FOLFIRINOX for advanced pancreatic cancer: The Princess Margaret experience.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 417-417 ◽  
Author(s):  
Muralidharan Chllamma ◽  
Natalie Cook ◽  
Kazim Giby ◽  
Anna Dodd ◽  
Lisa Wang ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Head ◽  
Validated Questionnaire ◽  
Significant Difference ◽  
Starting Dose ◽  
Grade 3 ◽  
Dose Reductions

417 Background: The FOLFIRINOX regimen has been shown to significantly increase both overall (OS) and progression free (PFS) survival in metastatic pancreas cancer (MPC), albeit with an increase in adverse events (AEs). It is not known whether initial dose reductions compromise FOLFIRINOX efficacy and there are limited data regarding treatment of locally advanced pancreatic cancer (LAPC). Methods: We conducted a retrospective review of patients (pts) treated with FOLFIRINOX for MPC or LAPC at Princess Margaret Cancer Centre, and began treatment between Dec 2011 and April 2014. The primary objective was to evaluate the efficacy and safety of FOLFIRINOX when used with dose modifications. Results: 102 pts were identified; 66 MPC and 36 LAPC. Median age was 65 years. 72% of pts had pancreatic head tumors. At baseline 95% of pts had an ECOG performance status of 0 or 1; 95% had bilirubin < 1.5 ULN and 45% had a biliary stent. 68% of pts initiated treatment with a dose reduction (93% reduction or omission of bolus 5FU, 88% reduction in Irinotecan, 68% reduction in Oxaliplatin and 66% reduction in infusional 5FU). Median number of cycles was 6 (1-31); 25% of pts received <4 cycles. Median OS in metastatic pts was 12.9 months (mo) and 23 mo in LAPC; Median PFS was 8.7 mo (metastatic) and 11.1 mo in LAPC. There was no significant difference in PFS (10.9 vs. 10.3 mo; p=0.60) or OS (11.1 vs. 14.0 mo; p=0.19) between the full starting dose and reduced starting dose groups respectively. Partial response or stable disease was achieved in 57% of pts; 11% of the LAPC pts had a surgical resection. Grade 3/4 hematologic AEs were observed in 43% of pts (febrile neutropenia in 6%). Only 13% of pts received G-CSF support. Grade 3/4 non-hematologic AEs were observed in 28% of pts, including vomiting (19%), nausea (16%) and diarrhea (16%). 18% of pts had a treatment related hospitalization (5% neutropenic sepsis, 13% GI toxicity/dehydration.) There was one treatment related death. Pt wellbeing (scored on a validated questionnaire) significantly improved from baseline to cycle 4 (p=0.002). Conclusions: Modest dose reductions do not appear to compromise efficacy of FOLFIRINOX. Our median PFS, OS and AEs are comparable to other studies using FOLFIRINOX in both LAPC and metastatic disease.

Prognostic impact of chemoradiation-related lymphopenia in patients with locally advanced pancreatic cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 439-439
Author(s):  
Daniel W Kim ◽  
Grace Lee ◽  
Colin D. Weekes ◽  
David P. Ryan ◽  
Aparna Raj Parikh ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Cox Model ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Head ◽  
Locally Advanced Pancreatic Cancer ◽  
Ductal Adenocarcinoma ◽  
Prognostic Impact ◽  
Entire Cohort ◽  
Grade 3

439 Background: Chemoradiation (CRT) induced lymphopenia is common and associated with poorer survival in multiple solid malignancies. The objective of this study was to evaluate the prognostic impact of lymphopenia in patients with nonmetastatic, unresectable pancreatic ductal adenocarcinoma (PDAC) treated by neoadjuvant FOLFIRINOX (5-fluorouracil [5FU]/leucovorin/irinotecan/oxaliplatin) followed by CRT. We hypothesized that severe lymphopenia would correlate with worse survival. Methods: The inclusion criteria for this single-institution retrospective study were: 1) biopsy-proven diagnosis of unresectable PDAC, 2) absence of distant metastasis, 3) receipt of neoadjuvant FOLFIRINOX followed by CRT, and 4) absolute lymphocyte count (ALC) available prior to and two months after initiating CRT. In general, CRT consisted of 5FU or capecitabine and RT with 58.8 Gy over 28 fractions. Lymphopenia was graded according to CTCAE v5.0. The primary variable of interest was lymphopenia at two months, dichotomized by ALC of < 0.5/μl (Grade 3 lymphopenia). The primary endpoint was overall survival (OS). Cox modeling and Kaplan-Meier methods were used to perform survival analyses. Results: A total of 138 patients were identified. Median follow-up for the entire cohort was 16 months. Median age was 65. Fifty-six percent were female, 86% were Caucasian, and 97% had ECOG ≤1. Median tumor size was 3.8 cm. Tumor location was pancreatic head in 63%, body in 22%, tail in 8%, and neck in 7%. Median baseline ALC for the entire cohort was 1.5 k/ul. Two months after initiating CRT, 106 (77%) had severe (Grade 3 or worse) lymphopenia. While there were no significant differences in baseline patient or disease characteristics, patients with severe lymphopenia received higher doses of RT with longer duration of treatment compared to those without severe lymphopenia. On multivariable Cox model, severe lymphopenia at two months was significantly associated with increased hazards of death (HR = 4.00 [95% CI 2.03-7.89], p < 0.001). Greater number of neoadjuvant FOLFIRINOX cycles received prior to CRT was associated with lower hazards of death (HR = 0.84 [95% CI 0.77-0.92], p < 0.001). The 12-month OS was 73% vs. 90% in the cohort with vs. without severe lymphopenia, respectively (log-rank p < 0.001). Conclusions: Treatment-related lymphopenia is common and severe lymphopenia may be a prognostic marker of poorer survival in locally advanced pancreatic cancer. Closer observation in high-risk patients and minimization of RT dose and duration are potential approaches to mitigating CRT-related lymphopenia. Our findings also suggest an important role of the host immunity in pancreatic cancer outcomes, supporting the ongoing efforts of immunotherapy trials in pancreatic cancer.

A phase III trial of virulizin plus gemcitabine vs. gemcitabine alone in advanced pancreatic cancer: Results of subgroup analysis

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4116-4116 ◽  
Author(s):  
J. A. Wright ◽  
J. Osterlee ◽  
S. Fekete ◽  
Y. Lee ◽  
A. H. Young
Keyword(s):  
Pancreatic Cancer ◽  
Metastatic Cancer ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Double Blind ◽  
Significant Difference ◽  
Ecog Ps ◽  
To Receive

4116 Background: Virulizin (V) is a novel antitumor immune modulator that improves survival in pancreatic cancer patients (pts) as monotherapy. A double-blind, multicenter, randomized, phase III study was conducted to evaluate the survival benefits and safety of V in combination with gemcitabine (G) in pts with advanced pancreatic cancer. Methods: Chemo-naive pts with locally advanced or metastatic pancreatic cancer with ECOG Performance Status (PS) of 0, 1 or 2 were enrolled. Pts were randomized to receive intramuscular injections of either V or placebo (P) 3 times weekly + G (1,000 mg/m2 weekly ×7 with 1 week rest, then weekly ×3 q4w). Randomization was stratified according to ECOG PS (0 or 1, and 2) and extent of disease (locally advanced and metastatic). Pts who showed no clinical benefit or were intolerant to G entered 2nd-line therapy (stage 3), in which pts continued to receive either V or P alone or with 5-FU, or best supportive care. The primary endpoint was survival, defined as time from baseline/treatment day 1 to time of death from any cause. Results: The intent to treat (ITT) population comprised 434 pts, of which 377 were efficacy evaluable (EE). Median overall survival for V + G was 6.3 months for the ITT population (6.8 months for EE pts) and 6 months for P + G for both ITT and EE pts. While differences in survival times were not statistically significant, exploratory analysis showed encouraging results in specific subgroups treated with V + G ( table ). Importantly, a significant difference was found in stage 3 pts who received V in a salvage setting compared to pts who received P. Conclusions: Pancreatic cancer pts with either low ECOG PS or metastatic cancer showed a survival benefit when treated with V + G, which was significant in pts who continued to receive V as a salvage therapy. Further studies in these targeted patient populations are being considered. [Table: see text] No significant financial relationships to disclose.

FOLFIRINOX versus gemcitabine nab-paclitaxel for advanced pancreatic cancer: KU Cancer Center experience.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15744-e15744 ◽  
Author(s):  
Anup Kasi ◽  
Akshay Middinti ◽  
An Cao ◽  
Pratikkumar Vekaria ◽  
Devangi Patel ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Adverse Events ◽  
Objective Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Head ◽  
Cancer Center ◽  
Disease Rate ◽  
First Line ◽  
Significant Difference

e15744 Background: FOLFIRINOX (FFN) and Gemcitabine plus nab-paclitaxel (GN) have been established as first line chemotherapy in advanced pancreatic cancer (PC). But there is no head-to-head randomized trial data available to support preferable first line choice between these two regimens. Methods: We retrospectively evaluated 154 chemotherapy-naïve locally advanced and metastatic PC patients treated with FFN or GN at KU Cancer Center between January 2011 and November 2016. FFN consisted of Oxaliplatin 85mg/m2, Irinotecan 180mg/m2, 5-FU 400mg/m2 as a bolus and 2,400 mg/m2over 46 hour on days 1 and 15 every 4 weeks. GN consisted of Gemcitabine 1000mg/m2 plus nab-paclitaxel 125mg/m2 day1,8,15 every 4 weeks. We compared characteristics, efficacy and adverse events between FFN and GN. Results: 107 patients were treated with FFN and 47 patients with GN as first line therapy. Demographic and baseline characteristics (FFN/GN) were as follows: Median age 61/63 years, ECOG performance status (0-1): 90% / 83%, Gender (male): 57% / 54%, distant metastases: 52%/70%, biliary stenting: 41%/20%, locally advanced tumor: 48%/30%, pancreatic head tumors: 63%/55%, median number of cycles: 4/4 respectively. Objective response rate (13% vs. 10%), Stable disease rate (76% vs 82%) and disease control rate (89% vs. 92%, p = 0.5) were similar in FFN and in GN. Median PFS was 11.7 months (95% CI: 7.2-16.1) in FFN and 5.7 months (95% CI: 2.7-8.8) in GN [p = 0.07]. Median OS was 15.9 months (95% CI: 13.7-18.1) in FFN and 10.8 months (95% CI: 7.1 – 14.5) in GN [p = 0.17]. Incidences of grade 3 or higher adverse effects were neutropenia (33% vs. 17%), anemia (14% vs 31%), thrombocytopenia (28% vs 6%), elevated creatinine (2.8% vs 4%), elevated transminases (3.7% vs 6%), diarrhea (5% vs. 0%), and peripheral neuropathy (6% vs. 6%) respectively. Conclusions: Patients treated with FFN showed statistically better PFS compared to GN. However this difference in PFS did not translate into statistically significant difference in OS. Response rates were similar. Incidences of adverse events were relatively more with FFN compared to GN as expected.

scholarly journals P-P57 The first experience of intraoperative radiotherapy for pancreatic cancer in the UK

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
Rahul Bhome ◽  
Karavias Dimitrios ◽  
Armstrong Tom ◽  
Zaed Hamady ◽  
Arshad Ali ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Visceral Pain ◽  
Performance Status ◽  
Locally Advanced ◽  
Operating Time ◽  
Advanced Pancreatic Cancer ◽  
Pancreatic Head ◽  
Intraoperative Radiotherapy ◽  
High Dose ◽  
University Hospitals

Abstract Background Intraoperative radiotherapy (IORT) involves giving a targeted single fraction of high dose radiation to the resection bed. The main advantages are exclusion of vulnerable structures from the radiation field and ability to direct the electron beam to threatened margins.  IORT in pancreatic cancer is not new, with Japanese centres reporting series from the 1970s. Early reports were exciting, suggesting that IORT was useful in reducing visceral pain, achieving local control and improving survival in locally advanced and unresectable patients. However, paucity of randomised trials in the ensuing decades has limited its widespread adoption. Methods With funding from the PLANETS charity (www.planetscharity.org), University Hospitals Southampton acquired a Mobetron 2000 linear accelerator (IntraOp, USA) in 2016. Testing was done at the National Physical Laboratory (Teddington, UK) over two months to collect beam data and ensure consistency in treatment delivery. Staff training included visits to the Heidelberg Cancer Centre and several dry runs. Inclusion criteria were: (i) patients with pancreatic head adenocarcinomas; (ii) threatened vascular margins; (iii) WHO performance status 1-2; (iv) no evidence of distant metastasis. Results Nineteen patients had pancreaticoduodenectomy (traditional or pylorus preserving) combined with IORT. Median age was 66 (42-81) years. Median ASA grade was 2 (2-3). 16/19 had locally advanced pancreatic cancer and 18/19 had neoadjuvant chemotherapy. Median IOERT dose was 15 (10-15) Gy, energy 7.5 (6-12) MeV, to a mean depth of 1.6 +/- 0.8 cm, with median cone size 5 (4-6) cm and bevel angle 15 (0-30) degrees. All tumours were pT1-T3 and 10/19 had positive regional nodes. 10/19 were R1 resections, with 4/19 specimens exhibiting vascular invasion and 6/19 perineural invasion. Mean operating time (including IOERT) was 534 +/- 77 min. Median length of stay was 8.5 (6-41) days. 30-day mortality was zero. 6/19 patients had post-operative complications (Clavien-Dindo 1-2 only), with clinically detectable pancreatic fistula in 1/19. Conclusions This is the first UK experience of IORT for pancreatic cancer, showing that this treatment modality is safe and feasible. With the appropriate expertise, an IORT service can be implemented within 12 months of acquiring the Mobetron system. We hope that these data will encourage other UK and European HPB units to consider setting up regional IORT services, such that larger scale prospective trials can be initiated to demonstrate its efficacy.

Gemcitabine in Combination With Oxaliplatin Compared With Gemcitabine Alone in Locally Advanced or Metastatic Pancreatic Cancer: Results of a GERCOR and GISCAD Phase III Trial

2005 ◽  
Vol 23 (15) ◽  
pp. 3509-3516 ◽  
Author(s):  
C. Louvet ◽  
R. Labianca ◽  
P. Hammel ◽  
G. Lledo ◽  
M.G. Zampino ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Benefit ◽  
Performance Status ◽  
Combined Treatment ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Phase Iii Study ◽  
Grade 3

Purpose Gemcitabine (Gem) is the standard treatment for advanced pancreatic cancer. Given the promising phase II results obtained with the Gem-oxaliplatin (GemOx) combination, we conducted a phase III study comparing GemOx with Gem alone in advanced pancreatic cancer. Patients and Methods Patients with advanced pancreatic cancer were stratified according to center, performance status, and type of disease (locally advanced v metastatic) and randomly assigned to either GemOx (gemcitabine 1 g/m2 as a 100-minute infusion on day 1 and oxaliplatin 100 mg/m2 as a 2-hour infusion on day 2 every 2 weeks) or Gem (gemcitabine 1 g/m2 as a weekly 30-minute infusion). Results Three hundred twenty-six patients were enrolled; 313 were eligible, and 157 and 156 were allocated to the GemOx and Gem arms, respectively. GemOx was superior to Gem in terms of response rate (26.8% v 17.3%, respectively; P = .04), progression-free survival (5.8 v 3.7 months, respectively; P = .04), and clinical benefit (38.2% v 26.9%, respectively; P = .03). Median overall survival (OS) for GemOx and Gem was 9.0 and 7.1 months, respectively (P = .13). GemOx was well tolerated overall, although a higher incidence of National Cancer Institute Common Toxicity Criteria grade 3 and 4 toxicity per patient was observed for platelets (14.0% for GemOx v 3.2% for Gem), vomiting (8.9% for GemOx v 3.2% for Gem), and neurosensory symptoms (19.1% for GemOx v 0% for Gem). Conclusion These results confirm the efficacy and safety of GemOx, but this study failed to demonstrate a statistically significant advantage in terms of OS compared with Gem. Because GemOx is the first combined treatment to be superior to Gem alone in terms of clinical benefit, this promising regimen deserves further development.

FOLFIRINOX in the real-world setting: The multicentric experience of six Canadian institutions.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 367-367 ◽  
Author(s):  
Carl Amireault ◽  
Julie Beaudet ◽  
Guylaine Gaudet ◽  
Nicolas Raymond ◽  
Jean-Pierre M. Ayoub ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Primary Prophylaxis ◽  
Curative Surgery ◽  
Advanced Tumor ◽  
Grade 3 ◽  
One Year

367 Background: FOLFIRINOX has emerged as a new standard for patients with performance status ECOG 0-1 in metastatic pancreatic cancer and non-randomized studies also support this regimen in locally advanced disease. This regimen is however associated with significant toxicity. The purpose of this study was to assess efficacy and toxicity outside of a clinical trial, including community hospitals. Methods: We conducted a retrospective study of patients with pancreatic adenocarcinoma who received FOLFIRINOX between January 2011 and June 2013 in six institutions in the province of Quebec, Canada. Patients' characteristics, objective response, survival and toxicities were collected. Results: Forty-six patients were included (23 metastatic and 23 locally advanced). Median age was 59 years. Tumor was localized at the head in 65% of patients and 41 % had a biliary stent. Median overall survival was 12,6 months and survival at one year was 61% for metastatic patients. Survival at one year was 95% for locally advanced pancreatic cancer patients and no one with locally advanced tumor became candidate for curative surgery after FOLFIRINOX. Hospitalization rate was 54% with sepsis being the leading cause. There were three treatment-related deaths (7%) and two of them occurred after the first cycle. Neutropenia grade ≥ 3 was observed in 33% of patients and four patients had febrile neutropenia (9 %) with 61% of patients receiving colony stimulating factors (CSFs) for primary prophylaxis. Three patients had cholangitis and diarrhea grade ≥ 3 occurred in 15% of patients. Five patients (11%) experienced transient dysarthria during Irinotecan administration. Conclusions: Survival in our cohort is comparable with data reported by previous studies. However, toxicities were significant and higher than reported. These data highlight the importance of patient selection and support the universal use of CSFs in this population.

Dose Finding and Early Efficacy Study of Gemcitabine Plus Capecitabine in Combination With Bevacizumab Plus Erlotinib in Advanced Pancreatic Cancer

2009 ◽  
Vol 27 (33) ◽  
pp. 5499-5505 ◽  
Author(s):  
Naureen Starling ◽  
David Watkins ◽  
David Cunningham ◽  
Janet Thomas ◽  
Janine Webb ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor ◽  
Skin Rash ◽  
Performance Status ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Dose Finding ◽  
Survival Times ◽  
Female Ratio ◽  
Grade 3

PurposeThis study evaluated safety and efficacy of chemotherapy (gemcitabine plus capecitabine) plus bevacizumab/erlotinib in advanced pancreatic cancer because dual epidermal growth factor receptor/vascular endothelial growth factor blockade has a rational biologic basis in this malignancy.Patients and MethodsPatients with untreated, unresectable, locally advanced or metastatic pancreatic carcinoma were enrolled onto one of the following four sequential dose levels (DLs) of escalating capecitabine doses (days 1 to 21): DL1, 910 mg/m2; DL2, 1,160 mg/m2; DL3, 1,400 mg/m2; or DL4, 1,660 mg/m2. Doses of coadministered gemcitabine (1,000 mg/m2on days 1, 8, and 15), bevacizumab (5 mg/kg on days 1 and 15), and erlotinib (100 mg/d) every 28 days (up to six cycles) were fixed. Using a 3+3 study design, dose-limiting toxicity (DLT) was assessed in cycle 1.ResultsTwenty assessable patients were enrolled (DL1, n = 8; DL2, n = 3; DL3, n = 6; and DL4, n = 3); 97 cycles were administered. Median age was 63 years (range, 33 to 77 years), and male-to-female ratio was 10:10. Performance status was 0 and 1 in two and 17 patients, respectively; and nine and 11 patients had locally advanced and metastatic disease, respectively. DLT occurred in one patient at DL1 (grade 3 epistaxis) and two patients at DL4 (grade 3 diarrhea and grade 3 skin rash > 7 days). Common grade 3 and 4 toxicities (10% to 20%) were diarrhea, hand-foot syndrome, stomatitis, and skin rash. Grade 3 lethargy and grade 3 or 4 neutropenia occurred in 40% and 45% of patients, respectively. No GI perforation, grade 3 GI hemorrhage/hypertension, or pneumonitis occurred. Ten partial responses were observed. Median overall and progression-survival times (all patients) were 12.5 and 9.0 months, respectively.ConclusionThe maximum-tolerated dose of capecitabine was 1,660 mg/m2. The recommended capecitabine dose in this cytotoxic doublet/biologic doublet regimen is 1,440 mg/m2; this regimen is under evaluation in an ongoing phase II study.

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.

Model-based analysis to support dose selection of pevonedistat (PEV) combined with azacitidine (AZA) in patients (pts) with higher-risk myelodysplastic syndromes (MDS)/chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7042-7042
Author(s):  
Xiaofei Zhou ◽  
Diane R. Mould ◽  
Dan Zhao ◽  
Mikkael A. Sekeres ◽  
Lionel Adès ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Phase 1 ◽  
Performance Status ◽  
Disease Type ◽  
International Prognostic Scoring System ◽  
Population Pharmacokinetic ◽  
Starting Dose ◽  
Grade 3 ◽  
The Impact ◽  
Dose Reductions

7042 Background: PEV+AZA has been studied in higher-risk MDS/CMML and AML, with encouraging efficacy and an acceptable safety profile without added myelosuppression. This pooled analysis was performed to evaluate the impact of PEV exposure on safety and efficacy. Methods: Data from three studies (NCT01814826, NCT02782468 and NCT02610777) were used in the PEV exposure–safety analyses, including ≥ grade 3 neutropenia (NEU3), febrile neutropenia (FN), ≥ grade 3 thrombocytopenia, ≥ grade 3 alanine aminotransferase elevation, ≥ grade 3 aspartate aminotransferase elevation and ≥ grade 3 treatment-emergent adverse event (TEAE3), in pts with higher-risk MDS/CMML and AML who received PEV+AZA. Data from NCT02610777 were used for exposure–efficacy analyses, including overall survival (OS), event-free survival (EFS), complete response (CR) and CR+partial response (PR), in pts with higher-risk MDS/CMML who received PEV+AZA. The exposure metrics for individual pts were derived from a previously developed population pharmacokinetic model with pooled data from eight phase 1/2 studies. PEV exposure–safety relationships for the toxicity endpoints, exposure–CR and exposure–CR+PR, were estimated by logistic regression. Age, sex, race, baseline Eastern Cooperate Oncology Group (ECOG) Performance Status score and disease type were evaluated as covariates. Cox proportional-hazards models were used to evaluate the PEV exposure–survival for higher-risk MDS/CMML, with age, sex, baseline ECOG PS score, Revised International Prognostic Scoring System score (IPSS-R) and disease type as potential covariates. Results: In total, 135 pts (median age, 74 years; male, 64%; Caucasian, 82%) and 41 pts (median age, 74 years; male, 76%; Caucasian, 90%; median IPSS-R, 5.5) were included in PEV exposure–safety and exposure–efficacy analyses, respectively. PEV exposure was significantly related to the incidence of NEU3 ( p = 0.003), FN ( p = 0.02) and TEAE3 ( p = 0.02), supporting PEV dose reductions for pts with treatment-related toxicities. Relationships between PEV exposures and CR, CR+PR, EFS or OS indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. Conclusions: The association between exposure and safety supports PEV dose reductions for pts with treatment-related toxicities. The exposure–efficacy analyses indicated consistent clinical benefit across ranges of PEV exposure following a starting dose of 20 mg/m2. These results support a favorable benefit–risk profile of the 20 mg/m2 PEV dose on days 1, 3 and 5 in combination with AZA 75 mg/m2 for 7 days in 28-day cycles. Clinical trial information: NCT01814826 , NCT02782468 , NCT02610777.

Gemcitabine Plus Capecitabine Compared With Gemcitabine Alone in Advanced Pancreatic Cancer: A Randomized, Multicenter, Phase III Trial of the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group

2007 ◽  
Vol 25 (16) ◽  
pp. 2212-2217 ◽  
Author(s):  
Richard Herrmann ◽  
György Bodoky ◽  
Thomas Ruhstaller ◽  
Bengt Glimelius ◽  
Emilio Bajetta ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Performance Status ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Phase Iii ◽  
Metastatic Pancreatic Cancer ◽  
Karnofsky Performance Score ◽  
Phase Iii Trial ◽  
Good Performance Status ◽  
Grade 3

PurposeThis phase III trial compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (GemCap) versus single-agent Gem in advanced/metastatic pancreatic cancer.Patients and MethodsPatients were randomly assigned to receive GemCap (oral capecitabine 650 mg/m2twice daily on days 1 to 14 plus Gem 1,000 mg/m2by 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m2by 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Patients were stratified according to center, Karnofsky performance score (KPS), presence of pain, and disease extent.ResultsA total of 319 patients were enrolled between June 2001 and June 2004. Median overall survival (OS) time, the primary end point, was 8.4 and 7.2 months in the GemCap and Gem arms, respectively (P = .234). Post hoc analysis in patients with good KPS (score of 90 to 100) showed a significant prolongation of median OS time in the GemCap arm compared with the Gem arm (10.1 v 7.4 months, respectively; P = .014). The overall frequency of grade 3 or 4 adverse events was similar in each arm. Neutropenia was the most frequent grade 3 or 4 adverse event in both arms.ConclusionGemCap failed to improve OS at a statistically significant level compared with standard Gem treatment. The safety of GemCap and Gem was similar. In the subgroup of patients with good performance status, median OS was improved significantly. GemCap is a practical regimen that may be considered as an alternative to single-agent Gem for the treatment of advanced/metastatic pancreatic cancer patients with a good performance status.

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