Testing targeted demethylation to overcome resistance to epidermal growth factor receptor (EGFR) blocking agents in wild-type (wt) KRAS metastatic colorectal cancer patients (mCRC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3057-3057 ◽  
Author(s):  
Ignacio Garrido-Laguna ◽  
Kimberly McGregor ◽  
Mark Wade ◽  
John R. Weis ◽  
Laura Burr ◽  
...  
Keyword(s):  
Cpg Island ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Median Number ◽  
Response To Therapy ◽  
Small Subset ◽  
Cpg Island Methylator Phenotype ◽  
Pik3ca Mutations ◽  
Previously Treated ◽  
Ecog Ps

3057 Background: Panitumumab, a monoclonal antibody against EGFR, led to improved progression-free survival (PFS) in patients with (wt)KRAS mCRC. However, the benefit of panitumumab is limited to a not yet identified small subset of (wt)KRAS patients. The CpG island methylator phenotype (CIMP-high) is present in 15-20% of CRC patients. Epigenetic silencing through methylation of PTEN and/or genes in the EGFR pathway might play a role in resistance to therapy. We assessed whether decitabine (a hypomethylating agent) reverted resistance to anti-EGFR therapies. Methods: Patients (n=19) with (wt)KRAS mCRC previously treated with anti-EGFR therapies were enrolled. Patients were treated with decitabine 45mg/kg IV on day (d)1 and d15 and panitumumab 6mg/kg IV on d8 and d22 q28days. Peripheral blood, skin biopsies and buccal smear samples were collected on d1, d8, d15 and d22 to assess methylation changes in PTEN, RASSF1A and SOCS-1 in response to therapy. Tumors were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exon 9 and 20 by PCR as well as for PTEN by immunohistochemistry. Results: Median age was 53 (range 31-72). Eleven (58%) patients were female; 15 (79%) had ECOG PS 1; 3 (16%) had ECOG PS 2; and 1 had ECOG PS 0. Median number of previous therapies was 4. The most common toxicities were rash (68%), hypomagnesemia (26%) and neutropenia (10%) (all grade 1-2). The most common grade 3-4 toxicities were neutropenic fever (5%) and hypomagnesemia (5%). Of 19 (wt)KRAS mCRC patients previously treated with anti-EGFR therapies, 2 (11%) had a partial response (PR) (-50% and -30%, respectively) and 3 (16%) had stable disease (SD) >4 months (7.8, 5.9 and 4.2 months). Both responders were (wt)PIK3CA and (wt)PTEN. Clinical benefit rate (PR+SD) was 27%. Median PFS was 60 days (95% CI 45.4-74.5), similar to median PFS after last anti-EGFR therapy, 61d (95% CI 50.6-71.3). Conclusions: Panitumumab + decitabine is an active combination in a subset of patients with mCRC previously treated with anti-EGFR therapies (2 PRs in this population). Efficacy assessment in an anti-EGFR therapy naïve population is warranted. Methylation studies are ongoing.

Efficacy and safety of continuous daily sunitinib dosing in previously treated advanced non-small cell lung cancer (NSCLC): Results from a phase II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7542-7542 ◽  
Author(s):  
J. R. Brahmer ◽  
R. Govindan ◽  
S. Novello ◽  
R. Rosell ◽  
C. P. Belani ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Mucosal Inflammation ◽  
Previously Treated ◽  
Ecog Ps ◽  
Continuous Dosing

7542 Background: Sunitinib malate (SU), an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, has demonstrated activity in recurrent advanced NSCLC on the 4/2 schedule (4 weeks [wks] on treatment followed by 2 wks off), with a partial response (PR) rate of 11% (Socinski, ESMO 2006). A continuous dosing (CD) schedule of SU was additionally evaluated for safety and efficacy in this multicenter phase II study. Methods: Eligible patients (pts) had stage IIIB/IV NSCLC previously treated with 1–2 chemotherapy regimens, ECOG PS =1, and adequate organ function. Pts with brain metastases or recent gross hemoptysis were excluded. Pts received oral SU 37.5 mg/day continuously in 4-wk cycles. The primary endpoint was objective response rate per RECIST. Secondary endpoints included progression-free survival (PFS), overall survival, and safety. Results: Forty-seven pts were treated on the CD schedule: median age 60 yrs (range 37–81); male 57%; ECOG PS 0/1/2 49%/49%/2%; adenocarcinoma 53%, squamous cell carcinoma 15%, other 32%; median number of SU cycles initiated: 3 (range 1–10). One pt (2%) had a confirmed PR and 8 pts (17%) had stable disease >3 months. Median PFS was 12.1 wks (95% CI: 8.6–13.7). SU was generally well tolerated; most adverse events (AEs) were grade 1/2 and included fatigue/asthenia, pain/myalgia, nausea/vomiting, diarrhea, dyspnea, and stomatitis/mucosal inflammation. Grade =3 AEs included fatigue/asthenia (15%), hypertension (6%), hypoxia (6%), dyspnea (4%), and hemoptysis (2%). Treatment-related serious AEs included congestive heart failure (CHF; 1 pt), gastrointestinal bleeding (1 pt), hypomagnesemia (1 pt), and hypoxic respiratory failure (1 pt). One pt died due to possible treatment-related CHF. Conclusions: SU on a CD schedule is associated with an acceptable safety profile when administered to previously treated NSCLC pts, and there is documented preliminary evidence of activity, with 1 PR and a median PFS of 12.1 wks. These data support further study of continuous dosing of SU in combination with other treatments for NSCLC. No significant financial relationships to disclose.

Characterization of BCL-2 alternative proteins and outcome in patients with peripheral T-cell lymphoma (PTCL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19531-e19531
Author(s):  
Mario L. Marques-Piubelli ◽  
Luisa Maren Solis ◽  
Luis Malpica ◽  
Sushant Gouni ◽  
Ranjit Nair ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Response To Therapy ◽  
Rank Test ◽  
Cell Transplant ◽  
Functional Studies ◽  
Tissue Biopsy ◽  
Previously Treated

e19531 Background: The outcome of patients with PTCL, NOS is generally very poor, and the identification of biologically rational targets, which may translate into effective and non-toxic treatment strategies, is a high priority. The pro-survival BCL-2 family members BCL-2, BCL-XL (BCL2L1), BCL-W (BCL2L2), BCL2A1 and MCL-1 contribute to tumor maintenance, progression, and chemo-resistance across a range of cancers, but their contributions in PTCL, NOS are poorly understood. Methods: Patients with PTCL, NOS treated between 09/2000 and 09/2019 and with available tissue biopsy were included in the study. Diagnosis was retrospectively confirmed by two expert hematopathologists. BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 expression was assessed by immunohistochemistry (IHC), and the percentage of positive tumor cells assessed by standard microscopy. The 2014 Lugano Classification was used to define response to therapy. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and were compared using log-rank test between patient groups. Results: Twenty-seven patients were included in the study: 67% were male, 52% ≥ 65 year old, and 48% had stage IV disease; 59% were previously treated and 41% received > 2 lines of therapy, including stem cell transplant (SCT) in 19%. The median expression of BCL-2, BCL-XL, BCL-W, BCL2A1 and MCL-1 by IHC was: 30% (range: 0-100%), 10% (range: 0-90%), 100% (range: 40-100%), 20% (range: 0-90%), and 70% (range: 1-100%), respectively. BCL-2A1 was significantly higher in previously treated patients (35% vs 5%, p = 0.02), and in those who had previously received > 2 lines of therapy (40% vs 5%, p = 0.02). Twenty-four (89%) patients were treated after tissue biopsy, 17 (63%) with chemotherapy, 7 (26%) with biological therapy, and 6 (22%) received subsequent SCT. Five (24%) patients achieved complete remission (CR); only BCL-W associated with response, a higher expression (quartiles 3 and 4) being observed among patients not achieving CR (median 100% vs 90%, p = 0.07). After a median follow-up of 28 months (95% CI, 14-42 months), 22 (81%) patients progressed or died, and median PFS was 4 months (95% CI, 2-6 months); only BCL-W associated with PFS, a shorter median PFS being observed for patients with higher expression (3 months vs 7 months, p = 0.001). At most recent follow-up, 17 (63%) patients died, and median OS was 6 months (95% CI, 1-12 months). only BCL-W associated with OS, a shorter median OS being observed for patients with higher expression (4 months vs not reached, p = 0.004). Conclusions: High expression of BCL-W associates with significantly worse outcome in patients with PTCL, NOS. While clinical trials investigating the safety and efficacy of BCL-2 inhibition in PTCL, NOS are ongoing, these results suggest that concomitant BCL-W inhibition may be beneficial, and functional studies aimed at confirming these findings are highly needed.

Addition of Aflibercept to Fluorouracil, Leucovorin, and Irinotecan Improves Survival in a Phase III Randomized Trial in Patients With Metastatic Colorectal Cancer Previously Treated With an Oxaliplatin-Based Regimen

2012 ◽  
Vol 30 (28) ◽  
pp. 3499-3506 ◽  
Author(s):  
Eric Van Cutsem ◽  
Josep Tabernero ◽  
Radek Lakomy ◽  
Hans Prenen ◽  
Jana Prausová ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Growth Factor ◽  
Metastatic Colorectal Cancer ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
The United States ◽  
Phase Iii ◽  
Survival Times ◽  
Previously Treated

Purpose Treatment for metastatic colorectal cancer (mCRC) commonly involves a fluoropyrimidine-based chemotherapy regimen such as infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) or fluorouracil, leucovorin, and oxaliplatin, often combined with bevacizumab or an epidermal growth factor receptor monoclonal antibody. We studied the effect of adding the novel antiangiogenic agent aflibercept (also known as ziv-aflibercept in the United States) to FOLFIRI in patients with mCRC previously treated with oxaliplatin, including patients who received prior bevacizumab. Patients and Methods Patients were randomly assigned to receive aflibercept (4 mg/kg intravenously; 612 patients) or placebo (614 patients) every 2 weeks in combination with FOLFIRI. Treatment was administered until disease progression or unacceptable toxicity. The primary end point was overall survival. Results Adding aflibercept to FOLFIRI significantly improved overall survival relative to placebo plus FOLFIRI (hazard ratio [HR], 0.817; 95.34% CI, 0.713 to 0.937; P = .0032) with median survival times of 13.50 versus 12.06 months, respectively. Aflibercept also significantly improved progression-free survival (PFS; HR, 0.758; 95% CI, 0.661 to 0.869; P < .0001), with median PFS times of 6.90 versus 4.67 months, respectively. The effects on overall survival and PFS exhibited a consistent trend across prespecified subgroup analyses, including bevacizumab pretreated patients. Response rate was 19.8% (95% CI, 16.4% to 23.2%) with aflibercept plus FOLFIRI compared with 11.1% (95% CI, 8.5% to 13.8%) with placebo plus FOLFIRI (P = .0001). Adverse effects reported with aflibercept combined with FOLFIRI included the characteristic anti–vascular endothelial growth factor effects and also reflected an increased incidence of some chemotherapy-related toxicities. Conclusion Aflibercept in combination with FOLFIRI conferred a statistically significant survival benefit over FOLFIRI combined with placebo in patients with mCRC previously treated with oxaliplatin.

CpG Island Methylation Is a Poor Prognostic Factors in Myelodysplastic Syndrome Patients and Is Reversed by Decitabine Therapy-Results of a Phase III Randomized Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 790-790 ◽  
Author(s):  
Lanlan Shen ◽  
Hagop Kantarjian ◽  
Hussain Saba ◽  
E. Lin ◽  
Don Berry ◽  
...  
Keyword(s):  
Supportive Care ◽  
Cpg Island ◽  
Randomized Study ◽  
Cpg Islands ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Multiple Time ◽  
Cpg Island Methylator Phenotype ◽  
Methylator Phenotype ◽  
Multiple Time Points

Abstract Background. In human neoplasia, aberrant methylation of CpG islands leads to gene silencing, and has an essential role in tumorigenesis through down regulation of tumor suppressor genes. A phase III randomized study comparing a DNA methyltransferase inhibitor; decitabine (DAC) versus supportive care has been completed recently in myelodysplastic syndrome (MDS) patients. The purpose of our study was to determine the prognostic significance of CpG islands methylation in these patients, to test the significance of methylation events in predicting drug response, and to explore the correlation between modulation of DNA methylation and response to DAC. Methods. DNA was extracted from blood and bone marrow of 89 patients before treatment (baseline) and also from a subset of 34 patients at multiple time-points and modified by bisulfite. In this study, we selected 24 CpG islands based on previous studies and ongoing efforts to identify methylated genes by MCA/RDA. For 14 genes, very low levels of methylation were detected in an initial group of 20 MDS patients, and we excluded them from further study. We then analyzed the methylation status of a total of 10 genes in all the samples. Bisulfite-PCR followed by Pyrosequencing was used to analyze DNA methylation levels of each gene. For statistical analysis, methylation levels of each gene were normalized by a Z score method, and each patient was assigned a methylation “score” based on the sum of Z scores for all genes, or a selected group of genes. Samples before and after treatment were available for 20 patients on supportive care (SC) and 14 patients on DAC, and methylation levles at each time point were averaged across the 10 genes. Results. Methylation frequencies of RIL, PGRA, PGRB, Olig2, p15, CDH13, NPM2, ECAD, NOR1 and ER ranged from 7% to 70% in MDS patients at baseline. Methylation levels of all these genes were significantly linked, suggesting concurrent methylation affected by CpG Island Methylator Phenotype (CIMP). There was no association between methylation by Z scores with age, IPSS, or cytogenetics. There was no correlation between baseline methylation and response to DAC therapy. By univariate analysis, methylation was significantly associated with both shortened overall survival and progression-free survival. In multivariate analysis, IPSS score and methylation were independent predictors of progression free survival, and methylation was the only independent predictor of overall survival. Methylation changes were then analyzed for correlation with response in 34 patients (Decitabine arm: 2 CR, 3 PR, 4HI, 4 SD, 1 PD; supportive care arm: 2 HI, 6 SD, 12 PD) at multiple time-points. At the latest available time-point (&gt;4 months at therapy), methylation decreased by 11.2% in patients in DAC but increased by 20.1% in patients in SC. A greater decrease was observed in patients with CR or PR (40.6+/− 15.7%) compared to HI (9.8+/− 13.2%). Methylation increased by 15.4% in patients with SD and 27.2% in patients with PD. Conclusions. Concordant methylation of multiple genes suggests the existence of a CpG island methylator phenotype in MDS. This methylation was associated with poor prognosis and risk of leukemia transformation. Decitabine therapy was associated with reduced methylation over time, which was associated with clinical responses.

Phase II trial of irinotecan/docetaxel for advanced pancreatic cancer with randomization between irinotecan/docetaxel and irinotecan/docetaxel plus C225, a monoclonal antibody to the epidermal growth factor receptor (EGF-r) : Eastern Cooperative Oncology

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4519-4519 ◽  
Author(s):  
B. A. Burtness ◽  
M. Powell ◽  
J. Berlin ◽  
D. Liles ◽  
A. Chapman ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Median Survival ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Advanced Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Distant Metastases ◽  
Median Number ◽  
Number Of Cycles ◽  
Ecog Ps

4519 Background: Gemcitabine (G) is standard for metastatic pancreatic cancer (PC), with median survivals of 6 months (m). Second cytotoxic or biologic agents do not substantially advance survival. EGFR is expressed on PC and a phase II trial of G plus cetuximab (C) resulted in favorable 1 year survival. A phase II trial of irinotecan/docetaxel (I/D) chemotherapy reported a median survival for metastatic patients (pts) of 9 m. We conducted this randomized phase II trial to confirm the activity of this non-G regimen, and determine whether combining it with C was feasible and active. The primary endpoint was response. Methods: Pts required histologic confirmation of adenocarcinoma of the pancreas, evidence of distant metastases, ECOG PS 0–1, normal bilirubin, written informed consent, and were randomly assigned to Arm A (N=47) or B (N=45). Imaging with CT or MR within 4 weeks (wk) was used for tumor measurement. Dexamethasone was given 12 hours (h), 1 h before and 12 h after chemotherapy. Pts on Arm A received D 35 mg/m2 over 1 h and I 35 mg/m2 over 30 minutes weekly x 4 in a 6 wk cycle. Pts on Arm B received the same therapy, but C (loading dose 400 mg/m2 wk 1, 250 mg/m2 weekly thereafter) was given before D. Pts not receiving therapeutic anticoagulation received enoxaparin 40 mg per day. Pts were restaged (RECIST) after 2 cycles. Results: Median age Arm A: 59.9, Arm B: 60.2 years. Arm A 55% male, 32% PS 0, 97% EGFR immuno+. Arm B 84% male, 42% PS 0, 97% EGFR +. Median number of cycles for each arm 2 (1 -10). >4 cycles were delivered to 10.5% of pts Arm A, 20.9% Arm B. Grade ¾ neutropenia 26% Arm A, 33% Arm B. Grade 3 nausea 28% Arm A, 18% Arm B; Grade ¾ diarrhea 33% Arm A, 44.4% Arm B. 1 treatment-related death per arm. Median overall survival (OS), with 70.2% of pts known to have died, 6.5m [(95% CI (4.8, 8.6)] in Arm A. With 86.7% of pts known to have died in Arm B, OS 7.4 m [95% CI (4.4, 10.7)]. Response/progression data will be available at time of presentation. Conclusions: Weekly I/D ± C is associated with high rates of grade ¾ neutropenia/diarrhea. Median survival is 6.5m for I/D and 7.4m for I/D/C. Non-G containing therapy is active in metastatic PC. [Table: see text]

Phase II trial of high dose imatinib in recurrent glioblastoma multiforme (GBM) with platelet derived growth factor receptor (PDGFR) expression

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 2056-2056 ◽  
Author(s):  
F. S. Viola ◽  
A. Katz ◽  
A. Arantes ◽  
A. Gaiger ◽  
C. Vasconcellos ◽  
...  
Keyword(s):  
Poor Prognosis ◽  
Significant Proportion ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Initial Therapy ◽  
Recurrent Glioblastoma ◽  
High Dose ◽  
Recurrent Glioblastoma Multiforme ◽  
Disease Stabilization ◽  
Ecog Ps

2056 Background: GBM are the most common primary brain tumors in adults. Despite available treatment they carry a poor prognosis with recurrences in most patients (pts) after initial therapy. PDGF signaling has been postulated to play a role in GBM transformation. We have demonstrated that PDGFRβ is expressed in tumor cells in 50% and in peritumoral endothelial cells in 65% of GBM (Barrios et al, abstract 11518, Proc ASCO 2006). Imatinib, an inhibitor of PDGFRa/β kinase activity could have therapeutic activity in these cases. Methods: We evaluated Imatinib in pts with recurrent GBM (previous radiation and chemotherapy) selected by PDGFR expression. Analysis of PDGFRa/β was performed by standard IHC. Positivity was considered in case of any qualitative expression. Pts were treated with 800 mg/day of Imatinib until tumor progression. All were on steroids and taking enzyme inducing antiepileptic drugs. Response was determined by MRI with spectroscopy and perfusion every 8 weeks according to RECIST criteria. Results: Twenty pts were enrolled (18 GBM, 2 AA). Median age: 51 (21–74), 7 were females. ECOG-PS at inclusion: 0 (3), 1 (10), 2 (7). All pts had expression of PDGFRa and 55% expressed PDGFRβ. Response data are available for all 20 pts. Main adverse events (all grade 1–2) were: edema (55%), nausea (50%), diarrhea and fatigue (35% each). We did not observe any PR but 13 pts (65%) showed disease stabilization. Median progression-free survival was 7.8 months with 60.8% of pts alive at 6 months; 6 months PFS was 52.2%. Conclusions: Imatinib was well tolerated in this group of poor prognosis highly pre-treated GBM pts demonstrating disease stabilization in a significant proportion of cases. These results, in a limited sample, compare favorably with historical data in similar populations. Selection of pts according to the specific molecular expression of their tumor may lead to better therapeutic results. No significant financial relationships to disclose.

A phase II study of S-1 for previously treated small cell lung cancer (SCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e19074-e19074
Author(s):  
K. Kudo ◽  
F. Ohyanagi ◽  
A. Horiike ◽  
E. Miyauchi ◽  
I. Motokawa ◽  
...  
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Median Number ◽  
Ecog Performance Status ◽  
Treatment Regimens ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

e19074 Background: S-1 is a novel oral 5-fluorouracil derivative that exhibits obvious activity against various tumor types including NSCLC. However, the effects of S-1 against SCLC have not been reported. The present phase II trial assesses the efficacy and safety of S-1 in previously treated SCLC patients. Methods: Eligible patients had pathologically documented SCLC that relapsed after platinum-based chemotherapy, ECOG performance status (PS) 0–2, and adequate bone marrow, kidney and liver function. Patients with untreated or symptomatic brain metastasis were excluded. Treatment comprised the oral administration of S-1 at 40 mg/m2 twice each day for 28 days every 6 weeks. The primary end point was the objective tumor response rate (RECIST). Secondary endpoints included progression-free survival and overall survival. Results: Twenty-six evaluable patients were enrolled (Simon's two-stage optimal design; α = 0.1; β = 0.1; P0 = 0.05; P1 = 0.25) with the following characteristics: male: female, 22/4; median age, 68 (33 - 79) y; PS0–1, n = 21; PS2, n = 5. The median number of prior treatment regimens was 2 (1–3). S-1 was administered for a mean of 1.3 cycles (1 - 5). One patient (3.8%) partially responded, 10 (38.5%) had stable and 15 (57.7%) had progressive disease. The overall response rate was 3.8% and the disease control rate was 42.3%. The median time to progression was 33 days. The median survival time was 8.0 months and the 1-year survival rate was 23%. This regimen was well tolerated. The common grade 3/4 toxicities included neutropenia (7.7%), leukopenia (7.7%), anemia (7.7%), hyponatremia (7.7%), rush (7.7%), infection (7.7%), and diarrhea (3.8%). None of the patients developed febrile neutropenia and no deaths were attributed to treatment. Conclusions: S-1 is well tolerated but has low activity as a single agent in previously treated patients with SCLC. No significant financial relationships to disclose.

Combination of gemcitabine and cetuximab in patients with advanced cholangiocarcinoma: A phase II study of the Belgian Group of Digestive Oncology.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 245-245 ◽  
Author(s):  
I. Borbath ◽  
A. Ceratti ◽  
C. Verslype ◽  
A. Demols ◽  
T. Delaunoit ◽  
...  
Keyword(s):  
Skin Rash ◽  
Phase Ii ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Standard Of Care ◽  
Egfr Expression ◽  
Prior Systemic Therapy ◽  
Ecog Ps

245 Background: Cholangiocarcinomas (CCK) are uncommon tumors with an increasing incidence and a poor prognosis. Epidermal growth factor receptor (EGFR) expression and activation in CCK have been demonstrated. Methods: We conducted a multicenter phase II trial combining cetuximab (Ctx), an anti-EGFR chimerized IgG1 monoclonal antibody, to gemcitabine (Gem). Patients with either locally advanced (LA) or metastatic (M) CCK (excluding gallbladder) were included; no prior systemic therapy was allowed. Ctx was administrated at the initial dose of 400 mg/m2 and further injections at 250 mg/m2 every 7 days, and Gem was administrated at 1000 mg/m2 on days 1, 8, and 15 every 4 weeks. The primary endpoint was the progression-free survival (PFS) rate at 6 months. A Simon 2-stage design was used. We hypothesized that Gem/Ctx would improve 6 month-PFS rate from 20% to 40%. We needed 3 patients with PFS ≥ 6 months from the first 13 to further include a total of 43 patients. Results: Forty-four patients with advanced CCK (41% LA/59%M) were enrolled from 09/2008 to 01/2010. Median age was 61.5 years (range 40-86) and baseline ECOG PS was 0 for 68% and 1 for 32% of the patients. Forty-three percent of the patients had prior surgery. Forty-six percent of the patients were free from progression at 6 months. Median PFS was 5.8 months (95% CI, 4.4-7.4 m) and median overall survival was 11.6 months (95% CI, 8.7-14.6 m). Nine patients (20.9%) had partial response with a median duration of 5 months (range 2-10 m). Disease control rate (PR + SD > 8 weeks) was 81.4%. The most common grades 3/4 related-toxicities were haematological abnormalities (47.7%), skin rash (13.6%) and fatigue (11.3%). Due to toxicity, 6 patients discontinued study treatment; 14 and 3 patients had a Gem and Ctx dose reduction respectively. Among the nine responders, 8 experienced a skin rash of at least grade 2, suggesting a relationship between skin toxicity and efficacy. Conclusions: Our study met its endpoint, i.e., a PFS rate of 46% at 6 months, suggesting that Gem-Ctx combination had promising activity with a manageable toxicity profile in advanced CCK. Adding Ctx to the new standard of care Gem-cisplatin deserves further investigations in CCK. [Table: see text]

A phase II trial of gemcitabine, irinotecan, and panitumumab in advanced cholangiocarcinoma, with correlative analysis of EGFR, KRAS, and BRAF: An interim report.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4111-4111
Author(s):  
Davendra Sohal ◽  
Ursina R. Teitelbaum ◽  
Takeshi Uehara ◽  
Kristine Mykulowycz ◽  
Christopher D. Watt ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Tumor Stage ◽  
Primary Objective ◽  
Response To Therapy ◽  
Braf V600e ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Tissue Specimens

4111 Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches achieve modest results. The epidermal growth factor receptor (EGFR) pathway appears to be associated with tumor stage, prognosis and response to therapy. This trial was designed to evaluate the tolerability and efficacy of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan, in patients with advanced cholangiocarcinoma. Molecular analysis of EGFR pathway genes was planned as well. Methods: Patients with advanced (unresectable or metastatic) cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, and gemcitabine (1000 mg/m2) and irinotecan (100 mg/m2) on days 1 and 8 of a 21-day cycle. Tissue specimens were collected at diagnosis for correlative molecular analyses. Primary objective is to evaluate the 5-month progression-free survival (PFS) rate. Secondary objectives include overall response rate (ORR), overall survival (OS) and toxicity of the combination. Mutational analysis of EGFR (del 19; 858), KRAS (codons 12, 13) and BRAF (V600E) was done on samples with adequate material for testing. Results: There have been 26 (of planned 42) patients recruited to the study. A median of 6 (0-30) cycles were administered. There were no treatment related deaths. The most common gr 3 or higher toxicities were neutropenia (10 pts, 38%), thrombocytopenia (10 pts, 38%), skin rash (10 pts, 38%) and diarrhea (3 pts, 12%). During the study, there were 3 CR, 6 PR, 10 SD (disease control rate of 90%), and 2 PD (by RECIST) in 21 evaluable pts. Two pts went on to have surgical resection. Median OS is 12.7 months. Of 13 testable samples, no EGFR or BRAF mutations were identified; however, there were 7 KRAS mutations. Retrospective analysis showed no difference in OS by KRAS mutation status. Conclusions: Interim evaluation of this ongoing study showed encouraging tolerability and efficacy of this regimen. Several patients have KRAS mutations; there appears to be no association with response, however. The pre-specified efficacy criteria to continue enrollment were met.

An interim evaluation of efficacy and safety of the combination of panitumumab, gemcitabine, and irinotecan in patients with advanced or metastatic cholangiocarcinoma: A phase II study.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 328-328
Author(s):  
Weijing Sun ◽  
Davendra Sohal ◽  
Kristine Mykulowycz ◽  
Ursina R. Teitelbaum ◽  
Nevena Damjanov ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Tumor Stage ◽  
Infusion Reaction ◽  
Primary Objective ◽  
Over Expression ◽  
Epidermal Growth ◽  
Efficacy Criteria ◽  
Tissue Specimens ◽  
Ecog Ps

328 Background: Cholangiocarcinoma is an aggressive neoplasm. Current chemotherapy approaches suggest that combinations may be superior to single agents in this disease. Over-expression of epidermal growth factor receptor (EGFR) is associated with tumor stage and prognosis. This study was designed to evaluate the efficacy and tolerability of the combination of panitumumab, a monoclonal anti-EGFR antibody, with gemcitabine and irinotecan in patients with advanced and metastatic cholangiocarcinoma. Methods: Pts with advanced unresectable or metastatic cholangiocarcinoma, ECOG PS 0-2, and adequate liver, kidney and bone marrow function were treated with panitumumab (9 mg/kg) on day 1, gemcitabine (1000 mg/m2/100 min) iv and irinotecan (100 mg/m2) iv on days 1 and 8 of a 21-day cycle. Tissue specimens were collected based on availability for future biomarker analyses. The primary objective was to evaluate the 5-month progression-free survival (PFS) rate. The secondary objectives include overall response rate (ORR), overall survival rate (OS) and toxicity of the combination. Results: There have been 24 (of planned 42) pts recruited to the study. Toxicity of the combination was assessed in all enrolled pts. There were no treatment related deaths. The most common gr 3 or higher toxicity was were neutropenia (10 pts [40%]), thrombocytopenia (6 pts, [25%]), skin rash (4 pts [17%]) and diarrhea (3 pts, [12%]). One pt developed a gr 2 infusion reaction, which was considered related to panitumumab. Efficacy was evaluated in 20 pts. Among them, there were 2 CR, 6 PR, and 10 SD (with disease control rate of 90%), and 2 PD (assessed by RECIST criteria). Two pts went on to have surgical resection. Eight pts had ≥ 10 cycles of the therapy, and dose modification/interruption were needed for some of these pts. Conclusions: The data of this on-going study showed encouraging results of the combination of panitumumab with gemcitabine and irinotecan in both tolerability and efficacy. The pre-specified efficacy criteria to continue enrollment were met. Further analysis by biomarker status (KRAS/BRAF/EGFR) is forthcoming.

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