Gemcitabine In Patients Research Articles

Second-line therapy after nab-paclitaxel plus gemcitabine or after gemcitabine for patients with metastatic pancreatic cancer.

Correction to: British Journal of Cancer (2016) 115, 188–194. doi: 10.1038/bjc.2016.185; Published online 28 June 2016. Upon publication of the above paper in the British Journal of Cancer, the authors identified several errors in their manuscript and Supplementary Material. Table 3 contained minor rounding errors and was incorrectly formatted.

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors

Objective: LY2603618, a selective inhibitor of checkpoint kinase 1 (CHK1) and key regulator of the DNA damage checkpoint, may enhance the effects of antimetabolites. This phase I study defined the recommended phase II dose of LY2603618 combined with gemcitabine. Patients and Methods: Patients with advanced/metastatic disease were administered doses of LY2603618 (70-250 mg/m² or flat-fixed doses of 200 or 230 mg) after gemcitabine (1,000 mg/m²). Safety and pharmacokinetics (PK) were assessed. Results: Among the 50 patients enrolled, frequent adverse events possibly related to study drug treatment included fatigue (44%), decreased platelets (42%), decreased neutrophils (32%), nausea (26%), and decreased hemoglobin (20%). Systemic exposure of LY2603618 increased dose dependently, while clearance was relatively dose independent. The mean LY2603618 half-life varied; however, the durations were still suitable for maintaining human exposures while minimizing accumulation. LY2603618 PK were not altered by gemcitabine administration. Plasma exposures that correlate with the maximal pharmacodynamic effect in nonclinical models were achieved for all doses. One patient with non-small cell lung cancer carcinoma achieved a partial response; 22 patients had stable disease. Conclusions: The maximum tolerated dose of LY2603618 combined with gemcitabine was 200 mg/m², but a fixed LY2603618 dose of 230 mg combined with gemcitabine was selected as the recommended phase II dose.

Nab-paclitaxel plus gemcitabine in patients with metastatic or recurrent pancreatic cancer: A single institution experience

Nab-paclitaxel plus gemcitabine in patients with metastatic or recurrent pancreatic cancer: A single institution experience

Concurrent radiotherapy with gemcitabine in patients with locally advanced pancreatic cancer: A retrospective analysis

Concurrent radiotherapy with gemcitabine in patients with locally advanced pancreatic cancer: A retrospective analysis

ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma.

LBA4006 Background: The ESPAC-3 trial compared adjuvant GEM with 5-fluorouracil/folinic acid for resected pancreatic cancer. GEM is the standard of care based on similar survival and less toxicity. ESPAC-4 aimed to determine whether combination chemotherapy with GEM/CAP improved survival compared to GEM monotherapy. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4 week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was overall survival; secondary endpoints were toxicity, relapse free survival, 2 and 5 year survival and quality of life. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2 year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was 65 years, 57% were men. WHO performance status was 0, 1 or 2 in 42% 55% and 3% respectively. Postoperative median CA19-9 was 19 kU/L. Median maximum tumor size was 30 mm, 60% were R1 resections, 80% were node positive and 40% were poorly differentiated. On Dec 11 2015 the Independent Trial Steering Committee requested that the trial proceed to full analysis. The data freeze was on March 2 2016. Median survival (months) for patients treated with GEM/CAP was 28.0 (95% CI, 23.5 – 31.5) and 25.5 (22.7 – 27.9) for GEM. Stratified log-rank analysis revealed an HR=0.82 [95% CI, 0.68 – 0.98]; χ2 (1) = 4.61, P=0.032. 196 out of 366 GEM patients in the safety set reported 481 grade 3/4 adverse events, while 226 out of 359 GEM/CAP patients reported 608 grade 3/4 adverse events ( P=0.242). Conclusions: Adjuvant GEM/CAP for pancreatic cancer had a statistically significant improvement in survival compared to GEM monotherapy. Clinical trial information: ISRCTN96397434.

ESPAC-4: A multicenter, international, open label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP), versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma

LBA4006Background: The ESPAC-3 trial compared adjuvant GEM with 5-fluorouracil/folinic acid for resected pancreatic cancer. GEM is the standard of care based on similar survival and less toxicity. ESPAC-4 aimed to determine whether combination chemotherapy with GEM/CAP improved survival compared to GEM monotherapy. Methods: Patients with pancreatic ductal adenocarcinoma were randomized within 12 weeks of surgery (stratified for R0/R1 resection margin status and country) to have either six 4 week cycles of IV GEM alone or GEM with oral CAP. The primary endpoint was overall survival; secondary endpoints were toxicity, relapse free survival, 2 and 5 year survival and quality of life. 722 patients (480 expected events), 361 in each arm, were needed to detect a 10% difference in 2 year survival rates with 90% power (log-rank test with 5% two-sided alpha). Results: Between Nov 10 2008 and Sep 11 2014, 732 patients were randomized with 730 included in the full analysis set (366 GEM, 364 GEM/CAP). Median age was ...

Dose modification and efficacy of nab-paclitaxel plus gemcitabine vs. gemcitabine for patients with metastatic pancreatic cancer: phase III MPACT trial.

Dose modifications following adverse events (AEs) are an important part of the management of patients with pancreatic cancer treated with chemotherapy. While dose modifications are utilized to ensure patient safety, the subsequent influence of dose adjustments on treatment exposure and efficacy have not been reported in detail. This exploratory analysis examined the influence of dose modifications on treatment exposure and efficacy in the phase III MPACT trial, which demonstrated superior efficacy of nab-paclitaxel (nab-P) plus gemcitabine (Gem) to Gem alone for the treatment of metastatic pancreatic cancer. Patients received either nab-P 125 mg/m(2) + Gem 1,000 mg/m(2) on days 1, 8, and 15 every 4 weeks or Gem 1,000 mg/m(2) weekly for the first 7 of 8 weeks (cycle 1) and then days 1, 8, and 15 every 4 weeks (cycle ≥2). The protocol allowed up to 2 dose reductions per agent. Dose delays were also used to manage toxicities. Toxicities that most commonly led to dose modifications were neutropenia, peripheral neuropathy, thrombocytopenia, and fatigue for nab-P and neutropenia, thrombocytopenia, and fatigue for Gem alone. Baseline characteristics were similar in patients with dose modifications and the intent-to-treat (ITT) population. Among the 421 treated patients in the nab-P + Gem arm, all patients initiated treatment at the per-protocol nab-P starting dose of 125 mg/m(2); 172 (41%) had a nab-P dose reduction, and 300 (71%) had a nab-P dose delay during the study. Most dose modifications occurred after the first 3 months (2 cycles) of treatment. The majority of patients (104/172, 60%) required only 1 nab-P dose reduction, and over half of patients (163/300) had either 1 or 2 dose delays. Patients who underwent dose modifications of nab-P had greater treatment exposure than those who did not in terms of treatment duration, number of cycles administered, and cumulative dose of nab-P delivered. Overall survival (OS) was shorter in the nab-P + Gem arm for patients who did not vs. did undergo dose reduction [median, 6.9 vs. 11.4 months; hazard ratio (HR), 1.93; 95% CI, 1.53-2.44; P<0.0001] and for those who did not vs. did undergo a dose delay (median, 6.2 vs. 10.1, HR, 2.05; 95% CI, 1.60-2.63; P<0.0001). Progression-free survival (PFS) and overall response rate (ORR) were also improved in patients with dose modifications. Similar trends were observed in the Gem-alone arm. Multivariate analyses confirmed that both dose delay and dose reduction were significantly associated with OS. This analysis suggests that although most doses of nab-P were given at the starting dose of 125 mg/m(2) the first 3 of 4 weeks, dose reductions and delays were effective when necessary to ameliorate toxicity allowing greater treatment exposure without compromising efficacy.

ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma.

ESPAC-4: A multicenter, international, open-label randomized controlled phase III trial of adjuvant combination chemotherapy of gemcitabine (GEM) and capecitabine (CAP) versus monotherapy gemcitabine in patients with resected pancreatic ductal adenocarcinoma.

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

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

A Phase II study of weekly nab-paclitaxel in combination with gemcitabine in patients with metastatic breast cancer.

e12514Background: Nanoparticle albumin-bound (nab)-paclitaxel has better efficacy and safety profiles especially no hypersensitivity risk compared with solvent-based paclitaxel. We performed a sing...

Intra-arterial and tumor-targeted infusion of gemcitabine in patients with unresectable pancreatic cancer

Intra-arterial and tumor-targeted infusion of gemcitabine in patients with unresectable pancreatic cancer

Evaluation of the combination of oxaliplatin and 5-fluorouracil or gemcitabine in patients with sporadic metastatic pulmonary carcinoid tumors

ObjectivesThe aim of this retrospective study was to analyse the efficacy of gemcitabine-oxaliplatin (gemox) or 5-fluorouracil-oxaliplatin (folfox) in the treatment of metastatic pulmonary carcinoid tumors. Patients and methods45 patients were included in two tertiary referral centers between January 1999 and January 2013. Typical, atypical carcinoids or not otherwise specified carcinoids were diagnosed according to WHO criteria in 19%, 57%, and 24% of cases by two expert pathologists. Patients had synchronous (38%) or metachronous (62%) metastastic disease (median of 2 (1–5) metastatic sites). Seventy-nine percent had progressive disease before start of chemotherapy. Treatment consisted of: gemcitabine 1000mg/m2 and oxaliplatin 100mg/m2 every 2 weeks (gemox regimen, n=24) or 5-fluorouracil (5-FU) (400mg/m2 in bolus injection and 5-FU 2400mg/m2 in 46h-infusion) and oxaliplatin 85mg/m2 (folfox regimen, n=21) every 2 weeks. Tumor response was assessed according to RECIST criteria every 8–12 weeks. Progression free survival and overall survival were assessed using Kaplan Meier curves. ResultsPatients received oxaliplatin-based chemotherapy in first-line (20%), second-line (33%), or post-second-line (47%) systemic treatment. The median number of cycles was 8 (1–12). Nine (20%) stopped oxaliplatin before 8 cycles because of toxicity. Nine patients (20%) had a partial response and 29 (64%) had stable disease. Median progression free survival (PFS) was 15 (6–25) months. Median overall survival (OS) was 34 (21–49) months. No significant difference was observed in response and PFS between either regimens. ConclusionsOur results suggest that either gemcitabine-oxaliplatin or 5-fluorouracil-oxaliplatin combinations are attractive chemotherapy regimen in metastatic pulmonary carcinoid tumors.

A phase Ib dose escalation, safety, and tolerability study of sonidegib in combination with gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.

371 Background: Sonidegib (LDE225) is a potent, selective, and orally bioavailable inhibitor of smoothened receptor that demonstrated preclinical activity in combination with gemcitabine (GEM). Here, we present data from a phase 1b trial of sonidegib in combination with GEM in patients (pts) with pancreatic adenocarcinoma (PA). Methods: Pts with histologically or cytologically confirmed, locally advanced, or metastatic PA who had not been treated previously or had progressed despite prior chemotherapy (other than GEM) were included in the study. Dose escalation started with sonidegib 400 mg, once a day, in combination with GEM 1000 mg/m2 IV infusion on days 1, 8, and 15 of a 28-day cycle. Results: A total of 18 pts were enrolled (9 pts each the in dose escalation and dose expansion phases). Pts discontinued the study because of disease progression (n = 11, 61.1%), consent withdrawal (n = 3, 16.7%), administrative problems (n = 3, 16.7%), and grade 3 or 4 blood creatine kinase (CK) elevation (n = 1, 5.6%). Three of 9 pts in dose escalation phase experienced dose-limiting toxicities during the first 8 weeks including grade 3 mucositis (n = 1), grade 3 CK elevation (n = 1), and grade 3 aspartate aminotransferase elevation (n = 1). Drug-related adverse events (AEs) of all grades were reported in 14 pts (77.8%) and grade 3 or 4 AEs were reported in 10 pts (55.6%). The most commonly reported AEs were anemia and nausea. No pharmacokinetic (PK) interaction was observed. Based on considerations of the statistical model, clinical assessment of safety, tolerability, PK, and pharmacodynamic results, maximum-tolerated dose and recommended dose were established as 400 mg of sonidegib in combination with the fixed standard dose of GEM (1000 mg/m2).The objective response rate was 11.1% and the median progression-free survival (PFS) was 4.9 months. Conclusions: The combination of sonidegib and GEM was generally well tolerated with moderate activity. Although no formal comparison can be made due to small sample size of this study, this combination provided a median PFS comparable to the current standard of care without conferring any additional clinical benefit. Clinical trial information: NCT01487785.

Neoadjuvant nab-paclitaxel and gemcitabine (AG) in borderline resectable (BR) or unresectable (UR) locally advanced pancreatic adenocarcinoma (LAPC) in patients ineligible for FOLFIRINOX.

328 Background: AG is superior to gemcitabine in patients with advanced pancreas cancer. There are limited data on the use of AG in BR or UR LAPC. Although FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan and oxaliplatin) is an option for such patients, many are not eligible due to age, poor performance status (PS) or comorbidities. Herein, we report our experience with neoadjuvant AG for BR/UR LAPC in patients ineligible for FOLFIRINOX. Methods: In this retrospective series, we included patients with BR/UR LAPC who received neoadjuvant AG. The treatment algorithm included AG for 3-4 months followed by radiation, then re-evaluation for surgery. The published AG regimen doses were modified based on patient tolerance. The primary outcome measure was R0 resection rate. Secondary outcomes were response rate, tolerability, and overall survival (OS). Results: Between 10/2013-9/2015, 20 patients (14 BR, 6 UR) at two institutions were treated with this approach. Median age was 69 years (range 44-90); 11/20 were female; PS ranged from 0-3; 14 patients have completed therapy and 6 remain on treatment. Five were converted to resectability by imaging and subsequently underwent operation; 4 had R0 resections (29% of patients who have finished therapy). To date, 6 patients died from progressive disease (PD), 2 are alive with PD and 12 remain alive on therapy or surveillance. All patients who achieved R0 resections are alive and disease free. The best response to AG was a partial response in 4 patients (20%), stable disease in 11, and progression in 2 with 3 patients still pending re-evaluation. Mean dose intensity was 77% for AG. Toxicities were similar to the published AG regimen. Conclusions: In this small series, both the R0 resection rate and the response rate were at least 20%, despite frequent dose reductions and relatively low dose intensity. Elderly and/or poor PS patients with LAPC have been historically excluded from curative-intent strategies. Our data suggest that these patients may now have a possibility for cure with the use of neoadjuvant AG.

Gemcitabine in patients previously treated with platinum-containing chemotherapy for refractory thymic carcinoma: radiographic assessment using the RECIST criteria and the ITMIG recommendations

The key drugs for chemotherapy of thymic carcinoma are gradually being revealed in phase II and conventional retrospective studies. Gemcitabine is regarded as one of these key drugs according to the findings of clinical trials in which it was combined with capecitabine. However, the activity of single-agent gemcitabine concerning refractory thymic carcinoma remains unclear. We conducted a retrospective review of the medical records of refractory thymic carcinoma patients previously treated with platinum-containing chemotherapy between 1980 and 2014. Of all 11 patients in this study, the objective response rate regarding gemcitabine was 36.4% [95% confidence interval (CI) 15.2-64.6] using the RECIST criteria and the response criteria proposed by the ITMIG. The median progression-free survival time was 4.3months (95% CI 0.7-11.0). The survival time from the start of gemcitabine treatment was 28.5months (95% CI 5.5-47.8), and from the start of first-line chemotherapy was 46.5months (95% CI 7.3-47.8). Gemcitabine achieved a moderate response and has the potential to be used as a key drug for thymic carcinoma. Some patients treated with gemcitabine demonstrated prolonged cancer control even in later lines of chemotherapy.

Development of Masitinib for the Treatment of Peripheral T-Cell Lymphoma

Increasing resistance to chemotherapy means that approximately 30% of patients afflicted with peripheral T-cell lymphoma will develop a relapsed/refractory form and eventually succumb to the disease. To date there is no clearly established second-line therapy and investigation of new therapies is necessary to address this unmet medical need.Masitinib is an oral tyrosine kinase inhibitor that potently and selectively targets c-Kit and platelet-derived growth factor receptor (PDGFR). Studies in human T-cell lymphoma have identified aberrant expression of PDGFR-alpha and that this kinase fosters peripheral T-cell lymphoma cell proliferation via an autocrine loop. Masitinib may therefore exert an antiproliferative and pro-apoptotic action on abnormal T-cells. In addition to this direct mechanism of action, masitinib can elicit antitumor effects by acting on mast cells and macrophages. By inhibiting mast cells, masitinib reduces the release of pro-tumoral M2-polarizing cytokines as well as factors favoring metastasis and angiogenesis. Masitinib can also promote macrophage infiltration into tumors, inducing an anti-tumoral Th1 immune response.Inhibition of cell proliferation was observed following single-agent masitinib treatment in the OSW canine T-cell lymphoma line, with an IC50 of 0.005 μM, suggesting that it could be used efficiently for the treatment of T-cell lymphoma. This hypothesis was further substantiated by a case study in a companion dog with T-cell lymphoma treated with masitinib monotherapy 12 mg/kg/day, reporting a complete response following 3 weeks of treatment with increased quality of life. This preliminary observation was repeated in two separate independent studies, each comprised of 11 dogs with T-cell lymphoma. A first study reported an overall response rate (ORR) of 73%, including 3/11 dogs with complete response (CR) and 5/11 dogs with partial response (PR) after 3 months of treatment. A second study reported an ORR of 45%, including 2/11 dogs with CR and 3/11 dogs with PR after 3 months of treatment. Meta-analysis of these data (n=23) showed that masitinib treatment of canine T-cell lymphoma resulted in a CR in 6/23 dogs (26%) and in a PR 8/23 dogs (35%), resulting in an ORR of 61%. Naturally occurring tumors in dogs have more clinical and biological similarities to human cancers than any other animal cancer model, hence these data provide strong medical plausibility for masitinib in the treatment of human peripheral T-cell lymphoma.The above in vitro and in vivo data led to initiation of a multicenter, randomized, open-label, three-parallel group, phase 2 study to evaluate the combination of masitinib plus dexamethasone with or without gemcitabine in patients with relapsed or refractory peripheral T-cell lymphoma. A recent decision to accelerate to a phase 3 study was based on an observed survival benefit for masitinib treated patients when compared with the control arm, and an acceptable safety profile; passage to phase 3 was validated by the independent Data Safety Monitoring Board with data blinded to sponsor and investigator. Specifically, pooled data from all masitinib-treated patients in the phase 2 stage (n=34) estimated a median overall survival (OS) of 9.0 months, which compares favorably against the literature benchmark median OS of 5.5 months for documented chemotherapy in this indication.This phase 3 study is currently open for patient recruitment in at least 14 countries and has OS as the primary endpoint. If successful, masitinib could provide a new treatment option in relapsed or refractory peripheral T-cell lymphoma. DisclosuresOff Label Use: Masitinib is a new orally administered tyrosine kinase inhibitor that targets mast cells and macrophages, important cells for immunity, through inhibiting a limited number of kinases. Based on its unique mechanism of action, masitinib can be developed in a large number of conditions in oncology, in inflammatory diseases, and in certain diseases of the central nervous system. In oncology due to its immunotherapy effect, masitinib can have an effect on survival, alone or in combination with chemotherapy. Through its activity on mast cells and consequently the inhibition of the activation of the inflammatory process, masitinib can have an effect on the symptoms associated with some inflammatory and central nervous system diseases and the degeneration of these diseases.. Marçais:AB Science: Consultancy. Dubreuil:AB Science: Consultancy. Moussy:AB Science: Other: CEO.

Abstract B26: Phase 1b trial of investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients (pts) with solid tumors

Abstract Introduction: Pevonedistat is a first-in-class NAE inhibitor. This open-label, multi-arm, dose-escalation study (NCT01862328) is the first study of pevonedistat plus standard-of-care (SoC) chemotherapy in pts with solid tumors. Methods: Objectives were to establish the MTD and safety/tolerability of pevonedistat (at &amp;lt;100 mg/m2) with 3 SoC therapies. Pts ≥18 yrs who could benefit from 1 of the SoC therapies received pevonedistat IV on d 1, 3, and 5 every 21 d, with docetaxel 75 mg/m2 IV (Arm 1) or paclitaxel 175 mg/m2 + carboplatin AUC5 (Arm 2) on d 1 (lead-in cohort: pevonedistat 15 mg/m2 + carboplatin AUC6), or pevonedistat + gemcitabine 1000 mg/m2 IV on d 1, 8, and 15 every 28 d (Arm 3). Pts were treated for up to 12 cycles (and could then continue single-agent pevonedistat) or until disease progression/unacceptable toxicity. Pevonedistat dose was escalated from 15 (Arm 1+2; 1 dose level below lowest single-agent dose tested) or 25 mg/m2 (Arm 3) using an adaptive Bayesian continual reassessment method. Once established, ∼6 additional pts were to be treated at each MTD. Results: As of 3 Jun 2015, 64 pts (median age 60.5 yrs; 47% male) had been enrolled: 22 to Arm 1, 26 to Arm 2 (6 in lead-in cohort), and 10 to Arm 3. Common tumor types were NSCLC (n = 16), breast, head and neck (each n = 6), and ovarian (n = 4) cancers. In Arm 1, MTD was pevonedistat 25 mg/m2 + docetaxel 75 mg/m2; 4 pts had dose-limiting toxicities (DLTs) of G3 AST/ALT elevations during dose escalation (n = 2) and expansion (n = 2), all at 25 mg/m2. In Arm 2, MTD was pevonedistat 20 mg/m2 + paclitaxel 175 mg/m2 + carboplatin AUC5; in the lead-in cohort 1 pt had a DLT of G3 AST/ALT elevation. Due to toxicity carboplatin AUC5 was used for dose escalation, DLTs included G3 febrile neutropenia (n = 1; 15 mg/m2), G3 AST/ALT elevation (n = 2; 20 mg/m2, n = 2; 25mg/m2), and G4 thrombocytopenia (n = 1; 20 mg/m2, C5D8). One DLT of G3 AST elevation occurred during MTD expansion. In Arm 3, MTD was not determined; the combination was deemed intolerable and discontinued. DLTs were G4/5 febrile neutropenia (n = 2) and G3 AST/ALT elevation (n = 1) at 25 mg/m2. Adverse events (AEs) were similar across arms; common drug-related AEs were fatigue (41%), nausea (34%), peripheral neuropathies (PN) (27%), and asymptomatic, reversible AST/ALT elevations (27/25%). 58% had &amp;gt;1 drug-related ≥G3 AE; most frequent were asymptomatic AST/ALT elevations (17/16%) and neutropenias (19%). Pevonedistat PK were unaffected by SoC therapies (n = 22/17/10 pts in Arms 1/2/3). Eleven objective responses were observed (3/22 pts Arm 1, 8/32 pts Arm 2; including pts previously exposed to carboplatin/cisplatin and paclitaxel). One pt with endometrial carcinoma achieved a complete response. Partial responses were observed in head and neck (n = 5), cholangiocarcinoma (n = 2), bladder, NSCLC, sarcoma, and breast cancer (each n = 1). Responses were durable for up to 12 cycles. Conclusion: Pevonedistat plus docetaxel or paclitaxel/carboplatin appeared well tolerated with MTDs of 25 and 20 mg/m2, respectively, and common drug-related AEs of fatigue, nausea, PN, and AST/ALT elevations. Preliminary data suggest antitumor activity with paclitaxel/carboplatin in pts with heavily pretreated solid tumors, notably endometrial carcinoma, head and neck cancer, cholangiocarcinoma, and NSCLC. Citation Format: A. Craig Lockhart, Todd M. Bauer, R. Donald Harvey, Carrie B. Lee, Charu Aggarwal, Roger B. Cohen, Farhad Sedarati, Ling Wang, Hélène M. Faessel, Bruce J. Dezube, Sergio Santillana, Afshin Dowlati. Phase 1b trial of investigational NEDD8-activating enzyme (NAE) inhibitor pevonedistat (TAK-924/MLN4924) in combination with docetaxel, paclitaxel/carboplatin, or gemcitabine in patients (pts) with solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B26.

Abstract B167: APX3330 drug development for clinical trials targeting APE1/Ref-1 in pancreatic cancer

Abstract Despite recent progress in the treatment of cancer over the past several decades, effective therapeutic options for pancreatic cancer remain as an area of high unmet medical need. Most patients with pancreatic cancer will survive less than six months following diagnosis. Targeted therapies including Gemcitabine (GemzarTM), FOLFIRINOX (5-FU/leucovorin/irinotecan/oxaliplatin), and sustained release, nab-paclitaxel (AbraxaneTM) offer some modest improvement in survival, albeit at an increase in side effects and unwanted toxicities. Data presented here will center on redox factor-1 (Ref-1) and a Ref-1 inhibitor developed in our laboratories, APX3330. Ref-1 regulates multiple transcription factors (TFs) involved in pancreatic cancer cell survival signaling due to its redox-coactivator activity on oxidized TFs including HIF-1α, AP-1, NFkB, and STAT3. High expression levels of Ref-1 also indicate decreased survival in pancreatic ductal adenocarcinoma (PDAC) as well as other cancers. APX3330 has been shown in multiple in vitro and in vivo models of pancreatic cancer to be effective in reducing tumor growth and metastases as a single agent. The mechanism of action has been extensively investigated and characterized and involves APX3330 binding to Ref-1. Furthermore, the safety and dose administration of APX3330 have been established by Eisai pharmaceutical company through a previous development program including toxicology, phase I, and phase II clinical evaluation in non-cancer patients in Japan. We have partnered with ApeX Therapeutics to develop APX3330 for cancer (IND submitted; phase I trial anticipated start date early 2016). Methods: We performed in vivo studies demonstrating single and combination effects of APX3330 with gemcitabine. Additionally, we tested single and combination studies of APX3330 in anex vivo 3-Dimensional tumor-stroma model system using patient derived tumor cells along with patient derived cancer-associated fibroblasts (CAFs). Results: In our ex vivo 3D co-culture system, APX3330 decreases the tumor area and intensity in a dose-dependent manner. We can quantitate the effect on both the tumor and the CAFs as they are labeled with different fluorescent markers. The combination of APX3330 with Gemcitabine (Gem) demonstrated an additive enhancement effect in the tumor. However, the combination treatment did not appear to sensitize CAF cells to Gemcitabine, which suggests that Gem+APX3330 treatment is more specifically targeting tumor cells. This suggests that blocking redox function in both tumor and CAF cells can stop the cross-talk between tumor and fibroblast, therefore sensitizing the tumor cells to Gemcitabine-induced cell killing. Using in vivo animal models, APX3330 has been shown to be effective in reducing tumor volume and metastases as a single agent. APX3330 also reduced the number of lymph node metastatic lesions. In our current combination in vivo study, APX3330 was combined with a standard dose of Gemcitabine and carried out over 63 days. There was a significantly decreased tumor volume in the combination treatments of APX3330 with Gemcitabine compared to the single-agents alone. Based on these findings we are proposing phase I/Ib studies of APX3330 in patients with solid tumors, and in combination with Gemcitabine in patients with advanced pancreatic ductal adenocarcinoma. Citation Format: Melissa L. Fishel, Huiwen Cheng, Safi Shahda, Mark R. Kelley. APX3330 drug development for clinical trials targeting APE1/Ref-1 in pancreatic cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B167.

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

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

Safety and efficacy of gemcitabine and trastuzumab in HER2-directed therapy pretreated patients with HER2-positive metastatic breast cancer: SBP-01 study.

142 Background: Prognosis of HER2-positive metastatic breast cancer (MBC) has been dramatically improved by trastuzumab (Tmab). More recently, newer anti-HER2 agents such as lapatinib, pertuzumab and T-DM1 have prolonged survival. Despite the efficacy of these drugs, most patients develop progressive disease during or after treatment, and alternative anti-HER2 agents plus chemotherapies are required in subsequent lines of treatment. However, there are few evidence on efficacy of Tmab-containing regimens after disease progression. Gemcitabine (GEM) is non-cross resistant to anthracycline and taxane. Preclinical studies have shown that the combination of Tmab and GEM has synergistic effect against HER2-positive breast cancer cell lines. SBP-01 study assessed the efficacy and safety of the combination of Tamb and GEM in patients with HER2-positive MBC previously treated with anti-HER2 therapy. Methods: SBP-01 study included patients treated with one or more anti-HER2 directed regimens for MBC. Patients were administered with GEM 1250 mg/m2 on days 1 and 8 of each 21-day cycle and Tmab 4mg/kg loading dose and then 2mg/kg weekly. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression free survival (PFS), overall survival, and safety. Results: Between June 2011 and June 2014, 35 patients were enrolled. Patients had ER positive tumor (37.1%), a median of 2 metastatic organ sites, visceral metastasis (80.0%), prior (neo) adjuvant Tmab (22.9%) and a median of 2 prior chemotherapy regimens for MBC. Previous HER2-directed drugs included Tmab (94.3%), lapatinib (37.1%), T-DM1 (8.6%) and pertuzumab (2.9%). ORR was 22.9% (95% CI, 8.6%-36.8%). Median PFS was 146 days. Patients with stable disease response received a median of 7 cycles (6-28 cycles) of treatment. Grade3/4 leukopenia (20.0%) and neutropenia (48.6%) were observed. All non-hematological toxicities were less than grade3. Conclusions: The Combination Tmab and GEM is effective and well-tolerated regimen for patients previously treated with HER2-directed therapy, and appears to make disease stable for long time period. Clinical trial information: UMIN000005881.