Phase I/II study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor in patients with advanced pancreatic cancer receiving treatment with gemcitabine.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 221-221 ◽  
Author(s):  
R. K. Ramanathan ◽  
V. Gressler ◽  
S. Shah ◽  
D. Loury ◽  
A. Hamdy ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Coagulation Factor ◽  
Hematologic Toxicity ◽  
Venous Thromboembolic Events ◽  
Grade 3 ◽  
To Receive

221 Background: PCI-27483 is a selective inhibitor of FVIIa, a serine protease activated by interaction with tissue factor (TF). TF upregulation in tumor cells correlates with angiogenesis and a worsened prognosis. Hydrolysis of protease activated receptors by the TF:FVIIa complex induces up-regulation of IL-8 and VEGF. PCI-27483 inhibited the growth of human pancreatic tumors in animal models at a 2.5x to 3.0x change in prothrombin time. PK/INR relationships from a phase I study in healthy volunteers were used to select initial doses of PCI-27483 for the current study. Methods: Patients (pts) with locally advanced or metastatic pancreatic cancer, ECOG performance status 0-1, and normal coagulation were enrolled. All pts in phase I and II receive gemcitabine (G) as a 30-min IV infusion at a dose of 1000 mg/m2 on 3 out of every 4 wks. PCI-27483 is administered twice daily by SC injection. In phase I, doses of PCI-27483 were intra-patient escalated (0.8 to1.2 to1.5 mg/kg) over 4 to 8 wks. The targeted peak INR, measured 2 h postdose, was 3.0. In phase II, pts are being randomized to a control arm to receive G only or to a PCI-27483 arm to receive G plus PCI-27483. Phase I pts receiving 80% of planned doses during in first 6 wks were considered evaluable. Spiral CT scans are performed at 8-wk intervals. Study endpoints: adverse event profile, progression-free survival, venous thromboembolic events, and overall survival. Results: Phase I—8 pts enrolled, 5 pts evaluable. Highest dose of PCI- 27483 achieved was 0.8 mg/kg for 2 pts, 1.2 mg/kg for 3 pts and 1.5 mg/kg for 3 pts. Hematologic toxicity: grade 3 neutropenia (n= 1) or anemia (n = 2). Other grade 3 toxicities: elevated INR (n = 4) or elevated aPTT (n = 1). Dose-level-specific mean 2-h INR values were 2.2 at 0.8 mg/kg (CV=9%; n=7), 3.2 at 1.2 mg/kg (CV=33%; n=6) and 2.9 at 1.5 mg/kg (CV=16%; n=3). No VTEs occurred. Radiologic evaluations of 5 evaluable pts: 4 SD at 16 wks (1st pt SD for >40 wks; 5th pt SD at 8 wks, 16-wk scan pending). Conclusions: PCI-27483 is well tolerated at doses up to 1.5 mg/kg bid with G 1,000 mg/m2. Sustained SDs occurred and INRs were generally within the expected range. The randomized phase II study is ongoing at a dose of 1.2 mg/kg bid. [Table: see text]

Phase I/II study of PCI-27483, a coagulation factor VIIa (FVIIa) inhibitor, in combination with gemcitabine in patients with advanced pancreatic cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15014-e15014 ◽  
Author(s):  
Sameer A. Mahesh ◽  
Nashat Y. Gabrail ◽  
Jitendra G. Gandhi ◽  
Alok A. Khorana ◽  
Robert Manges ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Factor Viia ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Coagulation Factor ◽  
Coagulation Cascade ◽  
Low Grade ◽  
Bleeding Events

e15014 Background: Tissue factor (TF) up-regulation is associated with increased tumor invasiveness and progression, worsened prognosis and increased thromboembolism (VTE). Activation of protease activated receptors by TF:FVIIa complex leads to increases in IL-8, VEGF and other invasiveness promoting factors. PCI-27483 (P), a selective FVIIa inhibitor, reduced pancreatic adenocarcinoma (PCa) xenograft growth in mice at doses producing 2.5 - 3.0 x PT changes. Methods: Escalating doses of P combined with gemcitabine (G) targeting peak (2 hr post) INR = 3.0 was studied in Phase I preceding randomization to G+P at the determined dose vs. G alone in Phase II. Eligible patients (pts) had measurable locally advanced or metastatic PCa, ECOG PS 0-1, and normal PT/aPTT, and no history of VTE. G was given IV at 1 G/m2 q wk X3 every 4 wks, and P was self-administered SC bid continuously. Tumor evaluation including spiral CTs were performed at baseline and q 8 wks. Results: In phase I, 8 pts were enrolled and the targeted INR was attained at 1.2 mg/kg. In phase II, 34 patients were randomized, 16 to G and 18 to G+P. The randomized arms were well balanced; overall 88% had metastatic disease; most had liver involvement. Among pts randomized to P+G, mean ± SD 2-hr post injection INR was 3.1 ± 1.2 on D8 and 2.8 ± 1.0 on D22 (n=13). P dosing was continued for up to 96 wks; mean ± SD: 17 ± 24 wks. Dose reduction to maintain target INR was required for 6 pts. Overall tolerability and safety of G+P was similar to that of G, with a higher incidence of mostly low grade bleeding events and decreased Hgb. Efficacy measures of G vs G+P pts were not significantly different (Table). Conclusions: PCI-27483 +G was well tolerated at doses of P up to 1.5 mg/kg bid. The safety profile of the combination was consistent with that expected of each agent. While the clinical endpoints were not achieved in pancreatic cancer, the targeted inhibition of the coagulation cascade was achieved. Clinical trial information: NCT01020006. [Table: see text]

Interim analysis of a phase II study of dose-modified FOLFIRINOX (mFOLFIRINOX) in locally advanced (LAPC) and metastatic pancreatic cancer (MPC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 256-256 ◽  
Author(s):  
Edward Samuel James ◽  
Xiaopan Yao ◽  
Xiangyu Cong ◽  
Stacey Stein ◽  
Kristin Kaley ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Interim Analysis ◽  
Historical Data ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Sensory Neuropathy ◽  
Open Label ◽  
Grade 3 ◽  
Ecog Ps

256 Background: Although FOLFIRINOX is superior to gemcitabine in MPC, the regimen is associated with significant toxicities (Conroy et al. N Engl J Med 2011;364:1817). In our prior retrospective analysis, efficacy was not compromised by dose attenuations of FOLFIRINOX (Gunturu et al. Med Oncol 2013;30:361). Based on this analysis, we are conducting a prospective phase II open label study to evaluate the efficacy & tolerability of mFOLFIRINOX in pts with advanced pancreatic cancer (PC). Methods: Previously untreated pts with MPC or LAPC received mFOLFIRINOX with 25% dose reductions of irinotecan & bolus 5-FU given every two wks until progression, unacceptable toxicity, or surgical resection. All pts received prophylactic pegfilgrastim. FDG-PET scans were obtained at baseline & after 2 cycles. CAT scans were obtained after every 4 cycles. Toxicities & response rate (RR) were compared to historical data reported by Conroy. Results: 53 pts with ECOG PS ≤1 have been enrolled to date between 11/11 and 08/13, Pt characteristics: LAPC 22; MPC 31; median age 62 yrs (range 46-86); male 30. Median # of cycles was 8 (range 1-21). Grade 3/4 toxicities were: anemia, febrile neutropenia (FN) & peripheral sensory neuropathy (PSN) – 3.8% each; ALT increased & thromboembolism – 5.7% each; diarrhea 7.5%; fatigue 11.3%; neutropenia 17%; thrombopenia 11.3% & vomiting 1.9%. Anemia ( p< 0.04), FN (p<0.04), PSN (p<0.04) and vomiting (p<0.02) were significantly decreased compared to historical data (Conroy). Response by RECIST (CR+PR) in 26 evaluable pts with MPC was 29% (0 CR, 9 PR, 14 SD, 3 PD) & similar to historical data (31.6%; p 0.85). 6/13 evaluable pts with LAPC underwent resection (46%).13/36 pts evaluable for PET response had a >50% decrease in SUV(max)(36%). Evaluation for OS & PFS is ongoing. Conclusions: Findings from our interim analysis suggests that mFOLFIRINOX, given along with prophylactic pegfilgrastim is associated with a similar RR and improved tolerability compared to full dose FOLFIRINOX in advanced PC. In pts with LAPC, neoadjuvant FOLFIRINOX appears to have substantial activity with 46% of evaluable pts undergoing resection. Accrual will continue to reach a goal of 70 pts. Clinical trial information: NCT01523457.

Clinical and immune responses using anti-CD3 x anti-EGFR bispecific antibody armed T cells (BATs) for locally advanced or metastatic pancreatic cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4135-4135 ◽  
Author(s):  
Lawrence G. Lum ◽  
Tri Minh Le ◽  
Minsig Choi ◽  
Archana Thakur ◽  
Matthew Reilley ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
T Cells ◽  
Phase I ◽  
Phase Ii ◽  
Bispecific Antibody ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Metastatic Pancreatic Cancer ◽  
Cytotoxic T Cell ◽  
Ifn Γ

4135 Background: Conventional chemotherapy (chemo) for locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC) has dismal responses and poor survival rates. Arming activated T cells (ATC) with anti-CD3 x anti-EGFR bispecific antibody (BATs) makes every ATC into an EGFR-specific cytotoxic T cell that secretes cytokines, proliferates, and kills tumor. Methods: We report on 5 phase I (P1) and 15 phase II (P2) patients. In our phase I study, BATs were used to treat LAPC or MPC patients at Karmanos Cancer Institute (NCT0140874) in a dose escalation involving 3 weekly infusions of 1, 2, and 4 x 1010 BATs/infusion, followed by a booster infusion at 3 months (mos) for a total of up to 8 x 1010 BATs. No dose limiting toxicities were observed in the outpatient infusions. Fifteen patients treated on a phase II (NCT02620865) at KCI and (NCT03269526) at University of Virginia received biweekly infusions of 1010 BATs/infusion over 4 weeks for a total of 8 x 1010 EGFR BATs. Results: Four patients had stable disease (SD) for 6.1, 6.5, 5.3, and 36 mos. Two patients had complete responses (CR) when chemo was restarted after BATs. The median overall survival (OS) for 17 evaluable patients (3 of 4 infusions in the P1 and all 8 infusions in the P2) was 31 mos, and the median OS for all 20 patients (3 in the P2 who did not complete 8 infusions) is 14.5 mos (95% CI, 7.5-45.2 mos). Patient IT20104 had an apparent “pseudoprogression” after 3 BATs infusions, but achieved a CR after restarting capcitabine and is alive off therapy at 54 mos (24 mos after stopping capecitabine). Immune evaluations on the P1 patients show specific cytotoxicity to MiaPaCa-2 by peripheral blood mononuclear cells (PBMC) increased from 21% to 31% 2 weeks after the 3rd infusion, and IFN-γ EliSpots increased from < 20 to 1000 IFN-γ EliSpots/106 PBMC (p < 0.03). Patient IT 20121 (SD for 36 mos) increased IFN-γ EliSpots from 250 to 3200/106 PBMC after 8 infusions. Innate cytotoxicity responses in the P1 patients increased significantly after infusions (p < 0.04). Levels of IP-10 increased significantly (p < 0.04), and levels of IL-8 decreased but not significantly (p < 0.07). Conclusions: Infusions of BATs are safe and induce endogenous adaptive anti-tumor responses. Targeting PC with BATs may stabilize disease, leading to improved OS, as well as evidence that BATs infusions can induce anti-tumor activity and immunosensitize tumors to subsequent chemo. Clinical trial information: NCT014084,NCT03269526,NCT02620865.

Upregulation of thymidine phosphorylase (TP) by radiation (XRT): Phase II study of capecitabine (CAP) with XRT in pts with locally advanced (LA) pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14001-14001
Author(s):  
S. Roy ◽  
S. Russo ◽  
G. Black ◽  
M. A. Eloubeidi ◽  
A. Steg ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Tnf Alpha ◽  
Mrna Levels ◽  
Gi Bleeding ◽  
Grade 3 ◽  
Dose Reductions

14001 Background: Preliminary studies have shown that XRT unregulates TP, the main enzyme responsible for activity of CAP. The objectives of this phase II study were to further evaluate effect of XRT on TP, DPD, and TNF-alpha as well as response and efficacy of CAP with concurrent XRT in pts with LA pancreatic cancer. Methods: Pts received 50.4 Gy XRT with CAP at 1600 mg/m2 M-F × 6 wks determined from our phase I study (JCO, Dec 2005). Following CAP-XRT, stable and responding pts on CT scan were treated with CAP 2000mg/m2 × 14 days q 3 wks till progression. Restaging was performed every 9 wks. Tumor specimens were procured with EUS-FNA 1 wk prior and 2 wks after CAP-XRT to evaluate TP, DPD, and TNF-alpha mRNA levels by RT-PCR. A sample size of 20 was selected (mean 1 vs. S with mean 0=13.5; alpha = 0.05; power = .99; t-test). Results: 19 pts (median age: 67; M/F: 7/12) were enrolled at UAB between March 2004 and June 2005. 4 pts (21%) had confirmed partial responses and 13 (68%) had stable disease. 2 pts underwent surgery (Ro in 1; extensive fibrosis in 1). Six-month survival rate was 89%. We have not met enough deaths to estimate median survival. Grade 3 and 4 toxicities included: nausea/vomiting (5%), thrombosis (5%), hyperbilirubinemia (5%), and grade 3 GI bleeding (5%). No hematological toxicities except grade 1 thrombocytopenia (5%) and grade 1 anemia (10%). All pts completed full CAP-XRT with 3 dose reductions (by 20%). Pts received mean of 5.4 cycles (range: 3–15) of CAP alone with a total of 104 cycles with dose reductions in 7 cycles (by 25%). TP was elevated during wk 2 when compared to pre-XRT TP (P = .005) but DPD was not (P = .13) nor was TNF-alpha (P = .37). No correlation between TP and TNF-alpha was noticed. No association between TP/DPD ratio and efficacy of CAP was identified. Tumor TP expression was higher (183.16) in pt with GI bleeding. Conclusions: This Phase II study further confirms our Phase I results that CAP-XRT is an effective, tolerable, and an easy alternative to infusional 5-FU regimen for pts with LA pancreatic cancer. Also TP upregulation by XRT was statistically significant. While these results support use of CAP-XRT in pancreatic cancer, there appears to be additional genes (other than TP, DPD) associated with response to CAP and CAP-XRT. [Table: see text]

A phase I study of erlotinib, bevacizumab and gemcitabine in patients with advanced pancreatic cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4611-4611 ◽  
Author(s):  
C. Gomez-Martin ◽  
J. C. Camara ◽  
H. Cortes ◽  
C. Jara ◽  
C. Gravalos ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Skin Rash ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Hematological Toxicity ◽  
Clinical Activity ◽  
Complete Treatment ◽  
Grade 3 ◽  
Karnofsky Index

4611 Background: Erlotinib is an EGFR TKI active in combination with gemcitabine in p with advanced pancreatic cancer (PC). The combination of gemcitabine and bevacizumab is also active in PC. A phase I of gemcitabine, bevacizumab and erlotinib in p with unresectable locally advanced or metastatic PC is being conducted. Methods: Two cohorts of 6 patients with advanced PC have been treated either with erlotinib (150 mg/day po), bevacizumab (5 mg/Kg iv, days 1 and 15, every 28 days), and either 10 mg/m2/min infusion of gemcitabine 850 mg/m2 or 1,000 mg/m2 days 1 and 15 every 28 days. P received a maximum of 6 cycles of 28 days. Cohort 1: Daily erlotinib 150 mg po + bevacizumab 5 mg/kg iv days 1 and 15 + gemcitabine 850 mg/m2 over 10 mg/m2/min infusion days 1 and 15. Cohort 2: daily erlotinib 150 mg po + bevacizumab 5 mg/kg iv days 1 and 15 + gemcitabine 100 mg/m2 over 10 mg/m2/min infusion days 1 and 15. Results: 12 p have been included in this study (6 cohort 1 and 6 cohort 2), being evaluable for toxicity. 11 p have concluded the study and 7 have received complete treatment as per protocol. Median age 62.6 yrs (range 38–71); male/female: 5/7 (42%/58%); stage III/IV: 3/9 (25%/75%); Karnofsky index 100%/80%: 2/10. 3 of 6 p in cohort 1 developed gr. 3 asthenia (50%), 2 p gr. 3 neutropenia (33.3%), whereas 1 p had grade 3 leucopenia and gr. 3 skin rash. In cohort 2, most severe adverse events were: 1 case of grade 4 GGT elevation, 1 p gr. 3 skin rash and 1 p. experienced asthenia gr. 3. No severe hematological toxicity in cohort 2 was reported. One p of each cohort required dose reduction of erlotinib, both due to skin rash. Mild diarrhea was reported in 11 of 12 p evaluated. No dose limiting toxicities has been reported. All p were available for response: 2 p reached partial response (both included in cohort 1) and 7 showed stabilization (3 and 4 in cohorts 1 and 2, respectively). No complete responses were observed. Overall disease control index was 75%. Conclusions: The combination of gemcitabine, erlotinib and bevacizumab is well tolerated. MTD has not been reached. Encouraging clinical activity in advanced pancreatic cancer has been observed. Phase I is still ongoing. Toxicity data for all the p will be presented. No significant financial relationships to disclose.

FOLFOX and nab-paclitaxel (nab-P) for advanced pancreatic cancer: A phase I study.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 258-258
Author(s):  
Howard Safran ◽  
Kevin Charpentier ◽  
Kimberly Perez ◽  
Kalyan Mantripragada ◽  
Trevor Clark Austin ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Maximum Tolerated Dose ◽  
Level 3 ◽  
Grade 3 ◽  
Level 2

258 Background: FOLFIRINOX improves survival in advanced pancreatic cancer, however the contribution of irinotecan is uncertain. The addition of irinotecan to gemcitabine was not superior to gemcitabine alone in pancreatic cancer, however nab-P demonstrates a survival benefit. This phase I study was designed to evaluate the maximum tolerated dose (MTD) of the addition of nab-P to fluorouracil, leucovorin, oxaliplatin (FOLFOX-A). Methods: Patients with metastatic or locally advanced pancreatic adenocarcinoma without prior treatment received oxaliplatin, 85 mg/m2, leucovorin 400 mg/m2 and 5-FU 2400 mg/m2 with 3 dose levels of nab-P (125, 150 and 175 mg/m2) every 2 weeks. Pegfilgrastim was required during the first 2 cycles. Dose limiting toxicities (DLTs) were defined in the first 2 cycles of treatment. Results: Fifteen patients were entered: Dose level 1 (n=6), dose level 2 (N=6), dose level 3 (N=3). The median age was 64 (35-81). Ten patients had metastatic and 5 had locally advanced disease. DLTs of nausea and fatigue occurred in 2 of 3 patients at dose level 3. Two patients developed grade 3 neuropathy after >= 10 cycles of treatment. One patient had grade 3/4 neutropenia. Eight of fifteen patients (53%) had a partial response. Conclusions: The MTD of nab-P is 150mg/m2 every 2 weeks with FOLFOX. Cumulative peripheral neuropathy, similar to other FOLFOX regimens, is the most significant toxicity generally occurring after >= 10 cycles of treatment. FOLFOX-A has substantial activity and may represent a promising regimen in pancreatic cancer. Patients are currently being accrued to an expansion phase utilizing dose level 2. Supported by the Davis and Browning families and LIFEcycle. Clinical trial information: NCT01744353.

scholarly journals Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer

2015 ◽  
Vol 33 (13) ◽  
pp. 1475-1481 ◽  
Author(s):  
Mitesh J. Borad ◽  
Shantan G. Reddy ◽  
Nathan Bahary ◽  
Hope E. Uronis ◽  
Darren Sigal ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Metastatic Disease ◽  
Tumor Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Randomized Phase Ii ◽  
Grade 3

Purpose TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients and Methods Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m2), gemcitabine plus TH-302 240 mg/m2 (G+T240), or gemcitabine plus TH-302 340 mg/m2 (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Results Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (−5,398 v −549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302–related AEs but were not associated with treatment discontinuation. Conclusion PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979).

A phase I trial of S-1 with concurrent radiotherapy for locally advanced pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14003-14003
Author(s):  
M. Ikeda ◽  
T. Okusaka ◽  
Y. Ito ◽  
H. Ueno ◽  
C. Morizane ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Maximum Tolerated Dose ◽  
Locally Advanced Pancreatic Cancer ◽  
Hematological Toxicity ◽  
Concurrent Radiotherapy ◽  
Grade 3

14003 Background: S-1 is a novel oral fluoropyrimidine derivative, and a phase II trial of this agent has demonstrated promising results with a response rate of 37.5% and a median survival of 8.8 months with a mild toxicity profile for patients with metastatic pancreatic cancer. This study investigated the maximum tolerated dose of S-1 based on the frequency of dose-limiting toxicities (DLT) of S-1 with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Patients and Methods: Patients with locally advanced pancreatic cancer in whom adenocarcinoma had been confirmed histologically or cytologically were enrolled in this study. S-1 was administered orally in escalating doses from 50 mg/m2, which is reported to be equivalent to 200 mg/m2 intravenous 5-fluorouracil, to 80 mg/m2 bid in 10 mg/m2 increments on the day of irradiation (Monday through Friday) during radiotherapy. Radiation therapy was delivered through four fields as a total dose of 50.4 Gy in 28 fractions over 5.5 weeks. DLT was defined as grade 4 hematological toxicity and grade 3 or 4 non-hematological toxicity during chemoradiotherapy. The maximum tolerated dose was defined when three or more patients in a cohort of six patients experienced DLT. Results: Twenty-one patients (50 mg/m2 3 patients; 60 mg/m2 5 patients; 70 mg/m2 6 patients; 80 mg/m2 7 patients) were enrolled in this trial between May 2004 and November 2005. At 70 mg/m2 S-1, two of six patients demonstrated DLT involving grade 3 nausea and vomiting and grade 3 hemorrhagic gastritis, while all patients at dose levels other than 70 mg/m2 did not demonstrate any sign of dose-limiting toxicity. Of all 21 patients enrolled, 4 (19.0%) showed a partial response. More than a 50% reduction in the serum level of carbohydrate antigen 19–9 was observed in 12 (75%) of 16 patients in whom the pretreatment level was 100 U/ml or greater. Conclusion: The recommended dose of S-1 with concurrent radiotherapy is 80 mg/m2. This regimen may offer an easy alternative to intravenous 5-fluorouracil, and may be a promising treatment for locally advanced pancreatic cancer. A multicenter phase II trial of this regimen in patients with locally advanced pancreatic cancer is now underway. No significant financial relationships to disclose.

N0321: A phase II study of bortezomib, paclitaxel, carboplatin (CBCDA), and radiotherapy (RT) for locally advanced non-small cell lung cancer (NSCLC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7073-7073
Author(s):  
Steven E. Schild ◽  
Nathan R. Foster ◽  
Julian R. Molina ◽  
Grace K. Dy ◽  
Kendrith M. Rowland ◽  
...  
Keyword(s):  
Survival Rate ◽  
Adverse Events ◽  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Locally Advanced ◽  
Hematologic Toxicity ◽  
Tumor Killing ◽  
Grade 3 ◽  
Ecog Ps

7073 Background: In preclinical studies, combinations of bortezomib and RT result in synergistic tumor killing (Cancer Chemother Pharmacol. 2007;59:207-15). Our group reported the results from the phase I portion of this study previously (J Clin Oncol. 200;28 (suppl; abstr 7085)). Based on these data, we undertook a phase II study of bortezomib in combination with paclitaxel/CBCDA and RT. Methods: Based on results from our previously reported phase I trial, systemic therapy included bortezomib (1.2 mg/m² IV days 1,4,8,11), paclitaxel (175 mg/m² IV day 2), and carboplatin (CBCDA; AUC=6 day 2) given every 3 weeks for 2 cycles. Thoracic radiotherapy (RT) included 60Gy/30 daily fractions starting day 1. The primary endpoint was the 12-month survival rate. If 41 or more of these 60 patients (68%) were alive at least 12 months after study entry, the trial would be deemed as positive and further study would be warranted. Results: 27 pts were enrolled to the phase II portion: M/F=17/10; stage IIIA/IIIB=13/14; ECOG PS 0/1=9/18; and median age: 58 (range 43-79). 18 pts (67%) completed therapy per protocol. At a planned interim analysis, 23 of 26 evaluable patients (88.5%, 95% CI: 70-98%) survived for at least 6 months, which exceeded the boundary of 21 or more needed to continue to full accrual. This trial could have continued per protocol, but was closed early due to slow accrual. With a median follow-up of 15.0 months in the 17 patients still alive, the 12-month survival rate was 71% (95% CI: 49 – 85). The median OS was 19 months (95% CI: 11 – no upper). Grade 3 or higher adverse events (regardless of attribution) were reported in 22 (82%) patients. Grade 4/5 adverse events were reported in 15 (56%) patients. There was one grade 5 event (pneumonitis). The most common (5 or more patients) grade 3/4 adverse events were fatigue (22%), leukopenia (63%), neutropenia (67%), and thrombocytopenia (44%). Conclusions: The addition of bortezomib resulted in high levels of severe hematologic toxicity, but also demonstrated evidence of activity with a 12-month survival rate of 71% and a median OS of 19 months. Further testing of this regimen in a larger study appears warranted.

A Critical Overview of Systematic Reviews of Chemotherapy for Advanced and Locally Advanced Pancreatic Cancer using both AMSTAR2 and ROBIS as Quality Assessment Tools

2020 ◽  
Vol 15 ◽  
Author(s):  
Amit Dang ◽  
Surendar Chidirala ◽  
Prashanth Veeranki ◽  
BN Vallish
Keyword(s):  
Pancreatic Cancer ◽  
High Risk ◽  
Systematic Reviews ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Risk Of Bias ◽  
Low Risk ◽  
Locally Advanced Pancreatic Cancer ◽  
Grade 3 ◽  
Critical Overview

Background: We performed a critical overview of published systematic reviews (SRs) of chemotherapy for advanced and locally advanced pancreatic cancer, and evaluated their quality using AMSTAR2 and ROBIS tools. Materials and Methods: PubMed and Cochrane Central Library were searched for SRs on 13th June 2020. SRs with metaanalysis which included only randomized controlled trials and that had assessed chemotherapy as one of the treatment arms were included. The outcome measures, which were looked into, were progression-free survival (PFS), overall survival (OS), and adverse events (AEs) of grade 3 or above. Two reviewers independently assessed all the SRs with both ROBIS and AMSTAR2. Results: Out of the 1,879 identified records, 26 SRs were included for the overview. Most SRs had concluded that gemcitabine-based combination regimes, prolonged OS and PFS, but increased the incidence of grade 3-4 toxicities, when compared to gemcitabine monotherapy, but survival benefits were not consistent when gemcitabine was combined with molecular targeted agents. As per ROBIS, 24/26 SRs had high risk of bias, with only 1/26 SR having low risk of bias. As per AMSTAR2, 25/26 SRs had critically low, and 1/26 SR had low, confidence in the results. The study which scored ‘low’ risk of bias in ROBIS scored ‘low confidence in results’ in AMSTAR2. The inter-rater reliability for scoring the overall confidence in the SRs with AMSTAR2 and the overall domain in ROBIS was substantial; ROBIS: kappa=0.785, SEM=0.207, p<0.001; AMSTAR2: kappa=0.649, SEM=0.323, p<0.001. Conclusion: Gemcitabine-based combination regimens can prolong OS and PFS but also worsen AEs when compared to gemcitabine monotherapy. The included SRs have an overall low methodological quality and high risk of bias as per AMSTAR2 and ROBIS respectively.

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