Gemcitabine-refractory Metastatic Pancreatic Cancer Research Articles

A randomized phase II study of second-line treatment with liposomal irinotecan, and S-1 versus liposomal irinotecan and 5-fluorouracil in gemcitabine-refractory metastatic pancreatic cancer patients.

TPS4664 Background: Pancreatic ductal adenocarcinoma (PDAC) is the deadliest form of cancer with a 5-year survival of less than 5% for patients with metastatic disease. Despite improvements over the past years, with the introduction of FOLFIRINOX and gemcitabine plus nab-paclitaxel, the majority has disease progression within 6 months after start of first line treatment. The NAPOLI trial was the first phase III study showing that patients with metastatic pancreatic cancer that progressed after treatment with gemcitabine-based chemotherapy benefitted from second line treatment. Patients received liposomal irinotecan (nal-IRI) either as a single agent or in combination with 5-fluorouracil/leucovorin (5-FU/LV), or 5-FU/LV alone. Patients treated with both nal-IRI and 5-FU/LV experienced a median overall survival (mOS) of 6.1 months versus 4.2 months for the 5-FU/LV group. Recently, two Japanese studies (GEST and JASPAC 01) reported on the use of S-1 in patients with PDAC. In patients with locally advanced or metastatic PDAC, S-1 was non-inferior compared to gemcitabine in terms of mOS (8.8 months for gemcitabine versus 9.7 months for S-1). In the adjuvant setting, S-1 showed superior mOS compared to gemcitabine, 46.5 and 25.5 months respectively, HR for mortality of S-1 compared with gemcitabine was 0.57 (95% CI 0.44–0.72). In view of these results, the objective of this NAPAN study is to compare the progression free survival (PFS) of nal-IRI plus S-1, with nal-IRI plus 5-FU/LV in a Western study population for second line treatment of PDAC. Methods: This is a multi-center, open label, randomized phase II trial. Patients ≥ 18 years of age with histologically or cytologically confirmed PDAC, previously treated with gemcitabine (-based) therapy, or progression within 6 months of adjuvant gemcitabine-based treatment are eligible. After a safety run-in of the nal-IRI plus S-1 regimen, patients will be randomized between nal-IRI plus S-1 and nal-IRI plus 5-FU/LV. Primary endpoint of the run-in phase is to determine dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of nal-IRI when co-administered with fixed dose S-1. The primary endpoint of the phase II part is to determine the efficacy of the treatment arms in terms of PFS. Secondary endpoints include OS, response rate according to RECIST 1.1, adverse events according to CTC version 5.0 and Quality of life. Until now 2 of the planned 120 patients have been enrolled. Clinical trial information: NCT03986294 .

Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.

Photodynamic Therapy Synergizes with Irinotecan to Overcome Compensatory Mechanisms and Improve Treatment Outcomes in Pancreatic Cancer.

The ability of tumor cells to adapt to therapeutic regimens by activating alternative survival and growth pathways remains a major challenge in cancer therapy. Therefore, the most effective treatments will involve interactive strategies that target multiple nonoverlapping pathways while eliciting synergistic outcomes and minimizing systemic toxicities. Nanoliposomal irinotecan is approved by the FDA for gemcitabine-refractory metastatic pancreatic cancer. However, the full potential of irinotecan treatment is hindered by several cancer cell survival mechanisms, including ATP-binding cassette G2 (ABCG2) transporter-mediated irinotecan efflux from cells. Here, we demonstrate that benzoporphyrin derivative-based photodynamic therapy (PDT), a photochemical cytotoxic modality that activates the apoptotic pathway, reduced ABCG2 expression to increase intracellular irinotecan levels in pancreatic cancer. Moreover, we show that PDT inhibited survivin expression. Although PDT potentiated irinotecan treatment, we also demonstrate that irinotecan reduced the tumoral expression of monocarboxylate transporter 4, which was upregulated by PDT. Notably, using orthotopic xenograft models, we demonstrate that combination of single low-dose PDT and a subclinical dose of nanoliposomal irinotecan synergistically inhibited tumor growth by 70% for 3 weeks compared with 25% reduction after either monotherapies. Our findings offer new opportunities for the clinical translation of PDT and irinotecan combination therapy for effective pancreatic cancer treatment.

A phase II study of lapatinib and capecitabine in second-line treatment of metastatic pancreatic cancer.

e14569 Background: The anti-EGFR therapy erlotinib was FDA approved for the treatment of patients with advanced pancreas cancer. Human epidermal growth factor receptor 2 (HER-2), a member of the ErbB family of growth factor receptor tyrosine kinases to which EGFR belongs, is found overexpressed in 20% of pancreatic cancers . Targeting EGFR and HER-2 with separate specific monoclonal antibodies showed synergistic inhibition of pancreatic cancer tumor progression in mice bearing xenograft of human pancreatic cancer cell lines. We performed an open-label single arm phase II study to evaluate the combination of lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2, and capecitabine in the second-line treatment of metastatic pancreatic cancer. Methods: Patients with metastatic, unresectable, gemcitabine-refractory pancreatic cancer with adequate performance status (ECOG 0-2) and normal hepatic and renal function were eligible. Patients received lapatinib 1,250 mg PO daily, and capecitabine 1,000 mg/m2 PO twice daily on days 1-14 of each 21-day cycle. Restaging studies were performed every 2 cycles. The primary endpoint was median overall survival (OS). Secondary endpoints included response rate (RR) and progression free survival (PFS). Results: Between 9-2009 and 8-2011, 17 patients received treatment. Six of 17 patients (24%) had disease progression after 2 cycles, 2 of 17 patients (12%) progressed after 4 cycles and 4 of 17 patients (24%) had stable disease and received more than 6 cycles. The median number of treatment cycles was 3 (range 1-22 cycles). The median PFS was 9 weeks (95% CI 7.1-18.9). Median OS was 25 weeks (95% CI 11 -34). Grade 3 nausea, vomiting in 3 patients (17%), grade 3 diarrhea in 2 patients (12%), grade 3 limb edema in 1 patient (6%), and grade 3 fatigue in 1 patient (6%). Serum was collected at baseline, three weeks and time of disease progression for microRNA analysis to identify biomarkers correlated with clinical outcome. Conclusions: The combination of lapatinib and capecitabine is a tolerated regimen for patients with gemcitabine-refractory metastatic pancreatic cancer. Some patients were able to receive 6 or more cycles of therapy. Molecular analysis of patients’ biosamples is ongoing.

Phase II and Coagulation Cascade Biomarker Study of Bevacizumab With or Without Docetaxel in Patients With Previously Treated Metastatic Pancreatic Adenocarcinoma

Treatment options are limited for advanced pancreatic cancer progressive after gemcitabine therapy. The vascular endothelial growth factor pathway is biologically important in pancreatic cancer, and docetaxel has modest antitumor activity. We evaluated the role of the anti-vascular endothelial growth factor antibody bevacizumab as second-line treatment for patients with metastatic pancreatic cancer. Patients with metastatic adenocarcinoma of the pancreas who had progressive disease on a gemcitabine-containing regimen were randomized to receive bevacizumab alone or bevacizumab in combination with docetaxel. Thirty-two patients were enrolled; 16 to bevacizumab alone (Arm A) and 16 to bevacizumab plus docetaxel (Arm B). Toxicities were greater in Arm B with the most common grade 3/4 nonhematologic toxicities including fatigue, diarrhea, dehydration, and anorexia. No confirmed objective responses were observed. At 4 months, 2 of the 16 patients in Arm A and 3 of the 16 patients in Arm B were free from progression. The study was stopped according to the early stopping rule for futility. Median progression-free survival and overall survival were 43 days and 165 days in Arm A and 48 days and 125 days in Arm B. Elevated d-dimer levels and thrombin-antithrombin complexes were associated with decreased survival and increased toxicity. Bevacizumab with or without docetaxel does not have antitumor activity in gemcitabine-refractory metastatic pancreatic cancer. Baseline and on-treatment d-dimer and thrombin-antithrombin complex levels are associated with increased toxicity and decreased survival.

A phase II study of bevacizumab plus erlotinib for gemcitabine-refractory metastatic pancreatic cancer

No standard of care exists for patients with metastatic pancreatic cancer following progression on first-line chemotherapy. Based on potential for additive or synergistic activity by concurrent inhibition of VEGF and EGFR, we conducted a phase II study evaluating the combination of bevacizumab plus erlotinib in this patient population. Patients with metastatic pancreatic adenocarcinoma, ECOG performance status 0-1, and previous exposure to 1-3 systemic therapies (at least one gemcitabine-based) were eligible. Treatment consisted of bevacizumab 15 mg/kg every 21 days plus erlotinib 150 mg daily. Thirty-six patients were enrolled, including eight who had previously received VEGF-targeted therapy and nine prior erlotinib. Median number of treatment cycles was 2 (range, 1-7). Common toxicities included rash (72%), diarrhea (25%), venous thromboembolic events (15%), and hypertension (11%). One patient demonstrated partial response and seven others stable disease for >2 cycles. CA19-9 decline ≥25% was observed in 4/26 patients with baseline levels >2x ULN. Estimated median time to progression was 40 days (95% CI, 35-41 days) and median survival 102 days (95% CI, 74-117 days), with a 6-month survival rate of 22%. Baseline concentration of circulating endothelial cells (CD45(-)/CD34(+)/CD31(+)) was inversely associated with overall survival. The combination of bevacizumab and erlotinib is safe but relatively ineffective in patients with gemcitabine-refractory metastatic pancreatic cancer. Future studies should focus on refining subsets of patients in this challenging population likely to benefit from treatment beyond first-line.

Weekly Docetaxel as Salvage Therapy in Patients with Gemcitabine-Refractory Metastatic Pancreatic Cancer

Gemcitabine-based chemotherapy provides very limited disease control in the treatment of advanced pancreatic cancer. Approximately half of the patients failing upfront treatment present good performance status and are willing to undergo further treatment. Docetaxel activity against pancreatic cancer is reported both in the preclinical and clinical setting. Between November 2004 and November 2005, 10 patients (median age 59; median KPS 80) with metastatic pancreatic adenocarcinoma, progressive disease after gemcitabine-containing chemotherapy, KPS >50, adequate organ function, were treated with weekly docetaxel at 30 mg/m2 until progressive disease.Docetaxel dose intensity was 100% of the intended dose. No grade >2 toxicity was observed. No objective response to treatment was obtained. Median progression-free survival was 1.5 months (range 1-3.5 months); median survival was 4.0 months (range 2.0-7.5). Weekly administration of single-agent docetaxel does not seem to have any activity in the treatment of gemcitabine-resistant metastatic pancreatic cancer

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.

Capecitabine Plus Erlotinib in Gemcitabine-Refractory Advanced Pancreatic Cancer

The addition of either capecitabine or erlotinib to gemcitabine in the first-line treatment of advanced pancreatic cancer is associated with modest improvements in overall survival. We evaluated an oral regimen of capecitabine and erlotinib in patients with advanced pancreatic cancer who had experienced treatment failure with standard first-line therapy with gemcitabine. Thirty patients with gemcitabine-refractory metastatic pancreatic cancer were treated with capecitabine, administered at a dose of 1,000 mg/m2 twice daily for 2 weeks, followed by a 1-week break. All patients also received erlotinib 150 mg daily. Patients were observed for evidence of response, toxicity, and survival. EGFR mutational status was assessed in available tumor blocks. Treatment with capecitabine and erlotinib in gemcitabine-refractory patients was associated with an overall objective radiologic response rate of 10% and a median survival duration of 6.5 months. In addition, 17% of the treated patients experienced decreases in tumor marker (CA 19-9) levels of more than 50% from baseline. Common toxicities included diarrhea, skin rash, fatigue, and hand-foot syndrome. EGFR mutations were detected in two of five available tumors; no association between treatment response and EGFR mutational status was evident. The combination of capecitabine and erlotinib is active in patients with gemcitabine-refractory pancreatic cancer. This regimen may represent an acceptable treatment option in patients who experience treatment failure with standard first-line therapy with gemcitabine or for whom gemcitabine may not be an appropriate first-line treatment option.

Phase I Dose-Finding Study of Weekly Docetaxel Followed by Flavopiridol for Patients with Advanced Solid Tumors

Flavopiridol is a cyclin-dependent kinase inhibitor that enhances docetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patients with advanced solid tumors. Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m2 in successive cohorts, administered weekly over 1 h. This schedule was repeated for 3 weeks of each 4-week cycle. Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 +/- 0.69 micromol/L (flavopiridol 20 mg/m2) to 4.54 +/- 0.08 micromol/L (flavopiridol 60 mg/m2) in cycle 1. Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer.

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

4115 Background: Gemcitabine (Gem) monotherapy or Gem-containing 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 (J. Furuse et al, Proc ASCO 2005: # 4104), 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 Gem-refractory metastatic pancreatic cancer. Methods: Eligibility criteria were pathologically-proven pancreatic cancer with confirmation of progressive disease while receiving Gem-based chemotherapy, Karnofsky performance status 80 to 100%, age 20 to 74 years, with measurable metastatic lesions, adequate hematological, renal and liver functions, and written informed consent. S-1 was administered orally at 40 mg/m2 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 study end point was objective response, secondary end points included toxicity, progression-free survival (PFS) and overall survival, as well as clinical benefit response in symptomatic patients. Results: Forty patients (pts) from two institutions were enrolled between September 2004 and November 2005. Thirty-three pts are currently evaluable for response in this ongoing trial. There have been 5 confirmed partial responses (12.5%), and 14 pts (35%) with stable disease. Median survival has not been reached. Median PFS was 2.1 months. Toxicity data were available for 28 patients. Grade 3 and 4 toxicities were anemia (1 pts), appetite loss (2 pts), and fatigue (2 pts). Conclusions: Preliminary results demonstrated the safety and activity of S-1 in Gem-refractory metastatic pancreatic cancer. Efficacy and toxicity analysis are ongoing. Final results will be presented at the meeting. No significant financial relationships to disclose.

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.