Prognostic and predictive value of circulating tumour DNA (ctDNA) by amplicon-based next generation sequencing (NGS) of advanced pancreatic cancer (APC) in a phase I trial of oxaliplatin capecitabine and irinotecan (OXIRI) triplet chemotherapy.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 730-730
Author(s):  
Amanda Oon Lim Seet ◽  
Su Pin Choo ◽  
David Wai-Meng Tai ◽  
Justina Yick Ching Lam ◽  
Tira Jing Ying Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
High Sensitivity ◽  
Clinical Results ◽  
Rank Test ◽  
Kras Mutations ◽  
Treatment Benefit ◽  
Mutational Status

730 Background: Tumoral KRAS mutations (KRAS mt) are detected in ~80% of APC and associated with a negative prognosis. Digital droplet PCR (ddPCR) has high sensitivity for circulating KRASmtbut narrower gene coverage. NGS using hybrid-capture methods has reported ctDNA KRASmtin ~30% of patients (pt). We previously presented clinical results of the Phase I trial of OXIRI (GI ASCO 18 #411). We now present the first prospective evaluation of ctDNA in APC by an amplicon-based NGS approach in this Phase I trial. Methods: Paired ctDNA and CA19-9 samples were taken at baseline, C2D1, C3D1 and end of trial. A targeted panel with error-correction (Lucence Diagnostics) was used to detect for mtin KRAS, TP53, SMAD4, CDKN2A, CTNNB1, GNAS, APC and MYC. CT scans were performed every 2 cycles. Survival curves by Kaplan Meier were compared by mutational status, ctDNA and CA19-9 response using the log-rank test. Spearman correlation of ctDNA and CA19-9 changes was performed. Results: ctDNA mtwas detected at baseline in 19/23 (83%) samples, comprising KRAS 17/23 (73%), TP53 (61%), SMAD4 (48%) and CDKN2A (30%). KRAS mtand SMAD4 mt conferred a negative prognosis for overall survival with a hazard ratio of 4.2 (CI: 1.6-10.4; p = 0.01) and 2.8 (CI: 0.9-8.65; p = 0.01) respectively. Drop in ctDNA and CA19-9 was associated with a trend for longer progression free survival at C2D1 (both) and C3D1 (ctDNA only). Radiological partial response (PR) was associated with lower ctDNA in 5/5 pt and CA 19-9 in 4/5 pt. Decrease in ctDNA and CA19-9 was associated with disease control (PR/SD) at C2D1 in 11/14 pt and 10/10 pt; at C3D1 in 11/12 pt and 6/7 respectively. No significant correlation between the amplitude of CA19-9 and ctDNA changes was found. Conclusions: ctDNA could be detected in 83% of pts of whom KRAS mtrates were similar to reports using tissue NGS. Determination of RAS mtand SMAD4 mtin ctDNA may aid in the prognostication of pts and decrease in ctDNA levels may predict for treatment benefit, similar in extent to CA 19-9. This may be particularly useful in non-CA19-9 secreting APC as an adjunct to imaging. Clinical trial information: NCT02368860.

KRAS mutation analysis in patients (pts) with locally advanced pancreatic cancer (LAPC) treated with gefitinib and chemoradiation therapy (CT-RT) in a phase I trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4106-4106 ◽  
Author(s):  
H. Chen ◽  
D. Raben ◽  
T. Schefter ◽  
M. Kane ◽  
M. McCarter ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Overall Survival ◽  
Phase I ◽  
Kras Mutation ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Kras Mutations ◽  
Direct Dna Sequencing ◽  
Kras Codon

4106 Background: Correlative studies that incorporate biomarkers to rapidly analyze response to new agents are needed. Unique to pancreatic cancer is the high incidence of KRAS mutations (over 90%). This pilot study evaluated plasma KRAS mutations for disease monitoring in LAPC pts treated on a Phase I trial combining CT-RT with the EGFR inhibitor, gefitinib. Methods: DNA was extracted from plasma of 11 pts collected at 3 timepoints: pre-gefitinib, pre-CT-RT, and post-gefitinib+CT-RT. Matched tissue DNA was obtained from 4 pts with available paraffin blocks. KRAS codon 12 mutations were detected using a two-stage RFLP-PCR assay. Cell line controls: Calu-1 (mutant KRAS) and LNCaP (wild-type KRAS). Mutations were confirmed by direct DNA sequencing. Results were related to pt clinical data. Results: KRAS mutations were detected in the pre-gefitinib plasma of 5/11 pts, and in the matched tumor tissue of 3/4 pts. Of the 5 pts with plasma KRAS mutations, 2 pts with no detectable mutant KRAS in the plasma post-gefitinib+CT-RT had overall survival of 8 and 21 months, whereas 2 pts who retained mutant KRAS had overall survival of only 2 and 5 months, and one pt withdrew early. Of the 3 tumor tissues containing mutant KRAS, the mutations were also detectable in the matched plasma in 2 pts (67%). KRAS codon 12 mutations spectrum: 4 GGT→GAT, 2 GGT→GTT and 1 GGT→AGT. Conclusions: Plasma KRAS mutations are readily detectable in LAPC pts, and the clearance or persistence of plasma KRAS mutations after treatments reflected the clinical course in some cases. The use of plasma KRAS mutation as a marker of survival and response will be further assessed in a recently approved phase I trial using a proteasome inhibitor with chemoradiation at the University of Colorado. No significant financial relationships to disclose.

scholarly journals Primary and Secondary Kinase Genotypes Correlate With the Biological and Clinical Activity of Sunitinib in Imatinib-Resistant Gastrointestinal Stromal Tumor

2008 ◽  
Vol 26 (33) ◽  
pp. 5352-5359 ◽  
Author(s):  
Michael C. Heinrich ◽  
Robert G. Maki ◽  
Christopher L. Corless ◽  
Cristina R. Antonescu ◽  
Amy Harlow ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Clinical Results ◽  
Clinical Activity ◽  
Wild Type ◽  
Mutational Status ◽  
Imatinib Resistant ◽  
Exon 9 ◽  
Exon 11 ◽  
The Impact

PurposeMost gastrointestinal stromal tumors (GISTs) harbor mutant KIT or platelet-derived growth factor receptor α (PDGFRA) kinases, which are imatinib targets. Sunitinib, which targets KIT, PDGFRs, and several other kinases, has demonstrated efficacy in patients with GIST after they experience imatinib failure. We evaluated the impact of primary and secondary kinase genotype on sunitinib activity.Patients and MethodsTumor responses were assessed radiologically in a phase I/II trial of sunitinib in 97 patients with metastatic, imatinib-resistant/intolerant GIST. KIT/PDGFRA mutational status was determined for 78 patients by using tumor specimens obtained before and after prior imatinib therapy. Kinase mutants were biochemically profiled for sunitinib and imatinib sensitivity.ResultsClinical benefit (partial response or stable disease for ≥ 6 months) with sunitinib was observed for the three most common primary GIST genotypes: KIT exon 9 (58%), KIT exon 11 (34%), and wild-type KIT/PDGFRA (56%). Progression-free survival (PFS) was significantly longer for patients with primary KIT exon 9 mutations (P = .0005) or with a wild-type genotype (P = .0356) than for those with KIT exon 11 mutations. The same pattern was observed for overall survival (OS). PFS and OS were longer for patients with secondary KIT exon 13 or 14 mutations (which involve the KIT-adenosine triphosphate binding pocket) than for those with exon 17 or 18 mutations (which involve the KIT activation loop). Biochemical profiling studies confirmed the clinical results.ConclusionThe clinical activity of sunitinib after imatinib failure is significantly influenced by both primary and secondary mutations in the predominant pathogenic kinases, which has implications for optimization of the treatment of patients with GIST.

A phase I trial of gemcitabine, S-1 and LV combination (GSL) therapy in advanced pancreatic cancer

2014 ◽  
Vol 74 (5) ◽  
pp. 911-915 ◽  
Author(s):  
Yousuke Nakai ◽  
Hiroyuki Isayama ◽  
Kei Saito ◽  
Takashi Sasaki ◽  
Naminatsu Takahara ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Advanced Pancreatic Cancer

Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a phase i trial

2002 ◽  
Vol 54 (1) ◽  
pp. 137-141 ◽  
Author(s):  
Howard Safran ◽  
Thomas Dipetrillo ◽  
David Iannitti ◽  
Daniel Quirk ◽  
Paul Akerman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Locally Advanced Pancreatic Cancer

Abstract B28: Phase I trial of gemcitabine, nab-paclitaxel and enzalutamide for treatment of advanced pancreatic cancer

2015 ◽  
Author(s):  
Amit Mahipal ◽  
Gregory Springett ◽  
Nancy Burke ◽  
Anthony Neuger ◽  
Domenico Copolla ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Phase I ◽  
Phase I Trial ◽  
Advanced Pancreatic Cancer

Phase I/II study incorporating intravenous hydroxyurea into high-dose chemotherapy for patients with primary refractory or relapsed and refractory intermediate-grade and high-grade malignant lymphoma.

1995 ◽  
Vol 13 (5) ◽  
pp. 1089-1095 ◽  
Author(s):  
W P Vaughan ◽  
E Kris ◽  
J Vose ◽  
P J Bierman ◽  
P Gwilt ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Progression Free Survival ◽  
High Dose Chemotherapy ◽  
Rank Test ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Stem Cell Rescue

PURPOSE A phase I/II study was performed to evaluate the incorporation of hydroxyurea (HU) into high-dose chemotherapy of non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS Thirty-eight patients with primary refractory and refractory relapsed NHL were treated with carmustine (BCNU) (300 mg/m2 on day -8), cyclophosphamide (Cy) (2.5 g/m2/d on days -8 and -7), etoposide (E) (150 mg/m2 every 12 hours on days -6, -5, and -4), and HU (BCHE) with autologous hematopoietic stem-cell rescue. Twenty-one patients received HU in a dose escalation of 2 to 12 g/m2 intravenously (IV) by 72-hour continuous infusion. When the IV formulation was not available, 17 patients were given 18 g/m2 of HU orally in divided doses every 6 hours over the same 72-hour period. RESULTS The dose-limiting toxicity of 72-hour continuous infusion HU in this regimen was mucositis. Endotracheal intubation was necessary to protect the airway in two thirds of patients treated at 12 g/m2. Six patients (oral BCHE, five of 17; IV BCHE, one of 21) died with nonresponding or progressive disease and, at least in part, from the complications of the high-dose chemotherapy. Seventeen patients (45%) achieved complete remission (CR). More patients treated with IV BCHE achieved CR than patients treated with oral BCHE (12 of 21 v five of 17; P < .1, chi 2 test). Nine patients (two of 17 oral BCHE and seven of 21 IV BCHE) remain disease-free as of January 31, 1994, with a minimum follow-up time of 3 years. The lower mortality and higher response rate with IV BCHE translated into a significantly superior probability of progression-free survival (PFS) (33% at 4 year v 12% for oral BCHE; P = .048, log-rank test). CONCLUSION High-dose BCHE is effective treatment for primary refractory and refractory relapsed NHL. Continuous IV HU appears to be less toxic and more effective than intermittent oral HU in this regimen.

Sign in / Sign up

Export Citation Format

Share Document