 PR, 4 SD) for which a phase II trial is currently planned. No significant financial relationships to disclose.

Phase II trial evaluating a 2 weekly regimen of irinotecan (IR) and 5-FU/leucovorin (LV) in patients with metastatic pancreatic cancer refractory to chemotherapy

4229 Background: Advanced pancreatic cancer has a poor prognosis despite treatment with gemcitabine. There is no established second line therapy and few trials have addressed this. IR is active in pancreatic cancer and exhibits synergy with 5-FU in preclinical studies. We conducted a phase II trial to evaluate the efficacy and toxicity of a 2 weekly regimen of IR combined with 5-FU/LV in relapsed and refractory metastatic pancreatic cancer. Methods: Patients with metastatic disease who progressed during chemotherapy or within 3 months of completion were recruited. IR (180mg/m2), LV (125mg/m2) and 5-FU (400mg/m2 bolus followed by 1200mg/m2 48hour infusion) were given 2 weekly to a maximum of 24 weeks. Response was evaluated after 12 weeks of treatment by CT. Treatment was stopped at disease progression or unacceptable toxicity. Results: Fifteen patients (7M,8F) were recruited and 13 were evaluable for response. The median age was 60 years (36 – 71). All patients were ECOG performance status 0–2. Thirteen p...

Irinotecan combined with gemcitabine, 5-fluorouracil, leucovorin, and cisplatin (G-FLIP) is an effective and noncrossresistant treatment for chemotherapy refractory metastatic pancreatic cancer.

Single agents have only modest activity as treatment for metastatic pancreatic cancer with response rates of less than 10% and median survivals of less than 6 months. Evaluations of single-agent gemcitabine and rubitecan as second-line treatment for relapsed pancreatic cancer have reported good patient tolerability and median survivals of 3.85 months and 4.7 months, respectively. Regimens incorporating two drugs have demonstrated encouraging activity and clinical impact compared with single-agent therapy. G-FLIP is a regimen designed to incorporate four active single agents into a tolerable and active combination. This analysis is a retrospective evaluation of the efficacy and safety of the G-FLIP regimen as second-line chemotherapy in a series of consecutively treated patients with metastatic pancreatic cancer. G-FLIP was administered over 48 hours and repeated every 2 weeks. Day 1 treatment consisted of sequentially administered gemcitabine 500 mg/m(2), irinotecan 80 mg/m(2), leucovorin 300 mg, 5-fluorouracil (5-FU) 400 mg/m(2) bolus followed by infusional 5-FU 600 mg/m(2) over 8 hours. Day 2 treatment consisted of leucovorin 300 mg and 5-FU 400 mg/m(2) bolus, followed by cisplatin 50 to 75 mg/m(2), and then infusional 5-FU 600 mg/m(2) over 8 hours. Thirty-four patients with histologically confirmed metastatic pancreatic cancer were consecutively treated. The median patient age was 64.5 years (range 41-82 years) and all patients had objective disease progression on prior therapy: 32 patients had disease progression with gemcitabine and 31 had disease progression with a gemcitabine/5-fluorouracil/cisplatin combination. Grade 3-4 hematological toxicities included anemia (23%), thrombocytopenia (53%), and neutropenia (38%). There were no grade 3-4 neutropenic fevers, treatment-related mortalities, or withdrawals. Nonhematological grade 3-4 toxicities were rare: nausea/vomiting (3%), neurotoxicity (3%), nephrotoxicity (6%), and diarrhea (3%). Based on RECIST criteria a partial response (PR) was attained in eight patients (24%) and seven patients had stable disease (SD). Seven and six patients who attained a PR or SD, respectively, had disease progression with prior gemcitabine-based therapy. The median time to disease progression for all 34 patients was 3.9 months and 5.9 months for the eight patients who attained a PR. Median overall survival for all 34 patients was 10.3 months. Adding a single new drug such as irinotecan to the same first-line chemotherapy combination upon disease progression may be an important alternative to switching to different drug classes for treatment of relapsed/resistant cancer. The promising clinical outcomes and moderate toxicity associated with G-FLIP in this heavily pretreated group warrant development of this novel regimen including tests as first-line therapy in patients with diseases likely to be responsive to the drugs contained in this combination.

Phase I and pharmacokinetic study of irofulven, a novel mushroom-derived cytotoxin, administered for five consecutive days every four weeks in patients with advanced solid malignancies.

To evaluate the toxicity and pharmacologic behavior of the novel mushroom-derived cytotoxin irofulven administered as a 5-minute intravenous (IV) infusion daily for 5 days every 4 weeks to patients with advanced solid malignancies. In this phase I trial, 46 patients were treated with irofulven doses ranging from 1.0 to 17.69 mg/m(2) as a 5-minute IV infusion (two patients received a 1-hour infusion) daily for 5 days every 4 weeks. The modified continual reassessment method was used for dose escalation. Pharmacokinetic studies were performed on days 1 and 5 to characterize the plasma disposition of irofulven. Forty-six patients were treated with 92 courses of irofulven. The dose-limiting toxicities on this schedule were myelosuppression and renal dysfunction. At the 14.15-mg/m(2) dose level, renal dysfunction resembling renal tubular acidosis occurred in four of 10 patients and was ameliorated by prophylactic IV hydration. The 17.69-mg/m(2) dose level was not tolerated because of grade 4 neutropenia and renal toxicity, whereas the 14.15-mg/m(2) dose level was not tolerable with repetitive dosing because of persistent thrombocytopenia. Other common toxicities included mild to moderate nausea, vomiting, facial erythema, and fatigue. One partial response occurred in a patient with advanced, refractory metastatic pancreatic cancer lasting 7 months. Pharmacokinetic studies of irofulven revealed dose-proportional increases in both maximum plasma concentrations and area under the concentration-time curve, while the agent exhibited a rapid elimination half-life of 2 to 10 minutes. Given the results of this study, the recommended dose of irofulven is 10.64 mg/m(2) as a 5-minute IV infusion daily for 5 days every 4 weeks. The preliminary antitumor activity documented in a patient with advanced pancreatic cancer and the striking preclinical antitumor effects of irofulven observed on intermittent dosing schedules support further disease-directed evaluations of this agent on the schedule evaluated in this study.