Clinical benefit of catumaxomab in malignant ascites in patient subpopulations in a pivotal phase II/III trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e14000-e14000 ◽  
Author(s):  
S. Parsons ◽  
M. Hennig ◽  
R. Linke ◽  
A. Klein ◽  
A. Lahr ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Primary Tumor ◽  
Poor Prognosis ◽  
Malignant Ascites ◽  
Rank Test ◽  
Control Group ◽  
Pivotal Phase ◽  
Significant Treatment ◽  
Free Survival

e14000 Background: Parsons et al. (ASCO 2008) reported the results of a pivotal phase II/III trial in patients with malignant ascites due to epithelial cancer. Treatment with the trifunctional antibody catumaxomab resulted in a clinically relevant prolongation of puncture-free survival, defined as the time to the next therapeutic puncture or the time to death, whichever occurred first. Malignant ascites is a typical late-stage manifestation of cancer associated with a poor prognosis and survival. Effective treatment options are limited. It is thus of special interest if all patient subgroups derive objective benefit from treatment. Methods: A post-hoc analysis was performed on the 258 patients with epithelial tumors treated with catumaxomab + paracentesis or paracentesis alone (control) in the pivotal trial to investigate any association between the primary endpoint (puncture-free survival) and the primary tumor, metastases, or other prognostic parameters. Results: Puncture-free survival was lower in patients with non-ovarian vs ovarian tumors and those with a poor prognosis (metastases vs no metastases, elderly vs younger, or low vs serum protein level). However, there was always a statistically significant treatment effect for catumaxomab compared with the respective control group (p≤0.0001, log rank test, for all comparisons) (see table). Conclusion: Catumaxomab demonstrated a significant clinical benefit in patients with malignant ascites independent of the primary tumor or other prognostic factors. Therefore, catumaxomab could be considered as a treatment option for patients with a poor prognosis. [Table: see text] [Table: see text]

Effect of catumaxomab treatment in patients with peritoneal carcinomatosis and malignant ascites due to gastrointestinal cancers on survival.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 490-490 ◽  
Author(s):  
M. A. Ströhlein ◽  
M. M. Essing ◽  
M. Hennig ◽  
D. Seimetz ◽  
M. G. Ott ◽  
...  
Keyword(s):  
Overall Survival ◽  
Peritoneal Carcinomatosis ◽  
Malignant Ascites ◽  
Rank Test ◽  
Control Group ◽  
Pivotal Trial ◽  
Treatment Benefit ◽  
Significant Treatment ◽  
Free Survival ◽  
Gi Cancer

490 Background: In 2009 the trifunctional antibody catumaxomab was approved for the intraperitoneal (i.p.) treatment of malignant ascites (MA) in EpCAM-positive carcinomas in Europe. Overall survival (OS) results for gastric cancer patients from the pivotal trial showed a significant treatment benefit of catumaxomab in this patient group. We present the results for the gastrointestinal (GI) cancer subgroup from the pivotal trial including long-term survivors. Methods: A total of 86 patients with MA due to GI cancer (gastric, pancreatic, colon, esophagus, rectum carcinoma) were treated with paracentesis plus catumaxomab (59 patients) vs. paracentesis alone (control, 27 patients). The primary endpoint was puncture-free survival; main secondary endpoints were time to next puncture, overall survival and safety parameters. The endpoints were compared between the catumaxomab and the control group using the Kaplan-Meier method and log-rank test. Analyses were performed for the Full Analysis Set (FAS) and the Safety Set (patients who received at least 1 catumaxomab infusion; 95%). Results: For puncture-free survival, a median of 35 days for catumaxomab vs. 14 days for control was observed (p<0.0001, HR: 0.340 with 95 % CI from 0.194 to 0.597, FAS). Time to next puncture resulted in a median of 118 days vs. 15 days (p<0.0001, HR: 0.161 with 95 % CI from 0.069 to 0.378, FAS). Although the study was not powered nor designed for OS, the difference between treatment and control arm was significant for the Safety Set (median: 61 vs. 44 days, p<0.05, HR: 0.553). ADRs were generally mild to moderate, limited to the treatment period and reversible. Conclusions: I.p. catumaxomab is an EMA-approved treatment for patients suffering from malignant ascites. The positive efficacy results were demonstrated in an advanced stage patient population together with a predictable and manageable safety profile. Patients suffering from peritoneal carcinomatosis with malignant ascites due to GI cancers experience a significant survival benefit from i.p. treatment with catumaxomab. [Table: see text]

Safety of catumaxomab: Cytokine-release-related symptoms as a possible predictive factor for efficacy in a pivotal phase II/III trial in malignant ascites

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3036-3036 ◽  
Author(s):  
C. Bokemeyer ◽  
M. Heiss ◽  
H. Gamperl ◽  
R. Linke ◽  
E. Schulze ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Predictive Factor ◽  
Mode Of Action ◽  
Symptomatic Treatment ◽  
Malignant Ascites ◽  
Rank Test ◽  
Cytokine Release ◽  
Pivotal Phase ◽  
Free Survival

3036 Background: As a targeted immunotherapy, the trifunctional antibody catumaxomab specifically binds to epithelial cell-adhesion molecule (EpCAM) on tumor cells and attracts T-cells via CD3 and accessory cells via its FcγRI/III+ region. The clinical relevance of this mode of action was demonstrated by Parsons et al. (ASCO 2008) in a pivotal phase II/III trial. Catumaxomab treatment resulted in a clinically relevant prolongation of puncture-free survival (defined as time to next puncture or time to death, which ever occurred first) in patients with malignant ascites. One of the most common adverse events associated with catumaxomab is cytokine-release-related-symptoms (CRRSs), which might be of predictive value for efficacy. Methods: The safety profile of catumaxomab was identified in the pivotal study. CRRSs (pyrexia, nausea, and vomiting) were among the most common adverse events in the catumaxomab group. A correlation between CRRSs and puncture-free survival, the primary endpoint, was performed to investigate whether patients who had CRRSs benefited from catumaxomab treatment more than those who had no CRRSs. Results: Among 157 patients, CRRSs were limited to the duration of catumaxomab treatment, with a median onset of 1 day after catumaxomab administration and a median duration of 1–2 days. Most of these symptoms were mild to moderate and were manageable by standard symptomatic treatment. Only 6 of 101 patients with CRRSs who were treated with concomitant medication required systemic corticoid therapy. Puncture-free survival was longer (48 days) in patients with (81%) CRRSs during catumaxomab treatment than in patients without (19%) CRRSs (27 days), although the difference was not statistically significant (p=0.1546, log rank test). Conclusions: CRRSs are a common occurrence with catumaxomab, due to its mode of action, during the treatment of patients with malignant ascites. Since CRRSs appear to be correlated with efficacy, they may therefore be a predictive factor for catumaxomab efficacy. [Table: see text]

Decrease of VEGF within malignant ascites during catumaxomab treatment: Results from a pivotal phase II/III study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3029-3029
Author(s):  
M. Jäger ◽  
A. Schoberth ◽  
B. Theissen ◽  
J. Hess ◽  
H. Friccius-Quecke ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Phase Ii ◽  
Total Protein ◽  
Protein Concentration ◽  
Malignant Ascites ◽  
Control Group ◽  
Pivotal Phase ◽  
Protein Ratio ◽  
Protein Levels ◽  
Vegf Protein

3029 Background: Treatment with the trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab efficiently eliminates tumor cells from the peritoneal cavity (Jäger et al., ASCO 2007) and led to clinically relevant prolongation of puncture-free survival (PuFS) in patients with malignant ascites (MA) in a pivotal phase II/III trial (Parsons et al., ASCO 2008). As vascular endothelial growth factor (VEGF) levels are markedly elevated in MA in comparison to cirrhotic ascites the question was addressed whether catumaxomab treatment impacts the expression or accumulation of VEGF within MA. Here we report that in addition to tumor cell depletion, VEGF protein levels in MA significantly decreased upon catumaxomab therapy. We propose that the strongly correlated tumor cell elimination and reduced VEGF protein levels are causative for the prolonged PuFS of patients suffering from MA. Methods: VEGF and total protein levels were measured by ELISA and BCA from MA supernatants before catumaxomab therapy, after the 1st infusion (10μg; day 3) and after the 4th infusion (150μg; day 11). Data were statistically analysed for the ratio of the VEGF protein concentration versus the total protein concentration for the MA treatment groups with ovarian (OC) or nonovarian cancer (NC) as underlying disease and the corresponding control groups that received paracentesis only. Results: One day after the last catumaxomab infusion 46 or 47 patients analysed in the OC or NC treatment group showed a statistically significant decrease in VEGF to total protein ratio when compared to the measurement before catumaxomab therapy (ANOVA p=0.034 for OC and p<0.001 for NC). These results are consistent with the tumor cell elimination previously assessed in these patients. In contrast, the OC control group showed a statistically significant increase of VEGF to total protein ratio (p=0.009), which is accompanied by an increase in tumor cell numbers. In the NC control group VEGF to total protein ratio remained unaffected (p=0.096). Conclusions: Catumaxomab therapy significantly reduced VEGF protein levels correlating with tumor cell elimination in MA, which in turn led to the prevention of fluid accumulation in the peritoneal cavity and finally to prolonged PuFS of patients suffering from MA. [Table: see text]

Predictors for response to cetuximab in a prospective clinical trial (E2303) of patients with head and neck squamous cell carcinoma (HNSCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 5576-5576 ◽  
Author(s):  
Amanda Psyrri ◽  
Ju-Whei Lee ◽  
Eirini Pectasides ◽  
Maria Vassilakopoulou ◽  
Barbara Burtness ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Cox Regression ◽  
Objective Response ◽  
Eastern Cooperative Oncology Group ◽  
Disease Stage ◽  
Rank Test ◽  
Free Survival ◽  
Cox Regression Analysis ◽  
Event Time

5576 Background: Theidentification of resistance mechanisms to Epidermal Growth Factor Receptor (EGFR) inhibitors remains critical lack in the management of HNSCC. We sought to determine predictors for response to cetuximab in a phase II clinical trial. Methods: 63 patients (pts) with operable stage III/IV HNSCC participated in E2303, an Eastern Cooperative Oncology Group (ECOG) phase II trial of induction chemotherapy with weekly cetuximab, paclitaxel and carboplatin x 6 followed by chemoradiotherapy with the same regimen. A tissue microarray was constructed and EGFR, ERK1/2, Met, pAkt and STAT protein expression levels were assessed using AQUA. The objectives of analysis were to determine association of biomarkers with E2303 efficacy outcomes (best objective response (OR), overall survival (OS), progression-free survival (PFS), and event-free survival (EFS)). The logistic regression model was used to examine relationship between marker measurements (on a continuous scale) and OR. The univariate and multivariate Cox proportional hazards models were used to evaluate the relationship between markers and event-time distributions. Fisher’s exact test was used to evaluate differences in response rate between groups (high vs. low AQUA scores). Event-time distributions were estimated by the Kaplan-Meier method and compared by the log-rank test. Results: Cytoplasmic ERK1/2 levels weresignificantly associated with PFS and OS (p=0.03 and 0.01, respectively). Nuclear ERK1/2 levels were significantly associated with OS (p=0.02) and tended towards significance for PFS (p=0.09). The multivariate Cox regression analysis shows that cytoplasmic and nuclear ERK1/2 are significantly associated with OS and PFS after controlling for primary site and disease stage, respectively There was no significant association between cytoplasmic or nuclear ERK1/2 status and OR (p-values 0.98 and 0.41, respectively).No association was found between expression of any of other biomarkers and outcome measures. Our data analysis was based on 35 pts with marker data available. Conclusions: Ras/MAPK/ERKpathway may be associated with resistance to cetuximab in HNSCC.

Phase II trial of combined chemotherapy with irinotecan, S-1, and bevacizumab (IRIS/Bev) in patients with metastatic colorectal cancer (mCRC): Hokkaido Gastrointestinal Cancer Study Group (HGCSG) trial—Comparison of the efficacy of KRAS status.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 536-536
Author(s):  
Michio Nakamura ◽  
Satoshi Yuki ◽  
Masayoshi Dazai ◽  
Yoshimitsu Kobayashi ◽  
Takashi Kato ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Statistical Tests ◽  
Progression Free Survival ◽  
Rank Test ◽  
Wild Type ◽  
Target Number ◽  
Mutant Type ◽  
Free Survival ◽  
Kras Status

536 Background: Mutations of the KRAS gene were identified as a predictive marker in mCRC for anti-EGFR antibody. Previously reported data suggest that the longer overall survival (OS) observed with bevacizumab (BV) treatment in mCRC is independent of alterations in the KRAS status. We analized efficacy of BV combined irinotecan and S-1 (IRIS/Bev) in mCRC relative to KRAS status. Methods: In the retrospective analysis (n=53) of patients who participated in the Phase II trial of IRIS/Bev, additional statistical analyses were done with data from KRAS mutational analyses. In this trial, eligible patients had to have mCRC with a confirmed diagnosis of adenocarcinoma, an age of >20 years, and no history of prior chemotherapy. S-1 40-60 mg twice daily p.o. was given on days 1-14 and irinotecan 100 mg/m2 and bevacizumab 5 mg/kg i.v. were given on days 1 and 15 of a 28-day cycle. The Response Evaluation in Solid Tumors (RECIST) criteria version 1.0 was used to assess tumor response. The Kaplan–Meier method was used to determine Progression-free survival (PFS) and OS. Log-rank test was used to compare with mutant or wild-type KRASin terms of PFS and OS. All statistical tests were performed using SPSS. Results: The target number of 53 patients was enrolled as of March 2009. KRAS status was assessed in 43 patients (wild = 27, mutant = 16). Response rate was 63.0% with wild-type and 68.8% with mutant-type KRAS, that was not significant (p=0.752). The median Progression-free survival was 17.1 months with wild-type and 22.7 months with mutant-type KRAS, that was not significant (p=0.531). And median OS was 49.0 months with wild-type and 38.0 months with mutant-type KRAS, that was not significant(p=0.906) as well. Conclusions: IRIS/Bev provides clinical benefit in patients with mCRC expressing either mutant or wild-type KRAS. Randomized control trial comparing this regimen with oxaliplatin containing regimen(XELOX or mFOLFOX6 plus bevacizumab: TRICOLORE study) is already started. Comparison of the efficacy of KRAS status is also planned in this study. Clinical trial information: NCT00569790.

1313 Catumaxomab treatment reduces VEGF protein levels within malignant ascites: data from a pivotal phase II/III study

2009 ◽  
Vol 7 (2) ◽  
pp. 142-143
Author(s):  
M. Jäger ◽  
A. Schoberth ◽  
B. Theissen ◽  
J. Hess ◽  
H. Friccius ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Ascites ◽  
Pivotal Phase ◽  
Protein Levels ◽  
Vegf Protein

scholarly journals Vitreous levels of interleukin-35 as a prognostic factor in B-cell vitreoretinal lymphoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Atsunobu Takeda ◽  
Eiichi Hasegawa ◽  
Shintaro Nakao ◽  
Keijiro Ishikawa ◽  
Yusuke Murakami ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Tumor Development ◽  
Rank Test ◽  
Control Group ◽  
Log Rank Test ◽  
Vitreoretinal Lymphoma ◽  
Infectious Uveitis ◽  
Cancer Types ◽  
Promote Tumor Development

Abstract Vitreoretinal lymphoma (VRL) is a rare disease of B-cell origin with poor prognosis. Regulatory cytokines promote tumor development by suppressing antitumor immunity in several cancer types, including B-cell malignancies. To identify the regulatory cytokines associated with poor prognosis in patients with B-cell VRL, we determined the regulatory cytokines profiles in the vitreous humor of patients with VRL. This retrospective study included 22 patients with VRL, 24 with non-infectious uveitis (NIU), and 20 with idiopathic epiretinal membrane (control). Vitreous concentrations of regulatory cytokines were assessed using a cytometric beads assay and association with clinical data was examined. IL-35 and soluble IL-2 receptor α levels were significantly higher in patients with VRL and NIU than those in the control group. The 5-year overall survival (OS) rates for the group with high intravitreal IL-35 was significantly poorer than those for the group with low intravitreal IL-35, who were diagnosed with VRL at the onset (P = 0.024, log-rank test). The 5-year OS rates with intravitreal IL-35 levels above and below the median were 40.0% and 83.3%, respectively. Our results suggest that high intravitreal IL-35 levels indicate poor prognosis for patients diagnosed with B-cell VRL at the onset.

Adjuvant chemotherapy of S-1 versus S-1 plus metformin for resected pancreatic cancer: A multicenter and randomized phase II trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS474-TPS474
Author(s):  
Masato Narita ◽  
Masayuki Furukawa ◽  
Ichiro Sakamoto ◽  
Yutaka Itoh ◽  
Hiroshi Nakano ◽  
...  
Keyword(s):  
Survival Rate ◽  
Adjuvant Chemotherapy ◽  
Phase Ii ◽  
Residual Tumor ◽  
Ductal Adenocarcinoma ◽  
Rank Test ◽  
Control Group ◽  
Study Group ◽  
Preoperative Treatment ◽  
Randomized Phase Ii

TPS474 Background: Adjuvant chemotherapy with S-1 in patients with resected pancreatic ductal adenocarcinoma (PDAC) improved the 5-year survival rate to 44.1% and therefore has been a standard of care in Japan. Recent epidemiologic data has revealed possibility of metformin (a drug for type II diabetes) improving the prognosis of PDAC. In this context, we compare the efficacy and safety of S-1 plus metformin with S-1 alone as adjuvant chemotherapy in patients with resected PDAC. Methods: This multicenter-randomized-phase II study is conducted at 29 institutions in Japan (Registry Number; UMIN000020681). Key eligibility criteria are age 20 years or more with good performance status; histologically proven PDAC of stage I-II without macroscopic residual tumor. Patients receiving preoperative treatment for PDAC and previously treated with DPP-4 inhibitor, GLP-1, and metformin are excluded. After giving written consent to the study, patients are randomly assigned either study group (S-1 plus metformin) or control group (S-1 alone), balancing residual tumor status, nodal status, and institutions. S-1 is given orally for 2 weeks in a 3-week cycle. Cycles are lasted for 6 months. In the study group, metformin is administrated together with S-1 for 2 years. The treatment would be discontinued when the patient has either recurrence or unacceptable toxicity. The primary endpoint is 2-year OS, and the secondary endpoints are relapse-free survival and incidence rate of adverse events. Sample size was calculated based on the data in previous trials, with an expected 2-year survival rate in the control group of 65%. An improvement in 2-year-survival rate from 65% in the control group to 78% in the study group, yielding a hazard ratio of 0.58, is considered clinically relevant in this population. A total of 73 events in each group were required for a power of 80% at a two-sided alpha 20% to detect a difference in OS using an unstratified log-rank test. A total of 160 patients (80 per group) were estimated to achieve the specified number of events in the scheduled follow-up. Duration of this study would be 5 years and it has been started from January 2018. Until September 2018, 17 patients have been enrolled. Clinical trial information: UMIN000020681.

Treatment of Philadelphia-Positive Acute Lymphocytic Leukemia (Ph+ ALL) in the Elderly with Imatinib Mesylate (STI571) and Chemotherapy. an Interim Analysis of the GRAALL AFR09 Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2742-2742 ◽  
Author(s):  
Andre Delannoy ◽  
Véronique Lhéritier ◽  
Xavier Thomas ◽  
Sylvie Castaigne ◽  
Hassan Farhat ◽  
...  
Keyword(s):  
Elderly Patients ◽  
Induction Chemotherapy ◽  
Interim Analysis ◽  
Complete Response ◽  
Rank Test ◽  
Induction Treatment ◽  
Control Group ◽  
Free Survival ◽  
Log Rank Test ◽  
One Year

Abstract Ph+ ALL accounts for approximately one third of ALL cases in patients aged 55 years or older. The median survival of older Ph+ ALL patients is one year, with practically no long-term survivor (Blood, 98, Supp1 p319a, 2001). Imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Ph+ ALL, which prompted the GRAALL to implement a treatment protocol associating imatinib and chemotherapy in previously untreated elderly patients: ALL patients aged 55 years or older are treated with steroids during one week and Ph+ve cases are then offered a specific therapy including an induction treatment with steroids, cyclophosphamide, daunorubicin and vincristine, followed, irrespective of response to induction chemotherapy, by imatinib, 600 mg daily, combined with intermittent steroids during 2 months. Patients in complete response are then given 10 blocks of alternating chemotherapy, including 2 additional two-month blocks of imatinib, for a total treatment duration of 2 years. Therapy of occult central nervous system leukemia includes 5 intrathecal injections of methotrexate and cranial irradiation. The study is intended to include 30 patients and its main objective is to improve overall one-year survival to 70%. Results are compared with those obtained in 21 Ph+ ALL elderly patients treated according to our previous protocol. Since January 2003, 21 patients aged 58 to 78 years (median: 64.7 years) were included in the AFR09 protocol. Their median follow-up is 3 months. 15/19 patients are in complete response after induction chemotherapy vs 6/21 in the historical controls given similar induction regimen but with no steroids before chemotherapy (p=0.002). The projected overall survival is 95% at 9 months vs 62% in the control group (p=0.08, log-rank test). The 9-month projected event-free survival is 83% vs 10% (p&lt;0.0001) and the projected 6-month relapse-free survival is 79% vs 22% (p=0.006, log-rank test). In conclusion, although preliminary, this interim analysis suggests that the use of imatinib in elderly patients with Ph+-ALL is very likely to dramatically improve prognosis. Of note, an unexpected high proportion of patients accrued in this study achieved a CR after induction chemotherapy possibly denoting a beneficial impact of steroids given before starting chemotherapy.

1312 Catumaxomab therapy eliminates putative CD133+ EpCAM+ cancer stem celles from malignant ascites: data from a pivotal phase II/III study

2009 ◽  
Vol 7 (2) ◽  
pp. 142
Author(s):  
H. Lindhofer ◽  
A. Schoberth ◽  
D. Pelster ◽  
J. Hess ◽  
J. Herold ◽  
...  
Keyword(s):  
Phase Ii ◽  
Malignant Ascites ◽  
Pivotal Phase
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