Gemcitabine In Patients Research Articles

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.

2312 Japanese phase I trial of hypoxia-activated prodrug evofosfamide (TH-302) as monotherapy in patients with solid tumors or in combination with gemcitabine in patients with advanced pancreatic cancer

2312 Japanese phase I trial of hypoxia-activated prodrug evofosfamide (TH-302) as monotherapy in patients with solid tumors or in combination with gemcitabine in patients with advanced pancreatic cancer

Abstract CT139: Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors

Abstract Background: Checkpoint kinase 1 (Chk1) acts at S and G2/M checkpoints to allow time for high-fidelity DNA replication and repair before cell cycle progression. Chk1 inhibition converts a transient genotoxic insult from chemotherapy into a cytotoxic event by overriding cell cycle arrest, allowing cells mitosis with DNA damage. GDC-0425 is an oral, selective Chk1 inhibitor. GDC-0425 enhances gemcitabine (gem) efficacy in tumor xenograft models. Greater chemopotentiation is observed in cancer cell lines lacking p53 activity. Methods: A phase I dose-escalation trial (3+3+3 design) included patients (pts) with refractory solid tumors and ECOG performance status (PS) ≤ 1. Pts received a single dose of GDC-0425 on day -7 for PK evaluation followed by 21-day cycles of gem on Days 1 and 8 and GDC-0425 on Days 2 and 9 at gem (mg/m2) + GDC-0425 (mg) dose levels of 750 + 60, 1000 + 60, and 1000 + 80. p53 was evaluated in archival tumor tissue by gene sequencing, immunohistochemistry, and gene expression signature. Safety, pharmacokinetics (PK), pharmacodynamics, and tumor response were investigated. Results: Of 40 pts treated, 55% were female, median age was 56 years (range 33-82), and 68% had ECOG PS 0. Most common tumor types were breast (n = 10), non-small cell lung (n = 5), and cancer of unknown primary (CUP, n = 4). Maximum concentrations of GDC-0425 were achieved within 4 hours of dosing and its half-life was approximately 16 hours. Target exposures associated with checkpoint abrogation and anti-tumor activity in preclinical models were exceeded at 60 mg. No PK interaction was observed with GDC-0425 and gem. Dose escalation was halted at GDC-0425 80 mg with gem 1000 mg/m2 as 3 of 6 pts experienced Grade 4 thrombocytopenia as a dose-limiting toxicity (DLT); 1 pt also had Grade 3 neutropenia that delayed Cycle 2 (DLT). Blood counts recovered with treatment interruption and supportive care. The maximum tolerated dose of GDC-0425 was 60 mg with gem 1000 mg/m2. The most frequent adverse events (AEs) (all grades) related to GDC-0425 and/or gem were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). Serious AEs related to GDC-0425 and/or gem occurred in 8 pts: neutropenia and thrombocytopenia (n = 2 each); leukopenia, ALT/AST/GGT increased, pyrexia, rash, dyspnea, gastric ulcer, and gastroenteritis (n = 1 each). Median number of administered cycles was 3.5 (range 1-14). There were 3 partial responses in pts with triple-negative breast cancer (TNBC, TP53 mutated), melanoma, and CUP (n = 1 each). Conclusions: It is safe and feasible to administer GDC-0425 with a standard dose of gem. At the doses assessed, bone marrow suppression is common but manageable and exposures exceed those predicted by preclinical models to inhibit Chk1. Clinical activity was observed, including 1 patient with TP53 mutated TNBC. Citation Format: Jeffrey R. Infante, Antoine Hollebecque, Sophie Postel-Vinay, Todd Bauer, Beth Blackwood, Marie Evangelista, Sami Mahrus, Frank Peale, Xuyang Lu, Srikumar Sahasranaman, Rui Zhu, Yuan Chen, Xiao Ding, Elaine Murray, Jennifer Schutzman, Jennifer Lauchle, Jean-Charles Soria, Patricia LoRusso. Phase I study of GDC-0425, a checkpoint kinase 1 inhibitor, in combination with gemcitabine in patients with refractory solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT139. doi:10.1158/1538-7445.AM2015-CT139

Abstract LB-003: High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer

Abstract Background: The genomes of metastatic pancreatic cancers contain a myriad of intrachromosomal aberrations indicating a likely high prevalence of DNA repair deficiencies indicating sensitivity to DNA damaging agents such as the platinum’s. Because of this, the drug cisplatin was added to an albumin-bound paclitaxel + gemcitabine regimen, which has already been determined to improve survival over gemcitabine alone in a randomized phase III trial (NEJM 2013; 369:1691-1703). Objectives: To determine the efficacy and safety of albumin-bound paclitaxel and gemcitabine plus cisplatin for patients with advanced pancreatic cancer Methods: Eligibility criteria included Stage IV pancreatic cancer, no prior chemotherapy for systemic disease, KPS ≥ 70; life expectancy ≥ 12 weeks and measurable disease. The doses were albumin-bound paclitaxel 125 mg/m2 undiluted, gemcitabine 1000 mg/m2 in 500 ml of normal saline (NS), each infused over 30 minutes on days 1 and 8 of a 21 day cycle, along with 3 different dose levels of cisplatin (25, 37.5 or 50 mg/m2) in 500 ml of NS infused over 60 minutes, after the nab-paclitaxel infusion. Pre and post cisplatin hydration was given. Results: To date, 10 patients have been entered on study with all patients being evaluable, (baseline and at least one follow up CT scans completed). There have been 2 complete responses (20%), 6 partial responses (PR), (60%), 1 stable disease (10%), and 1 patient with progressive disease (10%), by RECIST 1.1 criteria. An exponential decrease in CA19-9 correlating with the t1/2 of the marker was noted. Response was seen rapidly with PR observed at the first staging evaluation at 9 weeks in 7 of 10 patients. The 8th patient achieved a PR at 18 weeks. Serious adverse events occurred in 4 patients: non-neutropenic sepsis/pneumonia (n = 1), and non-neutropenic bacteremia (n = 1) in the cisplatin 25 mg/m2 cohort; clostridium difficile colitis (n = 1) with cisplatin 37.5 mg/m2; and neutropenic fever/pneumonia (n = 1) with cisplatin 50mg/m2. Discussion: The study has completed phase Ib and will be expanded at the phase II dose of cisplatin 25 mg/m2 for a total of 25 patients. If this favorable response rate is confirmed, this 3 drug regimen could be further developed both for patients with advanced disease as well as in neoadjuvant and adjuvant settings. Supported by grants from the Seena Magowitz Foundation and the SU2C Dream Team Citation Format: Gayle S. Jameson, Erkut Borazanci, Elizabeth Poplin, Michael T. Barrett, John Crowley, Adam Rosenthal, Amy Stoll-D'Astice, Karen L. Ansaldo, Steven Boone, Leticia Lebron, Ramesh K. Ramanathan, Ronald L. Korn, Daniel D. Von Hoff. High complete and partial response rate in a phase Ib pilot trial with cisplatin plus albumin-bound paclitaxel and gemcitabine in patients with advanced pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-003. doi:10.1158/1538-7445.AM2015-LB-003

Abstract A97: Control of PDAC tumor progression by RNA interference targeting indoleamine 2,3-dioxygenase using salmonella as a delivery vehicle facilitated by PEGPH20

Abstract The dismal prognosis of late stage, unresectable pancreatic adenocarcinoma (PDAC) patients has prompted the search for novel chemotherapeutic agents. However, PDAC tumors are encapsulated by a remarkable fibrotic extracellular matrix (ECM), termed desmoplasia that prevents efficient intratumoral delivery of therapeutics. Thus, current PDAC therapies such as gemcitabine, Abraxane, erlotinib, and folfirinox must be given at elevated doses resulting in systemic toxicity with only marginal improvement in patient survival. The increased deposition of ECM components, such as hyaluronan (HA), surrounding and internal to the tumor mass serves as the ideal target for reducing desmoplasia and improving drug delivery. PEGPH20 is a pegylated hyaluronidase developed by Halozyme Therapeutics that depletes HA and increases vascular permeability in spontaneous murine PDAC tumors. Data from a Phase 1b trial indicates a clinical benefit of using PEGPH20 with gemcitabine in patients with high levels of PDAC-associated HA. In the present work, we tested a unique combination of PEGPH20 with a Salmonella-based therapeutic, shIDO-ST, which expresses an inhibitory RNA (RNAi) that degrades indoleamine 2,3-dioxygenase (IDO) mRNA. We observed striking regression in 100% of mice (N=4/group) with our unique therapeutic combination leading to elimination of orthotopically transplanted PDAC tumors, whereas combinations of gemcitabine and Abraxane marginally stabilized tumor growth (p<0.001, ANOVA). The conditions of these experiments were 90 μg PEGPH20 administered alone or combined with shIDO-ST (5 million CFU on day 14 and 18 (post-tumor implantation)), shScrambled (Scr)-ST (5 million CFU on day 14 and 18), or Abraxane (120 mg/Kg given i.v. on days 14, 18, and 22) + Gemcitabine (100 mg/Kg given i.p. on days 14, 18, and 22). This remarkable and unexpected result is the first demonstration that PEGPH20 facilitates entry of a bacterium into the intratumoral space. This response was uniquely associated with accumulation of shIDO-ST and neutrophils in the tumor which confirms the importance of the shIDO component, since a control scrambled RNAi expressed from Salmonella did not accumulate nor caused regression of PDAC tumors. Tracking experiments in shIDO-ST + PEGPH20 treated mice revealed that the neutrophils originate from the spleen and later migrate into the tumor. Surprisingly, purified splenic neutrophils from these mice were sufficient to kill PDAC tumor cells ex-vivo in cytotoxicity assays. We also observed significant IDO knockdown in purified neutrophils that corresponded to a greater activation phenotype typical of anti-tumor (N1) polarized neutrophils. Neutrophil killing of tumor targets could be inhibited in a dose-dependent manner using heparin or polysialic acid treatment, which specifically acts to neutralize the apoptosis-inducing activity of histones in the DNA matrixes formed as part of neutrophil extracellular traps (NETs). Collectively, these data support continued development of a combination therapy that overcomes desmoplasia in PDAC with remarkable anti-tumor activity. Supported by R21 CA174306, the Tim Nesvig Foundation, and Halozyme Therapeutics Citation Format: Edwin R. Manuel, Melanie G. Lampa, Joseph Kim, Vincent Chung, Massimo D'Apuzzo, Curtis B. Thompson, Zhongdong Huang, Daniel C. Maneval, Don J. Diamond. Control of PDAC tumor progression by RNA interference targeting indoleamine 2,3-dioxygenase using salmonella as a delivery vehicle facilitated by PEGPH20. [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 A97.

Abstract IA28: BRCA-mutated pancreas adenocarcinoma: Emerging therapeutic implications

Abstract Germline BRCA mutations, in particular BRCA 2, incur an increased risk of developing pancreas adenocarcinoma. BRCA mutations occur in 5-7% of an unselected pancreas adenocarcinoma population. In patients with Ashkenazi Jewish heritage and pancreas adenocarcinoma the frequency of BRCA mutations may be significantly higher at 12-15%. In patients with familial pancreatic cancer, defined as having at least one first degree relative with pancreas adenocarcinoma, the frequency of BRCA 1 or 2 mutation carriers is estimated at 11-17%. PALB2 (partner and localizer to BRCA2) mutations occur in a smaller fraction of patients with pancreas adenocarcinoma. The PALB2 protein stabilizes the BRCA 2 protein and anchors it to the nucleus, allowing it to carry out its DNA repair function. More recently, PALB2 has been shown to associate with the BRCA 1 protein, providing a linkage between BRCA 1 and 2 in homologous recombination repair of double-stranded DNA breaks. Preclinical data has demonstrated hypersensitivity of BRCA 2 deficient pancreatic cell lines to DNA cross-linking agents mitomycin and cisplatin and more recently to the novel agents, poly (ADP-ribose) polymerases (PARP) inhibitors. We and others have reported increased sensitivity to DNA damaging agents in patients with pancreas adenocarcinoma arising on a background of a known BRCA 1 or 2 germline mutation. Poly ADP ribose polymerases are a family of enzymes, two of which, PARP1 and 2, are key components of the DNA repair mechanism for cells with single-strand breaks and nucleoside base damage. PARP inhibition has particular application in tumors with pre-existing defects in homologous recombination, such as BRCA 1 or 2 deficient cells. Inhibition of PARP in these cells leads to transformation of single-strand breaks into double-strand breaks (DSB), which are cytotoxic in cells, which are unable to repair DSBs by homologous repair. This effect of synthetic lethality provides the therapeutic rationale for development of PARP inhibitors for BRCA 1 or 2 mutation associated pancreas adenocarcinoma. Veliparib (ABT-888) is an orally available, small molecule inhibitor of polyADP-ribose polymerase. Three trials are evaluating the role of role of veliparib in combination with cisplatin-based therapy in patients with BRCA or PALB2 mutated pancreas adenocarcinoma. Data will be presented on the first of these trials, which is a phase IB study designed to determine the recommended phase II dose of veliparib in combination with cisplatin and gemcitabine for patients with a either a known BRCA or PALB2 mutation or a very strong personal or family history of malignancy. Between 02/12 and 10/13, 33 patients were screened and 17 enrolled. Male = 10, Female = 7. Median age = 60 years (range 42- 72). BRCA = 9. Non-BRCA = 8. Four dose levels of veliparib were evaluated; Two dose-limiting toxicities of veliparib were observed at an 80mg daily continuous dosing schedule (neutropenia, thrombocytopenia). Overall grade 3-4 toxicities: Hematologic, fatigue and one fatal bowel perforation tumor/diverticulitis. For N= 9 BRCA patients tumor response: 5 (56%) partial responses and 4 (44%) stable disease. No objective responses were seen in the non-BRCA patients. The recommended phase II dose of Veliparib is 80 mg PO BID day 1-12 q 3 weeks with fixed dose cisplatin and gemcitabine. The triplet combination of cisplatin, gemcitabine and veliparib shows high activity in BRCA-related pancreas adenocarcinoma. A randomized phase II trial evaluating cisplatin/gemcitabine +/- veliparib is underway in BRCA/PALB2-mutated pancreas adenocarcinoma (NCT01585805). In addition to the clinical trials, there are a series of correlative science questions focused around: (1) characterization of the molecular phenotype of BRCA/PALB2 mutated pancreas adenocarcinoma, (2) mechanisms of resistance to platinum and PARP inhibition, (3) evaluation of assays for homologous repair, (4) evaluation of loss of heterozygosity at BRCA 1, 2 loci in tumor, and other considerations.

A Novel Strategy to Improve the Therapeutic Efficacy of Gemcitabine for Non-Small Cell Lung Cancer by the Tumor-Penetrating Peptide iRGD.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, comprising approximately 75–80% of all lung cancers. Gemcitabine is an approved chemotherapy drug for NSCLC. The objective of this study was to develop a novel strategy to improve the therapeutic efficacy of Gemcitabine for NSCLC by the co-administered iRGD peptide. We showed that the rates of positive expression of αvβ3, αvβ5 and NRP-1 in the A549 cell line were 68.5%, 35.3% and 94.5%, respectively. The amount of Evans Blue accumulated in the tumor of Evans Blue+iRGD group was 2.5 times that of Evans Blue group. The rates of growth inhibition of the tumors of the iRGD group, the Gemcitabine group and the Gemcitabine+iRGD group were 8%, 59.8% and 86.9%, respectively. The results of mechanism studies showed that PCNA expression in the Gemcitabine+iRGD group decreased 71.5% compared with that in Gemcitabine group. The rate of apoptosis in the Gemcitabine+iRGD group was 2.2 time that of the Gemcitabine group. Therefore, the tumor-penetrating Peptide iRGD can enhance the tumor-penetrating ability and therapeutic efficacy of Gemcitabine in the A549 xenograft. The combined application of Gemcitabine with iRGD may be a novel strategy to enhance the clinical therapeutic efficacy of Gemcitabine in patients with NSCLC.

Cisplatin and gemcitabine in patients with advanced biliary tract cancer (ABC) and persistent jaundice despite optimal stenting: Effective intervention in patients with luminal disease

IntroductionThe advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1st-line regimen for patients with advanced/metastatic biliary tract cancer; patients with bilirubin ⩾1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin. MethodsPatients with ABC, receiving CisGem with a baseline bilirubin of ⩾1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected. ResultsThirty-three patients of 545 screened; median age 59years, range 23–79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55μmol/L (range 32–286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9months (95% confidence interval (CI): 4.4–9.0) and median overall survival (OS) 9.5months (95% CI: 5.7–12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6months; p=0.1633 and 9.8 versus 4.4months, hazard ratio (HR) 0.74; p=0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9months, HR 0.49; p=0.08 and 15.2 versus 5.4months, HR 0.12 p<0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS). ConclusionFor PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.

Gemcitabine Adjuvant Therapy for Resected Pancreatic Cancer

Gemcitabine (GEM) is an approved treatment for unresectable pancreatic cancer; however, its role in treating resected pancreatic cancer is less clear. The aim of this study was to investigate the evidence of the role of adjuvant GEM therapy on survival in resected pancreatic cancer. Four phase III randomized trials of adjuvant GEM in patients with resected pancreatic cancer were identified and the hazard ratio (HR) for overall survival were used in this meta-analysis; 2 studies compared GEM treatment with best supportive care and 2 studies with 5-fluorouracil/folinic acid therapy. The pooled data (n=2017 patients) indicated that the overall survival data were homogenous among the studies (Q=4.371; I=31.37%; P=0. 224). The combined HR significantly favors GEM over the other treatments. The overall HR was 0.88 (range, 0. 720 to 0.940; P=0.014). The results indicate that GEM prolongs overall survival compared with other treatments after the resection of pancreatic cancer.

P-175 Oncolytic Virus Therapy in Pancreatic Cancer: Clinical Efficacy and Pharmacodynamic Analysis of REOLYSIN in Combination with Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma

P-175 Oncolytic Virus Therapy in Pancreatic Cancer: Clinical Efficacy and Pharmacodynamic Analysis of REOLYSIN in Combination with Gemcitabine in Patients with Advanced Pancreatic Adenocarcinoma

A randomized, placebo-controlled phase III trial of masitinib plus gemcitabine in the treatment of advanced pancreatic cancer

Masitinib is a selective oral tyrosine-kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m(2)) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl-CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the 'ACOX1' subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the 'pain' subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. ClinicalTrials.gov:NCT00789633.

Role of gemcitabine as second-line therapy after progression on FOLFIRINOX in advanced pancreatic cancer: a retrospective analysis.

Cancer of the exocrine pancreas is a highly lethal malignancy. Surgical resection is the only potentially curative treatment. Unfortunately, because of the late presentation, the majority have either locally advanced cancer at initial diagnosis. Systemic chemotherapy provides benefit to patients with advanced pancreatic cancer, improving disease-related symptoms and survival when compared to best supportive care alone. Based on fase III study, FOLFIRINOX regimen became the standard first-line treatment. But, the optimal management strategy for patients who fail initial FOLFIRINOX is undefined. Despite the lack of clinical trials that report the real benefit of gemcitabine in patients with advanced exocrine pancreatic cancer as second line treatment. We aim at reporting our experience with this regimen. Patients with advanced exocrine pancreatic cancer who received gemcitabine (1.000 mg/m(2) on days 1, 8 and 15 every 4 weeks) until disease progression, as second-line therapy at our institution were retrospectively evaluated. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. A total of 20 patients were reviewed. Median age was 57 years (range, 43-74 years), and 55% were older than 60 years. Most patients were male (80%), had metastatic disease (60%), and ECOG performance status of 0 or 1 (65%). PFS and OS were 2.0 (95% CI, 1.2-2.8) and 5.7 months (95% CI, 3.9-7.4), respectively. There were no deaths due to the treatment. In this study, gemcitabine was a reasonable second-line treatment option for patients with advanced pancreatic adenocarcinoma and good ECOG performance status. Phase III trials are urgently needed comparing gemcitabine versus best supportive of care (BSC) can evaluate the real benefit of this chemotherapy after progression on FOLFIRINOX.

Pemetrexed versus taxane-containing platinum doublet therapy for advanced non-squamous non-small cell lung cancer (NSCLC): A systematic analysis.

e19046 Background: Pemetrexed (PEM) is superior to gemcitabine in patients (pts) with non-squamous (NS) histology, when given in combination with cisplatin. Comparative efficacy data of platinum do...

Safety, pharmacokinetics, pharmacodynamics, and antitumor activity of necuparanib combined with nab-paclitaxel and gemcitabine in patients with metastatic pancreatic cancer: Phase 1 results.

4114 Background: Preclinical studies have shown necuparanib (necu)’s ability to bind growth factors, adhesion molecules, and chemokines to inhibit tumor progression, invasion, metastasis, and angio...

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.

A Multicenter, Open-Label, Phase 1 Study Evaluating the Safety and Tolerability of Pegaspargase in Combination with Gemcitabine in Advanced Metastatic Solid Tumors and Lymphoma

Purpose: To evaluate the maximum tolerated dose, safety profile, pharmacokinetics, and pharmacodynamics of pegaspargase (PEG-ASP) in combination with gemcitabine in patients with advanced metastatic solid tumors and lymphoma. Methods: We conducted a multicenter, open label, nonrandomized, Phase 1 dose escalation study designed to evaluate up to 10 cohorts of patients with advanced or metastatic solid tumors and lymphoma. Seventeen patients were treated with of PEG-ASP in combination with gemcitabine. Results: The study was terminated early because the doses for PEG-ASP suggested for de-escalation were predicted not to provide desired sustained asparaginase concentrations based on the analysis of treated patients.

Phase I study of olaparib plus gemcitabine in patients with advanced solid tumours and comparison with gemcitabine alone in patients with locally advanced/metastatic pancreatic cancer

Olaparib (Lynparza) is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitor that induces synthetic lethality in cancers with homologous recombination defects. In this phase I, dose-escalation trial, patients with advanced solid tumours received olaparib (50-200 mg capsules b.i.d.) continuously or intermittently (days 1-14, per 28-day cycle) plus gemcitabine [i.v. 600-800 mg/m(2); days 1, 8, 15, and 22 (cycle 1), days 1, 8, and 15 (subsequent cycles)] to establish the maximum tolerated dose. A separate dose-escalation phase evaluated olaparib in tablet formulation (100 mg o.d./b.i.d.; days 1-14) plus gemcitabine (600 mg/m(2)). In an expansion phase, patients with genetically unselected locally advanced or metastatic pancreatic cancer were randomised 2 : 1 to the tolerated olaparib capsule combination dose or gemcitabine alone (1000 mg/m(2)). Sixty-six patients were treated [dose-escalation phase, n = 44 (tablet cohort, n = 12); dose-expansion phase, n = 22 (olaparib plus gemcitabine, n = 15; gemcitabine alone, n = 7)]. In the dose-escalation phase, four patients (6%) experienced dose-limiting toxicities (raised alanine aminotransferase, n = 2; neutropenia, n = 1; febrile neutropenia, n = 1). Grade ≥3 adverse events were reported in 38/47 patients (81%) treated with olaparib capsules plus gemcitabine; most common were haematological toxicities (55%). Tolerated combinations were olaparib 100 mg b.i.d. capsule (intermittently, days 1-14) plus gemcitabine 600 mg/m(2) and olaparib 100 mg o.d. tablet (intermittently, days 1-14) plus gemcitabine 600 mg/m(2). There were no differences in efficacy observed during the dose-expansion phase. Olaparib 100 mg b.i.d. (intermittent dosing; capsules) plus gemcitabine 600 mg/m(2) is tolerated in advanced solid tumour patients, with no unmanageable/unexpected toxicities. Continuous dosing of olaparib or combination with gemcitabine at doses >600 mg/m(2) was not considered to have an acceptable tolerability profile for further study. NCT00515866.

A randomized trial comparing concurrent chemoradiotherapy with single-agent cisplatin versus cisplatin plus gemcitabine in patients with advanced cervical cancer: An Asian Gynecologic Oncology Group study

ObjectiveA recent randomized trial demonstrated that concurrent chemoradiotherapy (CCRT) with weekly cisplatin and gemcitabine, followed by two adjuvant cycles of cisplatin and gemcitabine improved survival for advanced cervical cancer patients. An Asian Gynecologic Oncology Group (AGOG) study was designed to determine whether only adding gemcitabine in the chemoradiation phase without adjuvant chemotherapy could improve survival. MethodsBetween March 2009 and March 2013, 74 eligible patients with International Federation of Obstetrics and Gynecology stage III/IVA cervical cancer or stage I/II with positive pelvic/para-aortic nodal metastasis were enrolled. Thirty-seven patients were randomized to arm C (weekly cisplatin 40mg/m2) and 37 patients were randomized to arm CG (weekly cisplatin 40mg/m2 and gemcitabine 125mg/m2), for six cycles. Six eligible patients were excluded before the beginning of treatment. ResultsAn interim analysis showed superimposable progression-free (PFS) and overall survival (OS), a decision of closing accrual was made. A 3-year PFS was similar in both arms (arm C 65.1% vs. arm CG 71.0%, p=0.71), and a 3-year OS was 74.1% in arm C vs. 85.9% in arm CG (p=0.89), but crossed over at 5years. Grade 2–4 hematological toxicities, including neutropenia (p=0.028) and thrombocytopenia (p=0.001), were more frequent in arm CG than arm C. ConclusionsDespite limitation in power, it suggests that only adding gemcitabine at the CCRT phase does not provide substantially superior results, but treatment toxicities could increase. Further studies are required to determine the role of post-CCRT adjuvant chemotherapy in advanced cervical cancer.

Efficacy of prophylactic minocycline treatment for skin toxicities induced by erlotinib plus gemcitabine in patients with advanced pancreatic cancer: a retrospective study.

Erlotinib has been reported as being associated with a high incidence of skin toxicities such as acneiform rash, paronychia, and xerosis. The aim of this study was to evaluate the efficacy of prophylactic minocycline treatment for the skin toxicities induced by erlotinib as compared with deferred minocycline treatment in patients with pancreatic cancer treated with erlotinib plus gemcitabine. A total of 96 patients were studied retrospectively, of whom 44 received prophylactic minocycline between August 2012 and June 2013 and 52 received deferred minocycline treatment between August 2011 and July 2012 at the National Cancer Center Hospital East, Kashiwa, Japan. In the prophylactic minocycline group, 200 mg/day oral minocycline was prophylactically administered during the treatment period. The incidence rate of acneiform rash and xerosis of any grade during the first 6 weeks of treatment was significantly reduced in the prophylactic minocycline group compared with the deferred minocycline treatment group (47.7 vs. 80.8%, p<0.001; 2.3 vs. 19.2%, p=0.01). Multivariate analysis identified prophylactic minocycline as a significant independent factor associated with the incidence of acneiform rash and xerosis of any severity (odds ratio [OR] 0.16, 95% confidence interval [CI] 0.06-0.46, p<0.001; OR 0.11, 95% CI 0.01-0.90, p=0.04). Prophylactic minocycline appears to be useful for the management of erlotinib-related acneiform rash and xerosis during chemotherapy in patients with advanced pancreatic cancer.

A phase I dose-escalation trial of TH-302 with nab-paclitaxel and gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

TPS505 Background: TH-302 is a hypoxia-activated, nitroimidazole-linked prodrug of bromo-isophosphoramide mustard (Br-IPM), which is released under hypoxic conditions. TH-302 is currently being studied in combination with gemcitabine (G) in a phase III trial in patients (pts) with advanced pancreatic adenocarcinoma (PDAC) (NCT01746979). Encouraging preclinical activity of TH-302 plus nab-paclitaxel (nab-P) and G provides a rationale for further study of this triplet (Sun JD et al, AACR Special Conference on Pancreatic Cancer 2014; abstract #B88). Methods: Clinical trial: NCT02047500. Open-label, phase I, dose-escalation trial of TH-302 plus nab-P and G in pts with previously untreated locally advanced or metastatic PDAC. Dose escalation: 3 + 3 design with one of 3 planned dose levels of TH-302 (170, 240 and 340 mg/m2) on days 1, 8, and 15 of a 28-day cycle, plus nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Expansion cohort (n≥15): TH-302 at the recommended phase II dose (RP2D) with nab-P 100–125 mg/m2 followed by G 800–1,000 mg/m2. Treatment will be continued until disease progression or intolerable toxicity. Primary objectives: To evaluate safety and tolerability, define the maximum tolerated dose and determine the RP2D of TH-302 in combination with nab-P/G. The primary endpoint is no. of pts with dose-limiting toxicities during the first 28 days. Secondary objectives: To evaluate overall safety of the triplet regimen, metabolic response rate using EORTC criteria for 18F-FDG PET, CA19–9 response rate (defined as &gt;50% decline from baseline), and RECIST response rate of TH-302 plus nab-P/G. The pharmacokinetic (PK) profile of TH-302 and Br-IPM in the plasma of pts will also be evaluated, as will the effect of TH-302 on the PK of nab-P, and vice versa. Exploratory analyses include the association of pharmacogenomic markers, such as CYP2C9, BRCA1 and BRCA2, with PK, safety and efficacy. The association of potential hypoxia biomarkers (CA IX, GLUT1, VEGF, osteopontin) with antitumor activity will also be explored. The trial is in progress; 7 of an estimated 48 planned pts have been recruited (trial start Jan 2014, estimate end Aug 2016). Clinical trial information: NCT02047500.