Multicenter randomized controlled phase III clinical trial using TNFerade (TNF) with chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC): Interim analysis (IA) of overall survival (OS)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 4605-4605
Author(s):  
K. J. Chang ◽  
W. Fisher ◽  
D. Kenady ◽  
J. Klapman ◽  
M. Posner ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Human Tumor ◽  
Adenovirus Vector ◽  
Nonparametric Methods ◽  
Phase Iii ◽  
Open Label ◽  
Prognostic Information ◽  
Cancer Trial

4605 Intro: Local control of LAPC with CRT has historically demonstrated survival benefit vs. RT alone. TNF is a nonreplicating adenovirus vector delivering human tumor necrosis factor (TNF-α). Results from a phase II study with TNF in LAPC indicated a possible survival advantage. To confirm these findings, a randomized, open-label, controlled Pancreatic Cancer Trial with TNF (PACT) study was developed. Methods: The TNF arm received a 5 wk treatment of qw intratumoral inj of 4x1011 PU TNF, cont. iv 5-FU and 50.4Gy radiation. The standard of care (SOC) arm received CRT alone. Both groups received adjuvant gemcitabine(G) with the option of erlotinib(E). An IA of OS (primary efficacy endpoint) was planned after the first third (92) of the expected 276 total death events (from a total patient n=330). Nonparametric logrank of OS was planned; in addition, a lognormal model was used to account for an evident separation of the survival curves after the median. Results: 185 pts were available for OS analysis (117-TNF+SOC and 68-SOC). Survival in the TNF+SOC group demonstrated a HR of 0.753 (CI [0.494 - 1.15]) relative to SOC. Best fit parametric lognormal analysis indicated a median survival of 11.1 mo with TNF+SOC and 8.7 mo with SOC; nonparametric methods indicated a MS of 9.9 mo for both arms, with a pronounced “late effect” (75th percentile 19.4 mo with TNF+SOC and 11.8 mo with SOC). Prognostic information (G and E use, stage, etc) indicated equivalent distribution between groups. Conclusions: HR results of the OS IA indicate an encouraging trend in favor of the TNF treated group. Parametric medians may better reflect the true HR than nonparametric methods since the latter do not reflect the shape of the OS distribution. A second IA is planned after 2/3 total events. [Table: see text]

Phase III Randomized Comparison of Gemcitabine Versus Gemcitabine Plus Capecitabine in Patients With Advanced Pancreatic Cancer

2009 ◽  
Vol 27 (33) ◽  
pp. 5513-5518 ◽  
Author(s):  
David Cunningham ◽  
Ian Chau ◽  
Deborah D. Stocken ◽  
Juan W. Valle ◽  
David Smith ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Meta Analysis ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Primary Outcome Measure ◽  
Phase Iii ◽  
Open Label

PurposeBoth gemcitabine (GEM) and fluoropyrimidines are valuable treatment for advanced pancreatic cancer. This open-label study was designed to compare the overall survival (OS) of patients randomly assigned to GEM alone or GEM plus capecitabine (GEM-CAP).Patients and MethodsPatients with previously untreated histologically or cytologically proven locally advanced or metastatic carcinoma of the pancreas with a performance status ≤ 2 were recruited. Patients were randomly assigned to GEM or GEM-CAP. The primary outcome measure was survival. Meta-analysis of published studies was also conducted.ResultsBetween May 2002 and January 2005, 533 patients were randomly assigned to GEM (n = 266) and GEM-CAP (n = 267) arms. GEM-CAP significantly improved objective response rate (19.1% v 12.4%; P = .034) and progression-free survival (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .004) and was associated with a trend toward improved OS (HR, 0.86; 95% CI, 0.72 to 1.02; P = .08) compared with GEM alone. This trend for OS benefit for GEM-CAP was consistent across different prognostic subgroups according to baseline stratification factors (stage and performance status) and remained after adjusting for these stratification factors (P = .077). Moreover, the meta-analysis of two additional studies involving 935 patients showed a significant survival benefit in favor of GEM-CAP (HR, 0.86; 95% CI, 0.75 to 0.98; P = .02) with no intertrial heterogeneity.ConclusionOn the basis of our trial and the meta-analysis, GEM-CAP should be considered as one of the standard first-line options in locally advanced and metastatic pancreatic cancer.

A randomized phase III multi-institutional study of TNFerade biologic with 5-FU and radiotherapy for locally advanced pancreatic cancer: Final results

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4055-4055
Author(s):  
Aaron Tyler Wild ◽  
Dan Laheru ◽  
Hao Wang ◽  
Kenneth J. Chang ◽  
Gretchen Elizabeth Taylor ◽  
...  
Keyword(s):  
Early Stage ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Systemic Exposure ◽  
Adenovirus Vector ◽  
Phase Iii ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Tnf Α ◽  
Grade 3

4055 Background: TNFerade biologic (TNF) is a novel means of selective delivery of TNF-α to tumor cells by gene transfer through intratumoral (IT) injection. TNF is a replication deficient adenovirus vector containing TNF-α cDNA ligated downstream from a radiation-inducible Egr-1 promoter, allowing spatiotemporal constraint of TNF-α production to the radiation field. Herein we report the final results of a multi-center, randomized, open-label, controlled phase III trial of TNF with chemoradiotherapy for locally advanced pancreatic ductal adenocarcinoma (PDA). Methods: Pts with locally advanced PDA were randomized 1:2 to standard of care (SOC; 5-FU/RT followed by GEM) versus TNF + SOC. RT dose was 50.4 Gy in 28 fractions. Concurrent 5-FU (200 mg/m2/day IV) started on day 1 of RT each wk. TNF was injected IT ~4 hrs prior to RT weekly by percutaneous (PTA) or endoscopic (EUS) approach. 4 wks after RT, GEM (1000 mg/m2 IV) was given until progression or toxicity. Results: Of 277 pts, 187 were randomized to TNF and 90 to SOC. Demographic/baseline characteristics were similar between arms (all NS), as was GEM received (67 vs. 68%; 7.0 vs. 7.6 total wks). Median f/up was 9.1 mos (range, 0.1-50.5). Median OS for TNF by ITT analysis was 10.1 mos (95% CI, 9.1-11.7) vs. 10.0 mos (95% CI, 7.6-11.2) for SOC (p=0.6). TNF delivery method did not affect OS (9.4 mos for PTA vs. 11.5 for EUS; p=0.7). Baseline CA19-9 > 1000 was found to impart independent risk to TNF pts (HR=1.7; p=0.02). Subgroup analysis (SGA) of 86 pts with T1-T3 disease showed an OS benefit for TNF compared to SOC (10.9 vs. 9.0 mos, respectively; p=0.04). TNF resulted in more grade 1-2 fever/chills (p<0.001) as well as grade 3 (p<0.001) and 4 (p=0.05) toxicities (commonly lymphopenia, hypo/hyperkalemia, abd/chest pain) than SOC. Use of PTA vs. EUS did not affect grade 3/4 toxicity rates. Conclusions: TNF + SOC did not prolong OS for locally advanced PDA. SGA reveals a possible OS benefit for early stage (T1-T3) tumors and CA19-9 < 1000. PTA and EUS injection achieved similar rates of efficacy and toxicity. Grade 1-2 toxicity typical of systemic exposure to TNF-α (pyrexia/hypotension/chills) was common, but grade 3-4 was minimal.

Anlotinib Plus Toripalimab and Nab-Paclitaxel in Patients with Locally Advanced or Metastatic Pancreatic Cancer: Study Protocol for An Open-Label, Non-Randomized, Phase II Study (ATNPA)

2021 ◽  
Author(s):  
Jingwen Chen ◽  
Yiqian Liu ◽  
Yizhi Zhu ◽  
Shiyun Cui ◽  
Chongqi Sun ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Maintenance Therapy ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Pancreatic Cancer ◽  
Second Line ◽  
First Line ◽  
Open Label ◽  
Combination Strategy

Abstract Background There have not been standard second-line or maintenance regimens with definite survival benefits so far for patients with pancreatic carcinoma who have lost the opportunity of curable resections or failed first-line chemotherapy. Anlotinib, a potent small-molecule tyrosine kinase inhibitor, exhibits anti-angiogenic and anti-tumour effects by specifically binding to multiple targets such as VEGFR, FGFR, PDGFR, c-Kit and Ret. Toripalimab, a novel anti-PD-1 mAb, has been proved to significantly prolong progression-free survival (PFS) and overall survival (OS) in various solid tumours with manageable toxicities when combining with cytotoxic chemotherapy. We design this study to assess the combination of anlotinib, toripalimab and nab-paclitaxel as a second-line or maintenance therapy for locally advanced pancreatic cancer (LAPC) or metastatic pancreatic cancer (MPC). Patients and Methods: This is an open-label, non-randomized, single-arm phase Ⅱ study, aimed at evaluating the efficacy and safety profile of the above-mentioned combination strategy in first-line therapy-failed LAPC or MPC. Totally 53 patients are to be enrolled and receive anlotinib (12 mg, po. qd.) plus toripalimab (240 mg, ivgtt. q3w.) and nab-paclitaxel (125 mg/m2, ivgtt, d1, d8) every 3 weeks as a cycle until disease progression or intolerable adverse events. The primary endpoint is PFS. Secondary end points include OS, disease control rate (DCR), object response rate (ORR), quality of life (QoL) and safety. Enrollment started in April 2021, and follow-up will be finished in April 2023. Discussion and Significance: Combination of anlotinib, toripalimab and nab-paclitaxel may promote vessel normalization and drug delivery, and activate the immune response, thus exerting synergistic anti-tumour effects and counteracting the immunosuppressive microenvironment of pancreatic cancer. As the first intending to assess this combination in pancreatic cancer, this study will provide comprehensive evidence for second-line or maintenance therapy of LAPC and MPC. Trial registration: ClinicalTrials.gov: ATNPA, NCT04718701. Registered January 22, 2021. (https://clinicaltrials.gov/ct2/show/NCT04718701?term=NCT04718701&draw=2&rank=1)

Updated results of the GEST study: Randomized phase III study of gemcitabine plus S-1 (GS) versus S-1 versus gemcitabine (GEM) in unresectable advanced pancreatic cancer in Japan and Taiwan.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4035-4035 ◽  
Author(s):  
Akira Fukutomi ◽  
Takuji Okusaka ◽  
Kazuya Sugimori ◽  
Hideki Ueno ◽  
Tatsuya Ioka ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Primary Endpoint ◽  
Advanced Disease ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Locally Advanced Disease ◽  
Phase Iii Study

4035 Background: The GEST study (Ioka et al. ASCO 2011, Abstract 4007) demonstrated the non-inferiority of S-1 to GEM with respect to the primary endpoint of overall survival (OS) in patients with pancreatic cancer (PC). We now report the updated results of this study. Methods: The GEST study was a randomized, 3-arm, phase III study. Chemotherapy-naive patients with unresectable advanced PC, an ECOG Performance status (PS) of 0-1, and adequate organ functions were randomly assigned to receive GEM (1000 mg/m2, iv, d1, 8 and 15, q4w), S-1 (80/100/120 mg/day based on BSA, po, d1-28, q6w), or GS (GEM 1000 mg/m2, iv, d1 and 8 plus S-1 60/80/100 mg/day based on BSA po, d1-14, q3w). The primary endpoint was OS, used to assess the non-inferiority of S-1 and the superiority of GS to GEM. Patient information was updated in July 2011. Results: At the time of this follow-up analysis, median follow-up was 29.8 months with 795 OS events, compared with 18.4 months with 710 OS events out of 832 patients at the previous analysis. Median OS was 8.8 months (95% CI: 8.0–9.7) in the GEM group and 9.7 months (95% CI: 7.6-10.8) in the S-1 group (HR=0.96, 97.5% CI: 0.79-1.17, p<0.001 for non-inferiority), which is consistent with prior results (HR=0.96, 97.5% CI: 0.78-1.18, p<0.001). In the GS group, median OS was 9.9 months (95% CI: 9.0-11.2). The HR was 0.91 (97.5%CI: 0.75-1.11, p=0.28 for superiority versus the GEM group). On subgroup analysis, GS was associated with a non-statistically significant trend toward better OS compared with GEM among patients with locally advanced disease and those with a PS of 1. Median OS was 12.7 months (95% CI: 9.7–14.9) in the GEM group and 15.9 months (95% CI: 13.0-19.7) in the GS group (HR=0.72, 95% CI: 0.51-1.03) among patients with locally advanced disease, and 6.2 months (95% CI: 4.9–8.3) in the GEM group and 9.6 months (95% CI: 8.0-10.9) in the GS group (HR=0.62, 95% CI: 0.46-0.83) among patients with a PS of 1. Conclusions: The non-inferiority of S-1 to Gem in terms of the primary endpoint of OS was reconfirmed. Monotherapy with S-1 can be used as one of the standard treatments for advanced PC. As for GS therapy, there is room for further investigation.

A phase III randomized trial of chemoimmunotherapy comprising gemcitabine and capecitabine with or without telomerase vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer.

2013 ◽  
Vol 31 (18_suppl) ◽  
pp. LBA4004-LBA4004 ◽  
Author(s):  
Gary William Middleton ◽  
Juan W. Valle ◽  
Jonathan Wadsley ◽  
David Propper ◽  
Fareeda Y. Coxon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Randomized Trial ◽  
Statistical Significance ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Cell Trafficking ◽  
Concurrent Administration ◽  
Cross Presentation ◽  
Helper Epitope

LBA4004 Background: GV1001, a promiscuous class II epitope encompassing aa 611-626 of hTERT led to the development of CD4+ clones recognizing hTERT in patients with advanced pancreatic cancer (APC). Preclinically gemcitabine increases antigen cross-presentation, enhances T cell trafficking/activation, and reduces MDSCs and Tregs. Methods: Patients with APC were randomized 1:1:1 to: Arm 1 GemCap; 2 GemCap for 8/52 followed by GV1001 followed by further GemCap if no PD at week 8; 3 concurrent administration of GemCap and GV1001. 735 (69.2%) had metastatic disease and 948 (89.3%) had ECOG PS=0 or 1. Randomization was stratified by stage and PS. Primary endpoint was overall survival (OS); secondary endpoints included ORR, TTP, and AEs. Recruitment target was 1,110 patients (780 deaths) to permit detection of a hazard ratio of 0.748 between either GV1001 arm and Arm 1 using a 2-sided α=0.025 level of significance with at least 80% power. Results: 1,062 pts from 51 centers were randomized. Trial maturity was high (72.7% patients died): median follow-up was 6.11 months. The overall response rates were Arm 1=17.6%; Arm 2=8.9% (p=0.001); Arm 3: 15.5% (p=0.460 compared with Arm 1). Conclusions: OS with concurrent GemCap/GV1001 was not different to that with GemCap alone. OS with sequential GV1001 was not statistically different to GemCap alone as it did not meet the criterion for statistical significance (p<0.0175). The addition of a T helper epitope vaccine to GemCap did not improve outcome compared to GemCap alone. Clinical trial information: 43482138. [Table: see text]

LAPACT: An open-label, multicenter phase II trial of nab-paclitaxel (nab-P) plus gemcitabine (Gem) in patients (pts) with locally advanced pancreatic cancer (LAPC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS477-TPS477 ◽  
Author(s):  
Philip Agop Philip ◽  
Jill Lacy ◽  
Scot D. Dowden ◽  
Javier Sastre ◽  
Venu Gopal Bathini ◽  
...  
Keyword(s):  
Group Performance ◽  
Performance Status ◽  
Locally Advanced ◽  
Eastern Cooperative Oncology Group ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Open Label ◽  
Primary Tumors

TPS477 Background: In pts with LAPC, more effective systemic therapies may be associated with improved local control, delay of metastasis, and overall survival (OS). The phase III MPACT trial in pts with metastatic PC demonstrated longer OS (median, 8.7 vs 6.6 mos; HR, 0.72; P < 0.001) and an ≈ 3-fold greater shrinkage of primary tumors with nab-P + Gem vs Gem alone (−22.15% vs −7.02%), raising the possibility of improved local PC control with nab-P + Gem. LAPACT will assess the efficacy and safety of nab-P + Gem in LAPC. Methods: LAPACT will enroll treatment-naive pts (planned n ≈ 110) in the United States, Canada, and Europe with Eastern Cooperative Oncology Group performance status ≤ 1, confirmed unresectable LAPC, no distant metastases, and adequate organ function. Pts with mixed-origin tumors, any other malignancy within 5 years, peripheral neuropathy grade > 1, or clinically significant ascites are ineligible. Pts will receive nab-P 125 mg/m2 + Gem 1000 mg/m2 on days 1, 8, and 15 of each 28-day cycle. Pts without progressive disease (PD) or unacceptable toxicity after 6 cycles will receive investigator’s choice of surgery, chemoradiotherapy, or continued nab-P + Gem. If a major response is observed, surgery may occur prior to completing 6 cycles of nab-P + Gem. The primary endpoint is time to treatment failure (TTF; time from first therapy dose to discontinuation due to PD, start of a new non–protocol-defined anti-cancer therapy, or death). The study design allows for 80% power at a 1-sided α of 0.05 to detect a 30% increase over the 5.1-month median TTF observed for nab-P + Gem in the MPACT study. The secondary endpoints are disease control rate (DCR) after 6 cycles, overall response rate, progression-free survival, OS, safety, and quality of life. The exploratory endpoint is correlation of changes in circulating nucleic acids with PD and treatment response. An interim DCR analysis will occur after all pts have completed 6 cycles of nab-P + Gem, discontinued therapy due to PD, died, or started a new non–protocol-defined therapy before completing 6 cycles of therapy. Enrollment is ongoing (first pt enrolled in April 2015). Clinical trial information: NCT02301143.

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