Prospective analysis of microRNA 31-3p (miR31-3p) as a predictive biomarker of response to anti-epidermal growth factor receptor (anti-EGFR) monoclonal antibodies (mABs) in patients with metastatic colorectal cancer (mCRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 548-548
Author(s):  
Gayathri Anandappa ◽  
Andrea Lampis ◽  
David Cunningham ◽  
Kyriakos Kouvelakis ◽  
Khurum Khan ◽  
...  
Keyword(s):  
Single Agent ◽  
Growth Factor Receptor ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Liquid Biopsies ◽  
Logistic Regression Models ◽  
Best Response ◽  
Ras Status ◽  
Pre Treatment

548 Background: RAS status in tissue and/or liquid biopsies and tumour location (sidedness) are predictive markers of patients’ response to anti-EGFR mABs. MiR-31-3p expression has been correlated with clinical benefit from anti-EGFR mABs with chemotherapy. We aimed to validate the predictive power of miR-31-3p in a prospective cohort of chemo-refractory mCRC patients treated with single agent anti-EGFR mABs in the PROSPECT-C trial (NCT02994888). Methods: MiR-31-3p was tested by in-situ hybridization in 91 pre-treatment (PT) core biopsies from 45 mCRC patients. Sequential tissue biopsies obtained PT, at time of best response and at disease progression were tested to monitor changes in miR-31-3p expression over treatment. In 34 patients miR-31-3p, gender, sidedness, previous lines of treatment and RAS status in PT cell free (cf) DNA were evaluated in multivariate Cox and logistic regression models. Results: Patients with low miR-31-3p expression in PT biopsies showed better overall response rate (ORR: 58.3% vs 22.2%), median progression free survival (mPFS: 4.21 vs 2.27 months) and overall survival (mOS: 4.21 vs 2.27 mo) compared to those with high miR-31-3p expression (Hazard Ratio for PFS high vs low: 1.96; 95% CI: 0.98-3.88; p: 0.06 and HR for OS high vs low: 2.14; 95% CI: 1.04- 4.40; p: 0.04) adjusting for age, gender and sidedness. There was significant association between ORR and miR-31-3p expression (χ2 test p: 0.029). MiR-31-3p expression was an independent predictor of response, adjusting for gender, previous treatment lines and RAS (odds ratio: 0.14; 95% CI: 0.02-1.00, p: 0.048). A trend towards improved mPFS (5.10 vs 2.27 mo) and mOS (15.23 vs 4.67 mo) was noted in miR31-3p low vs high group in cfDNA RAS wild-type patients. No significant change in miR-31-3p expression were observed in archival tissue and sequential tissue biopsies. Conclusions: Our study validates the role of miR-31-3p as potential predictive biomarker of selection for anti-EGFR mABs. Further studies are needed to test if miR-31-3p combined with cfDNA RAS test can identify best responders in specific clinical niches.

Palliative chemotherapy in head and neck cancers: A tertiary care center experience with weekly paclitaxel and cetuximab.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e16028-e16028
Author(s):  
Kumar Prabhash ◽  
Vanita Noronha ◽  
Amit Joshi ◽  
Vijay Patil ◽  
S Juvekar ◽  
...  
Keyword(s):  
Care Center ◽  
Tertiary Care ◽  
Single Agent ◽  
Haematological Toxicity ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Outpatient Setting ◽  
Weekly Paclitaxel ◽  
Best Response ◽  
Grade 3

e16028 Background: The concept of combination of paclitaxel and cetuximab is an intersesting prospect as both these agents have single agent acitivity, minimal toxicity and hold a biological rationale for combination. The aim of our study was to see the safety,efficacy and feasibility of administration of this combination in a outpatient setting. Methods: This was a retrospective analysis of the prospectively collected data, of patients offered weekly paclitaxel and cetuximab from May 2010-May 2011. The standard schedule of cetuximab along with 80 mg/m2 of weekly paclitaxel was administered till either disease progression or withdrawl of patient's consent. The toxicity profile was noted in accordance with CTCAE version 4.02 and response in accordance with RECIST criteria. SPSS version 16 has been utilized for analysis. Descriptive statistics are been presented and analyis of estimation of overall and progression free survival has been done with Kaplan-Meier survival method. Results: 42 patients with a median age of 52 years (35-81 years) were included. The KPS score was 60 in 1 (2.4%),70 in 11 (26.2%) and 80 in 30 patients(71.4%). Nearly half of our patients 22 (52.4%) had a primary in oral cavity. Except 3 (7.1%) patients rest all had received some form of previous treatment. The median event free period(EFP) from previous first line treatment was 231 days, it was below 180 days in 38.5% of patients. Best response observed was CR in 1 patient (2.4%), PR in 11 (26.2%), SD in 17 (40.5%) and PD in 13 (30.9%). Grade 3-4 skin changes were seen in 3 patients, grade 3-4 neuropathy was seen in 3 patients and there were no episodes of grade 3-4 gastrointestinal or haematological toxicity. The overall estimated median PFS and OS were 128 and 256 days. The median estimated PFS for patients with EFP less than 6 months versus more than 6 months was 115 and 165 days respectively (p = 0.132). Conclusions: The combination of paclitaxel and cetuximab was found to be safe, feasible and appears to be clinically beneficial.

GEIS 39: Phase II trial of nabpaclitaxel for the treatment of patient with multiply relapsed/refractory desmoplastic small round cell tumor (DSRCT) and Ewing sarcoma (EwS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11529-11529
Author(s):  
Jaume Mora ◽  
Mariona Suñol ◽  
Nadia Hindi ◽  
Alicia Castañeda ◽  
Andrés Redondo ◽  
...  
Keyword(s):  
Single Agent ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Free Survival ◽  
Pediatric Solid Tumors ◽  
Meaningful Activity ◽  
Common Grade ◽  
Central Pathology ◽  
Grade 3 ◽  
Further Development

11529 Background: Nab-paclitaxel (albumin-bound paclitaxel) has shown preclinical activity against pediatric solid tumors. Preclinical data in EwS PDX models suggested high activity of nab-paclitaxel in tumors expressing high-levels of SPARC. Tumoral SPARC facilitates the accumulation of albumin in the tumor and increases the effectiveness of albumin-bound paclitaxel. Nab-paclitaxel utilizes albumin to deliver paclitaxel via caveolin-mediated endocytosis which is expressed in the EwS cells surface. We hypothesized that SPARC can be a predictive biomarker for nab-paclitaxel in EwS and DSRCT that could potentially be relevant for a better design of clinical trials and personalized treatments using nab-paclitaxel. Methods: Main endpoint of GEIS-39 was the overall response rate (ORR) assessed by RECIST 1.1 criteria with centralized pathology and imaging review. Secondary objectives included safety according to the CTCAE 4.0 criteria. Patients aged ≥ 6 months and ≤ 40 years, with relapsed/refractory DSRCT were eligible after having received at least one previous poly-chemotherapy line; EwS must have received at least two standard chemotherapy lines. Prior taxane therapy was accepted. Central pathology review selected for tumors with > Grade 3 (intense and diffuse) expression of SPARC by immunohistochemistry to be eligible. Nab-paclitaxel was administered as follows: age ≥ 21 and ≤ 40 years: 125 mg/m2 days 1, 8 and 15 in cycles of 28 days; age ≥ 6 months and ≤ 20 years: 240 mg/m2 days 1, 8 and 15 in cycles of 28 days. A 30% ORR was anticipated with a sample size of 25 patients needed to test the hypothesis. Stopping rule was set at 1 response within the first 16 treated pts. If 5 or more successes were observed in 25 pts, the results of the trial will warrant further investigation. Results: Twenty-nine patients were enrolled from June 2017 until October 2019, 11 DSRCT and 18 EwS. Median age was 32 years (range 14-69), and 5 females and 24 males were included, having received a median of 3 previous systemic treatment lines. Patients received a median of 3 cycles of nab-paclitaxel (range 1-17). In the EwS cohort an ORR of 33.3% (all partial responses, median duration 2 months) and 16.7% of stabilizations were achieved. No objective responses were observed among DSRCT pts, but 27.3% of pts achieved a stabilization. Overall, median progression free survival was 2.8 months and median overall survival 12.1 months, with no significant differences between DSRCT and EwS cohorts. Most common grade 3 toxicities were neutropenia (20.7%) and diarrhea (10.3%). Conclusions: Single agent nab-paclitaxel in biomarker selected EwS patients, but not in DSRCT, provided clinically meaningful activity that deserves further development. Nab-paclitaxel had a manageable adverse event profile. Clinical trial information: 2016-002464-14.

A phase Ib/II study of selinexor in combination with imatinib in patients with advanced gastrointestinal stromal tumor (GIST): SeliGIST/GEIS-41 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11534-11534
Author(s):  
Cesar Serrano ◽  
Claudia Valverde ◽  
Josefina Cruz Jurado ◽  
Javier Martinez-Trufero ◽  
Xavier Guri ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Nuclear Export ◽  
Single Agent ◽  
Progression Free Survival ◽  
Antitumoral Activity ◽  
Clinical Activity ◽  
Activity Data ◽  
Phase Ib ◽  
Best Response ◽  
Heavily Pretreated

11534 Background: KIT or PDGFRA oncogenic activation drives GIST progression throughout the disease course. Accordingly, currently approved agents in metastatic GIST focus on the therapeutic suppression of these receptors. However, the clinical benefit after imatinib (IM) progression is still modest, suggesting the co-operation of KIT/PDGFRA-independent mechanisms in GIST cell survival. Selinexor is an oral, selective inhibitor of XPO1-mediated nuclear export, and preclinical studies evidenced antitumoral activity in GIST as single agent and in combination with IM in both IM-sensitive and IM-resistant models. Methods: The phase Ib portion studied IM 400 mg daily plus weekly selinexor in patients (pts) with IM-resistant, advanced GIST. Prior intolerance to IM was not allowed. A standard 3+3 dosing schema was utilized to determine the recommended phase II dose (RP2D) of this combination. Investigator-assessed response was evaluated every 8 weeks using RECIST 1.1. Results: At data cutoff of Sep 25, 2020, 12 pts were enrolled and received treatment with IM 400 mg and selinexor once weekly at dose levels (DL) 1 (60 mg), DL2 (80 mg) and DL3 (100 mg). Median age 57 (range 46-77), 42% female, median prior therapies 4 (range 2-7). Although only 1/6 pts developed a dose limiting toxicity (DLT) at DL3, the RP2D was defined at DL2 (IM 400 mg daily and selinexor 80 mg once weekly) based on activity data in the DL2 and the need for dose reductions in 5/6 pts at DL3 after the DLT window. All pts were evaluable for toxicity and response. One DLT occurred at DL3 (G3 nausea). Non-DLT G3/4 toxicities were anemia (1/12 pts), neutropenia (1/12 pts), vomiting (1/12 pts) and fatigue (2/12 pts). Common G1/2 toxicities were nausea (11/12 pts), vomiting (10/12 pts), neutropenia (5/12 pts) and anemia, fatigue, diarrhea, and periorbital edema (4/12 pts each). No unexpected toxicities were observed. Overall response rate in the 12 pts evaluable for response was 67% (95% CI 0.349-0.901), with 2 pts achieving PR (17%) and 6 pts SD (50%) as the best response. Clinical benefit rate (CBR = CR, PR, SD) ≥ 16 weeks was 42% (95% CI 0.157-0.723). Median progression free survival was 3.5 months (95% CI 1.7-7.3). Four pts remain on trial at data cutoff. Conclusions: IM and selinexor combination is well-tolerated and has clinical activity in heavily pretreated GIST pts. The trial is currently exploring selinexor as single agent in the IM-resistant GIST population. Clinical trial information: NCT04138381.

Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial

2007 ◽  
Vol 25 (12) ◽  
pp. 1545-1552 ◽  
Author(s):  
Ulrich Gatzemeier ◽  
Anna Pluzanska ◽  
Aleksandra Szczesna ◽  
Eckhard Kaukel ◽  
Jaromir Roubec ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Double Blind

Purpose Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL). Results A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild). Conclusion Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.

Tissue tumor mutational burden (TMB) as a biomarker of efficacy with immune checkpoint inhibitors (ICI) in metastatic gastrointestinal (mGI) cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14559-e14559
Author(s):  
Robert William Lentz ◽  
Tyler Friedrich ◽  
Junxiao Hu ◽  
Alexis Diane Leal ◽  
Sunnie S. Kim ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Retrospective Chart Review ◽  
Progression Free Survival ◽  
Predictive Biomarker ◽  
Continuous Variable ◽  
Tumor Type ◽  
Logistic Regression Models ◽  
Kaplan Meier ◽  
Academic Center

e14559 Background: While TMB is very dependent on methodology, tissue TMB-H (≥10 mutations/megabase) may predict benefit with ICIs. Pembrolizumab received tissue-agnostic approval for TMB-H unresectable cancers in 2020, but little is known about TMB as a predictive biomarker in mGI cancers. We hypothesized that tissue TMB will correlate with efficacy of ICIs in mGI cancers. Methods: A retrospective chart review identified patients with mGI cancers who received an anti-PD-(L)1 drug and had known TMB at a single academic center from 2012 to 2020. The association of TMB with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was analyzed using the Fisher’s exact and Log-rank tests. Survival curves were generated using the Kaplan-Meier method. Cox proportional hazard and logistic regression models were used to adjust for microsatellite status. Significance was prespecified at 0.05. Results: 83 patients were identified and included. The most common cancer types were colorectal adenocarcinoma (AC, n = 29), esophageal/gastric AC (n = 21) and SCC (n = 4), cholangiocarcinoma (n = 11), anal SCC (n = 7), and pancreas AC (n = 7). Average age was 61, average number of lines of prior systemic therapy for advanced disease was 1.3 (range 0-4), and 37% of patients were treated on a clinical study. All patients received an anti-PD-(L)1 drug; 6%, 2%, and 36% also received ipilimumab, cytotoxic chemotherapy, and other combinations, respectively. Among those with esophageal/gastric cancer, 76% had known PD-L1 CPS (84% ≥1, 63% ≥5, 42% ≥10). TMB was primarily determined by Foundation One CDx (87%). TMB ranged from 0 to 54; n = 22 (27%) were TMB-H (of these, n = 10 were microsatellite instability-high (MSI-H)), and n = 61 were TMB-L ( < 10 mutations/megabase; of these, n = 2 were MSI-H). The prevalence of TMB-H and microsatellite stable (MSS) was 14.4%. TMB-L, compared to TMB-H, was associated with inferior ORR (3.5% vs 55.6%; odds ratio (OR) 0.045; p < 0.001) and PFS (median 12.7 vs 29.3 weeks; hazard ratio (HR) 2.70; p = 0.001), but not OS (HR 1.20; p = 0.60). In patients with MSS disease, TMB-L, compared to TMB-H, was associated with inferior ORR (OR 0.13; p = 0.04) but not PFS (HR 1.76; p = 0.07) or OS (HR 0.89; p = 0.79). In subgroup analyses, ORR was not significantly associated to tumor type in all or MSS patients. TMB as a continuous variable, in patients with MSS disease, was positively correlated with ORR (p = 0.02) and PFS (p = 0.04), but not OS (p = 0.59). Among all patients, PFS and OS data is immature (median follow-up 13 and 31 weeks). Conclusions: In a single center retrospective study of patients with mGI cancers treated with ICIs, TMB-H was associated with improved ORR and PFS compared to TMB-L. In patients with MSS disease, ORR remained significant. PFS and OS data are immature. TMB as a biomarker of efficacy with ICIs in mGI cancers warrants further study to guide clinical use.

scholarly journals No Correlation between KRAS Status and Advanced Pancreatic Adenocarcinoma Survival

2017 ◽  
Vol 6 (2) ◽  
pp. 45 ◽  
Author(s):  
Misato Ogata ◽  
Hironaga Satake ◽  
Takatsugu Ogata ◽  
Yukihiro Imai ◽  
Yukimasa Hatachi ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Growth Factor Receptor ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Predictive Biomarker ◽  
First Line ◽  
Kras Mutations ◽  
Kras Status ◽  
The Impact

Erlotinib plus gemcitabine is one of the standard chemotherapies for unresectable pancreatic cancer. Pancreatic cancer has the highest frequency of KRAS gene mutations among human cancers, and some studies suggest that KRAS status might be a predictive biomarker for anti-epidermal growth factor receptor treatment. However, the reliability of this biomarker has not been confirmed. Here, we evaluated the impact of KRAS mutations in pancreatic cancer patients treated with first line gemcitabine-based chemotherapy. 23 patients treated with gemcitabine-based chemotherapy whose KRAS status could be examined from primary or metastatic lesions were enrolled. KRAS mutations were analyzed by sequencing codons 12 and 13. We retrospectively evaluated the correlation between KRAS status, and prognosis and treatment efficacy. Patient characteristics were as follows: median age 68 years, male/female=6/17, PS 0/1=9/14, TNM stage III/IV=1/22, and gemcitabine alone/erlotinib plus gemcitabine=13/10. Among the 23 patients, KRAS codon 12 was mutated in 15, one of whom also had mutation on codon 13. Median progression-free survival (PFS) and overall survival (OS) of all patients were 4.3 months (95% confidence interval (CI): 3.1 to 5.4) and 8.1 months (95% CI: 5.9 to 10.0; events in 96%), respectively. KRAS status showed no association with PFS (p=0.310), OS (p=0.934), or the efficacy of treatment with (p=0.833) or without erlotinib (p=0.478). Thus, in this study, there was no correlation between KRAS status and the efficacy of first line chemotherapy with gemcitabine with or without erlotinib. Identification of a rationale for personalized medicine in pancreatic cancer will require further exploratory prospective studies.

Roar: A Phase Ib Trial of Oral Azacitidine (CC-486) in Combination with Lenalidomide and Dexamethasone (Rd) for Patients with Relapsed and/or Refractory (R/R) Multiple Myeloma Who Have Failed a Prior Lenalidomide-Containing Regimen

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2121-2121
Author(s):  
Anna Kalff ◽  
Kate Reed ◽  
Tiffany T. Khong ◽  
Sridurga Mithraprabhu ◽  
Malarmathy Ramachandran ◽  
...  
Keyword(s):  
Median Time ◽  
Dna Methyltransferase ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Employment Equity ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Best Response ◽  
Equity Ownership ◽  
Pre Treatment

Abstract Introduction Azacitidine (AZA) is a DNA methyltransferase inhibitor and cytotoxic agent with survival benefits in higher-risk MDS and AML. We have demonstrated that AZA rapidly induces apoptosis of MM cells, and induces synergistic killing when combined with lenalidomide (LEN). This, coupled with development of an oral AZA formulation (CC-486), provides rationale for pursuing this combination in MM. The cereblon [CBRN]-Ikaros/Aiolos-IRF4/c-MYC signalling pathway has been implicated in the mechanism of action of cytotoxicity for IMiD®compounds. This pathway, as well as immune markers (CD8, PD-1) may represent potential biomarkers for predicting outcomes/response to IMiD® compounds. Aims: In R/R myeloma patients who previously failed a LEN-containing regimen: to determine the maximum tolerated dose (MTD) of CC-486 in combination with Rd; to characterise safety/tolerability; to assess efficacy: overall response rate (ORR), progression free survival (PFS), overall survival (OS). To correlate pre-treatment MM protein expression (CRBN, Ikaros, Aiolos, IRF4, c-MYC), as well as whole marrow expression of CD8/PD-1 with response and survival (PFS/OS) in patients receiving CC-489 plus Rd. Methods: Phase Ib, single centre, 3 x 3 dose escalation study. LEN 25mg d1-21 and dexamethasone 40mg d1, 8, 15, 22 of 28 day cycle were combined with escalating doses of CC-489: initial dose 100mg for d1-14, increasing by either 7 days or 50mg/cohort, to a maximum of 200mg d1-21. Dose limiting toxicity (DLT) was assessed during cycle 1. Treatment continued until toxicity/progression. Single- and dual-IHC assays were performed on pre-treatment trephines (Single: CD8, PD-1; Dual: CD138 paired with CRBN, Aiolos, Ikaros, IRF4, c-MYC). In samples with >10% CD138, presence and sub-cellular localisation of each stain was documented, and given an H score: product of % of tumour positive and intensity of staining (0-3). Single CD8 and PD-1 IHC assays were reported as positive cells/mm2. Samples were grouped according to quartiles (Group1: lower quartile, Group2: mid-range, Group3: upper quartile) and analysis was performed using SAS statistical platform v9.4. Results: 22 patients commenced therapy (F=10, M=12), median age 67yrs (50-82yrs). Median prior lines of therapy: 5 (2-8), including 16 ASCT and 2 prior allogeneic transplant. All had failed LEN (R/R=18, primary refractory (PrimR)=4), 10/22 received and failed pomalidomide (POM) (R/R=4, PrimR=6). All had received bortezomib (R/R=10, PrimR=10), 18/22 were both bortezomib and LEN refractory. CC-486 dose reached was 200mg d1-21, with no DLTs observed at time of reporting. One patient died due to unrelated causes prior to end cycle 1, therefore was not evaluable for response. ORR (≥PR) was 43% (9/21): 8 PR, 1 VGPR. Of the remaining patients, 2 achieved MR, 5 SD, and 5 PD. (clinical benefit rate (≥MR) = 52%). Median time to best response in patients with ≥MR: 2.5m (1-3.7m). Responses were seen in cohorts: [100mg d1-14 (3PR=3), 100mg d1-21 (VGPR=1, PR=3), 150mg d1-21 (PR=2, MR=2)]. Median time on study: 3m; responders (≥MR): 6.3m (2.5-15m), non-responders: 1.7m (0.9-8m). Median PFS 3m, median OS 15m. One patient remains on study. 3/6 patients treated with LEN in prior 1-2 treatment lines responded (PR=2, VGPR=1), 1/6 had SD. 1/10 patients treated with POM in prior 1-2 treatment lines responded (PR), with 2 achieving MR and 3 SD. Patients with a lower expression of cMYC and IRF4 had superior PFS compared with patients with higher expression (cMYC: Group1 vs Group3 p=0.052; IRF4: Group1 vs Group2 p=0.04). Patients with lower numbers of CD8+ T-cells had better PFS than those with higher (p=0.069). There was no association between degree of expression of CBRN, Ikaros, Aiolos or PD-1 and survival (PFS/OS). As CRBN expression increased, patients were more likely to respond (≥PR) (p=0.07) and patients with low PD-1 expression were more likely to respond (≥ MR) (Group1 vs Group3 p=0.05). Conclusion CC-489 combined with Rd is well tolerated and effective with durable responses in a subset of heavily pre-treated R/R MM patients, including those who recently failed IMiD® compound therapy, suggesting that CC-489 may overcome drug resistance. IHC may have utility in identifying subsets of patients more likely to respond to CC-489 and Rd (CRBN, PD-1) and predict survival (cMYC, IRF4 and CD8). This trial has been expanded to include other sites and less heavily pre-treated patients. Disclosures Thakurta: Celgene: Employment, Equity Ownership. Wang:Celgene: Employment. Guzman:Celgene: Employment. Cuoto:Celgene: Employment. Ren:Celgene: Employment, Equity Ownership.

Randomized phase II trial of two dose schedules of carboplatin/paclitaxel/cetuximab in stage IIIB/IV non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7586-7586 ◽  
Author(s):  
M. N. Saleh ◽  
M. A. Socinski ◽  
D. Trent ◽  
T. Dobbs ◽  
L. M. Zehngebot ◽  
...  
Keyword(s):  
Phase Ii ◽  
Survival Data ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Stage Iiib ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Igg1 Monoclonal Antibody ◽  
Epidermal Growth

7586 Background: Cetuximab, an IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR) on both normal and tumor cells, has been investigated in advanced NSCLC as a single agent and in combination with chemotherapy. This ongoing randomized phase II open-label trial evaluates cetuximab in combination with carboplatin (Cb) and paclitaxel (Pac) when given in two dose schedules to patients (pts) with previously untreated stage IIIB/IV NSCLC. Methods: Eligible pts were randomized to 1 of 2 treatment arms. Cetuximab treatment was identical in both arms: 400 mg/m2 IV on day 1 and 250 mg/m2 weekly thereafter. Beginning on day 8, a schedule of Cb AUC=6 IV and Pac 225 mg/m2 IV given on a 3-week cycle was compared with a schedule of Cb AUC=6 IV q4 weeks and Pac 100 mg/m2 IV given weekly for 3 weeks of each 4-week cycle. Pts who achieve CR, PR, or SD after 4 cycles may continue weekly cetuximab monotherapy until disease progression or unacceptable toxicity. The primary objectives were to estimate median progression-free survival (PFS) and the PFS rate at 6 months. Secondary objectives included response rate. Results: The study has completed accrual, with 168 pts randomized and 165 treated. Data are available for 164 pts and confirmed responses for 155 pts. Conclusions: Cetuximab combined with Cb and Pac in both dose schedules demonstrated activity and an acceptable toxicity profile in pts with NSCLC. Final PFS and overall survival data are pending. No significant financial relationships to disclose. [Table: see text]

Phase I study of AMG 479, a fully human monoclonal antibody against the type 1 insulin-like growth factor receptor (IGF-1R), in Japanese patients (pts) with advanced solid tumors.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 318-318 ◽  
Author(s):  
T. Doi ◽  
N. Fuse ◽  
T. Yoshino ◽  
H. Murakami ◽  
N. Yamamoto ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Solid Tumors ◽  
Human Monoclonal Antibody ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Japanese Patients ◽  
Advanced Solid Tumors ◽  
Serious Adverse Events ◽  
Best Response ◽  
Grade 3

318 Background: AMG 479 is a fully human monoclonal antibody against human IGF-1R that inhibits the survival and proliferative signals driven by IGF-1 and -2. Methods: Patients (Pts) were enrolled into 1 of 3 dose cohorts (6, 12 or 20 mg/kg) of single-agent AMG 479 administered intravenously Q2W. Dose-limiting toxicity (DLT) was assessed for the first 28 days. The primary objectives were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 479 in Japanese pts with advanced solid tumors. An exploratory pharmacodynamic (PD) analysis was done to investigate the relationship between exposure and changes in the level of circulating factors in IGF-1R pathway (IGFBP-3 and total IGF-1). Results: Nineteen pts with ECOG 0-1 (6 in cohort 1 and 3, 7 in cohort 2) received at least 1 dose of AMG 479. Median age was 58.0 years. Tumor types included: breast (4), gastric (3), rectal (2), NSCL (2), thymic (2), and other cancers (6). Enrollment has been completed; 5 pts remained on study as of 15 March 2010. No DLTs were observed. Three serious adverse events (SAE) were reported, only respiratory tract haemorrhage in a subject with thymic carcinoma was considered by the investigator to be related to AMG 479. The most common grade ≥3 AEs were neutropenia (21%), leukopenia (16%) and lymphopenia (11%). There was a trend of dose-dependency on severity of thrombocytopenia, but not on that of neutropenia. No neutralizing anti-AMG 479 antibodies were detected. PK was dose-linear and similar to PK in non-Japanese pts. Tumor response data were available for 17 pts. Stable disease (defined as a lack of progression at the first 8-week assessment) as best response was reported in 6 pts and progressive disease was reported in 11 pts. Exploratory PD marker analysis demonstrating exposure dependent changes will be presented. Conclusions: AMG 479 up to 20 mg/kg was tolerable in Japanese pts with advanced solid tumors. The AE and PK profiles were similar to those previously observed in non-Japanese pts. An international phase 3 study in metastatic pancreatic cancer pts is planned based on the promising results from phase 1b/2 study (ASCO 2010, Abs 4035). [Table: see text]

RAS mutations and their correlation with survival of patients with advanced pancreatic adenocarcinoma.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 325-325
Author(s):  
Thiago Lins Almeida ◽  
Jessica Ribeiro Gomes ◽  
Marcel Cerqueira Cesar Machado ◽  
Antonio C. Buzaid ◽  
Fernando C. Maluf
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Predictive Factor ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Prognostic Impact ◽  
Free Survival ◽  
First Line Therapy ◽  
Ras Status ◽  
Epidermal Growth

325 Background: The prognosis of pancreatic adenocarcinoma (PA) remains poor despite FOLFIRINOX and nab-paclitaxel-gemcitabine based chemotherapy. The epidermal growth factor receptor (EGFR) has a major role in pancreatic cancer carcinogenesis.The RAS status showed to be a predictive factor for response to anti-EGFR therapy in colon cancer. We aim to analyze the K-RAS and N-RAS status in PA and its prognostic impact. Methods: Retrospective analysis included 24 patients with metastatic (67%) or locally advanced (29%) PA at diagnosis (AEMOC, Brazil). K-RAS and N-RAS profile were performed by polymerase chain reaction and bidirectional sequencing (codons 12, 13, 61, 117, 146). The results were then analyzed in regards to overall survival (OS) and progression-free survival (PFS) in PA. Results: The sample showed: median age of 63 years (28-86), 62.5% male, 45.8% smoker, head site (67%), ductal (68%), and mild differentiation features (45%). The first-line therapy was FOLFIRINOX (62.5%) and gemcitabine (33.3%). The median PFS and OS were 6.5 and 13 months (mo), respectively. Nineteen patients (79.1%) presented mutation in K-RAS: four c.35G>A (G12D), four c.34G>C (G12R), four c.35G>T (G12V), three c.35G>C (G12A), one c.437C>T (A146V), and one c.34G>T (G12C). Mutation in N-RAS (c.38G>A (G13D) was detected in only one patient (4%). The only independent factor for survival was K-RAS status: the c.35G>A (G12D) polymorphism yielded worse PFS and OS when compared to non-c.35G>A (G12D) mutation: 3 vs 7 mo [HR 0.25, 95% CI, (0.04–1.63)] for PFS (p<0,0043) and 3.5 vs13 mo [HR 0.17, 95% CI, 0.01-1.58)] for OS (p<0,0001), respectively. Conclusions: K-RAS was the only prognostic factor for PFS and OS, with the polymorphism c.35G>A (G12D) being related to a worse prognostic. Further studies are necessary to better evaluate whether K-RAS and N-RAS status is prognostic and/or predictive factor.

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