bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacodynamic biomarker-driven trial of MK-2206, an AKT inhibitor, with AZD6244 (selumetinib), a MEK inhibitor, in patients with advanced colorectal carcinoma (CRC).
Authors: Speranza Giovanna , Kinders Robert J. , Khin Sonny , Weil Marcie K. , Do Khanh Tu , Horneffer Yvonne , Juwara Lamin , Allen Deborah , Williams P. Mickey , Lih Chih Jian , Rubinstein Larry , Doyle Laurence A , Doroshow James H. , Kummar Shivaani 
Published: March 2020

3529 Background: The RAF/MEK/ERK and PI3K/AKT signaling pathways are commonly deregulated in CRC. Each can serve as a compensatory mechanism mediating resistance to single pathway blockade. Combined inhibition with MK-2206 and selumetinib (AZD6244) could enhance antitumor activity. Tolerable doses for the combination in solid tumors (ASCO 2011, abstr 3004) are less than single agent MTDs. We conducted a biomarker driven trial of MK-2206 and selumetinib at the established combination doses to determine extent of pERK and pAKT inhibition in tumor biopsies (bx), using new, clinically validated immunoassays for pERK and pAKT. Methods: Patients (pts) with advanced CRC, refractory to standard therapy, ECOG ≤ 2, adequate organ function, and disease amenable to bx were treated with oral MK-2206, 90 mg QW and selumetinib, 75 mg daily, stratified for KRAS mutation status (+ or WT). For each strata, pAKT and pERK levels from paired tumor bx, baseline and 3-6 hrs post-dose in 3 pts each on C1D1 or C1D22, were measured using a quantitative, chemiluminescence immunoassay (dilution linearity R2 = 0.985 pERK, 0.995 pAKT; % CV at 0 < 6). 70% inhibition was considered biologically significant based on levels observed in preclinical models that demonstrated antitumor activity. Results: 11 pts enrolled to date (KRAS +, 6 pts; WT, 5 pts). 2/9 pts had SD after 2 cycles. Gr 1/ 2 toxicities: rash, reversible retinal detachment, liver abnormalities, hypoalbuminemia, lymphopenia. Target protein inhibition data are available for 8 paired bx samples (Table). Conclusions: Although 4/8 pts demonstrated biologically significant inhibition in one marker, at the MTD for this combination no pt had ≥ 70% inhibition of both targets. If repeated dosing does not produce the desired inhibition of pERK and pAKT, we will conclude that the dose reductions for each agent necessitated by the toxicity of the agents used in combination preclude the possibility of providing adequate dual pathway inhibition. Loss of PTEN and DNA mutation analyses (KRAS, BRAF, PIK3Ca, AKT) are planned. [Table: see text]
Overall survival (OS) of advanced colorectal cancer (aCRC) patients (pts) treated with the multipeptide vaccine IMA910: Results of a matched-pair analysis with arm C pts from COIN.
Authors: Maughan Tim , Adams Richard A. , Mayer-Mokler Andrea , Nowara Elzbieta , Torday Laszlo , Cseh Jozsef , Hoehler Thomas , Hitre Erika , Folprecht Gunnar , Fisher David , Ludwig Joerg , Roessler Bernhard , Kuttruff Sabrina , Walter Steffen , Hilf Norbert , Schoor Oliver , Weinschenk Toni , Singh Harpreet , Reinhardt Carsten , Mayer Frank 
Published: March 2020

3530 Background: IMA910 is a novel cancer vaccine consisting of 10 class I and 3 class II tumor-associated peptides (TUMAPs), naturally presented on HLA molecules of CRC. Vaccine-induced immune responses are associated with prolonged OS of renal cell carcinoma pts treated with IMA901, a multi-peptide vaccine identified by the same antigen discovery platform. Methods: 92 HLA-A*02+ aCRC pts with stable or responding disease after 12 weeks of first-line oxaliplatin-based therapy were enrolled in this phase I/II trial. After immunomodulation with cyclophosphamide (300 mg/m2) to reduce regulatory T cells, pts were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF without (cohort 1; n=66) or with (cohort 2; n=26) topically applied imiquimod. Safety and PFS data was recently presented [Mayer et al., ASCO-GI 2012]. OS of IMA910 pts was compared to matched pts from arm C (intermittent chemotherapy) of the COIN trial [Adams et al., Lancet Oncology 2011]. Matching was performed in a prospectively defined, fully blinded fashion based on a propensity score involving all available prognostic factors. T-cell responses to individual IMA910 peptides were analyzed by HLA multimer and intracellular cytokine assays. Results: At a median follow up of 1.7 yrs, OS of IMA910 vaccinated pts was significantly longer in comparison to 1:1 matched HLA-A*02+ COIN pts (HR 0.675, 95% CI 0.458-0.995, p=0.047; 1 yr OS: 69% vs 55%; 2 yr OS: 40% vs 24%). Multi-TUMAP responders (≥2 CD8+ and ≥2 CD4+ vaccine-induced T cells) had a significantly longer OS (HR 0.45, p=0.04) compared to matched COIN pts while non-multi-TUMAP responders showed similar OS compared to matched COIN pts (HR 0.76, p=0.22). Conclusions: OS of IMA910 pts was significantly longer in comparison to matched COIN pts with separation of survival curves at ~9 months and increasing OS difference over time. Multi-TUMAP immune responders had a significantly longer OS compared to non-multi-TUMAP responders and compared to matched COIN pts. These clinical and immune response data strongly suggest clinical activity of IMA910 in 1st line CRC pts and warrant further development.
Molecular analysis of the randomized phase II/III study of the anti-IGF-1R antibody dalotuzumab (MK-0646) in combination with cetuximab (Cx) and irinotecan (Ir) in the treatment of chemorefractory KRAS wild-type metastatic colorectal cancer (mCRC).
Authors: Watkins David J. , Ayers Mark , Cunningham David , Tabernero Josep , Tejpar Sabine , Kim Tae-You , Kim Tae Won , Kim Sun Young , Roh Jae Kyung , Beale Philip James , Park Young Suk , Guren Tormod Kyrre , Loboda Andrey , Nebozhyn Michael , Mogg Robin , Lunceford Jared , Schmidt Emmett V. , Brown Holly M. , Sathyanarayanan Sriram , Mauro David J. 
Published: March 2020

3531 Background: Previously reported results of this randomized study demonstrated that the addition of dalotuzumab (Dz) worsened the PFS and OS of chemofractory mCRC patients receiving Cx and Ir (Watkins et al; ASCO 2011). Comprehensive molecular analysis has been undertaken retrospectively to identify possible predictors of Cx resistance and Dz response. Methods: Quantitative RT-PCR for IGF-1, IGF-2, immunohistochemistry for IGF-1R and microarray expression profiling was conducted on archival tumor tissue. All patients had received Cx and Ir with either placebo (n=107), weekly Dz (n=112), or 2 weekly Dz (n=110). Results: Data from 292 and 206 patients was successfully obtained by RT-PCR or microarray respectively. Within the placebo arm, high IGF-1 expression was found to be associated with resistance to Cx (IGF-1-/IGF-1+; PFS 6.7/3.7 months, OS 15.5/9.6 months). High IGF-1 expression was associated with benefit from the addition of weekly Dz (placebo/weekly Dz; PFS 3.7/5.7 months, OS 9.6/18.2 months). By contrast the addition of Dz was not effective in tumors with high IGF-2 expression (placebo/weekly Dz; PFS 8.4/2.7 months). Microarray analysis revealed distinct populations that differentially correlated with Cx and Dz response. An epithelial phenotype appeared more associated with Cx response, whereas a mesenchymal phenotype more associated with Dz response. Rectal cancers showed greater association with increased IGF-1 expression, EMT gene signature and Dz response. Conclusions: These data support IGF-1 and IGF-2 as potential biomarkers for response to Dz therapy and high IGF-1 as a marker of resistance to Cx therapy. Based on these data Dz is being further evaluated in a molecularly selected population of mCRC. [Table: see text]
Final results of study 20050181: A randomized phase III study of FOLFIRI with our without panitumumab (pmab) for the second‑line treatment (tx) of metastatic colorectal cancer (mCRC).
Authors: Sobrero Alberto F. , Peeters Marc , Price Timothy Jay , Hotko Yevhen , Cervantes-Ruiperez Andres , Ducreux Michel , Andre Thierry , Chan Emily , Lordick Florian , Tian Ying , Sidhu Roger 
Published: March 2020

3535 Background: The primary analysis of study 20050181 showed that in patients (pts) with wild-type (WT) KRAS mCRC, pmab plus FOLFIRI given as second-line therapy significantly improved progression-free survival (PFS) vs FOLFIRI alone. Here, we report on a prespecified descriptive analysis planned for 30 months (mos) after the last pt was enrolled. Methods: Pts with mCRC, ECOG 0-2, who had one prior fluoropyrimidine-based chemotherapy regimen were randomized 1:1 to pmab 6.0 mg/kg Q2W+FOLFIRI (Arm 1) vs FOLFIRI (Arm 2). Co-primary endpoints were OS and PFS (central assessment). Secondary endpoints included objective response rate (ORR) and safety. Tumor KRAS status was determined by a blinded central lab. Results: 1186 pts were randomised and received tx: 591 in Arm 1, 595 In Arm 2. 1083 pts (91%) had KRAS results. Adverse event rates were consistent with the primary analysis. Results are shown below. Conclusions: In pts with WT KRAS mCRC receiving pmab+FOLFIRI vs FOLFIRI, PFS and ORR were significantly improved, and there was a trend toward improved OS. Post-progression anti-EGFR tx may have attenuated any significant difference in OS between tx arms. In pts with MT KRAS mCRC, no difference in efficacy was observed between tx arms. KRAS testing is critical to select appropriate pts for tx with pmab. [Table: see text]
Patterns of chemotherapy (CT) use in a U.S.-wide population-based cohort of patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Abrams Thomas Adam , Meyer Gary , Moloney Julie , Meyerhardt Jeffrey A. , Schrag Deborah , Fuchs Charles S. 
Published: March 2020

3537 Background: Few population studies have examined treatment regimens and duration in mCRC since the introduction of biologic therapies in 2004. Methods: We assessed 4,877 consecutive mCRC pts who received CT between Jan 2004 and Mar 2011 at academic, private, and community hospital-based practices participating in a US-wide CT order entry (COE) system that captures patient demographics, stage and treatment data. Multivariate analyses of prospectively recorded patient and provider characteristics identified significant predictors of specific therapeutic approaches. Results: Among all pts, median age was 64; 55% male; (ECOG PS 0/1/2+) (56%/33%/11%). In first-line CT, 17% of pts received fluoropyrimidine (FU) only, while 16% received FU and irinotecan and 65% received FU and oxaliplatin. Older pts, those with poorer ECOG PS, and those treated in private practices were significantly more likely to receive FU only (all p ≤0.05). 53% of all pts received treatment in line 2, 28% in line 3, and 13% in line 4. Mean duration of treatment was 170 days (line 1), 139 (line 2), 135 (line 3) and 126 (line 4). Bevacizumab (bev) was administered to 65% of pts at some point in their treatment. Among the 51% who received bev in line 1, 33% continued bev beyond progression (BBP) in line 2. Pts treated at academic centers, pts who received longer duration of line 1 therapy, and pts whose providers had greater CRC pt volume were significantly more likely to continue BBP. Overall, 23% of pts received cetuximab (cet) (4% of all line 1 pts, 17% of line 2, 31% of line 3, and 29% of line 4). Mean duration of cet use was 168 days (line 1), 125 (line 2), 133 (line 3) and 129 (line 4). Pts treated at academic centers, pts who received longer duration of line 1 therapy, and pts treated in the West US were significantly more likely to ever receive cet. Cet use decreased by 18% following FDA label change restricting use to KRAS wt pts in Jun 2009 (p <0.001). Of all pts, 6% received panitumumab at some point. Of those, 39% had previously received cet. Conclusions: This population-based study provides insight into treatment patterns of mCRC in the US. Usage of biologic agents varies significantly according to patient, practice, and provider characteristics.
Utilization and outcomes of primary tumor surgery for stage IV colon cancer in the United States: A population-based study.
Authors: Sada Yvonne , Duan Zhigang , El-Serag Hashem , Davila Jessica 
Published: March 2020

3542 Background: Stage IV colon cancer treatment may include resection of the primary tumor. Current use of primary tumor surgery (PTS) in clinical practice is unknown. This study examined utilization and determinants of PTS and evaluated its effect on survival. Methods: Using national Surveillance, Epidemiology, and End Results registry data, stage IV colon cancer patients diagnosed from 1998-2008 were identified. Data on demographics, PTS, and tumor features were collected. Temporal changes in receipt of PTS were examined over 3 periods (1998-2000, 2001-2004, 2005-2008). Multiple logistic regression was used to identify significant determinants of PTS. 1- and 3-year cancer-specific survival was calculated in PTS and non-PTS patients. Cox proportional hazards models examined the effect of PTS on mortality risk. Results: 16,029 patients were identified. Median age was 69 (IQR: 57-78), and 50% were male. Approximately 67% of patients received PTS. Receipt of PTS significantly declined from 72% in 1998-2000 to 68% in 2001-2004, and 63% in 2005-2008 (p<0.01). Results from the logistic regression analysis showed that patients who were younger, white, married, had right sided cancer and higher tumor grade were more likely to receive PTS (all p<0.01). The 1- and 3-year survival was higher in patients who received PTS compared with those who did not (1-year: 55% (95% CI: 54-56) vs. 24% (95% CI: 23-26); 3-year: 19% (95% CI: 19-20) vs. 4% (95%CI: 3.4-4.9)). Adjusted for demographics and tumor features, risk of mortality was 54% (HR=0.46; 95% CI: 0.44-0.48) lower in patients who received PTS than those without PTS. Recent year of diagnosis (HR=0.88; 95% CI: 0.75-0.80) and being married (HR=0.90, 95% CI: 0.86-0.95) were associated with lower mortality. Older age (HR=1.48; 95% CI: 1.39-1.56), black race (HR=1.09; 95% CI: 1.03-1.15), right sided cancer (HR=1.21; 95% CI: 1.17-1.26), and poorly differentiated tumors (HR= 1.62; 95% CI: 1.46-1.80) were associated with increased mortality. Conclusions: PTS utilization for stage IV colon cancer has significantly declined, yet survival was higher in patients who received PTS. However, these findings are limited by the absence of co-morbidity and chemotherapy data.
Effect of bevacizumab on rate of oxaliplatin-induced thrombocytopenia and splenomegaly.
Authors: Raghav Kanwal Pratap Singh , Kalil Karime , Ferrarotto Renata , George Binsah , Eng Cathy , Garrett Chris R. , Loyer Evelyn , Hoff Paulo , Charnsangavej Chusilp , Kopetz Scott , Overman Michael J. 
Published: March 2020

3544 Background: Oxaliplatin-based chemotherapy can cause hepatic sinusoidal injury (HSI) leading to portal hypertension. This results in splenic sequestration of platelets and thrombocytopenia. Evidence suggests that bevacizumab may protect against HSI, although the clinical impact of this has not been well examined. The purpose of our study was to evaluate rate of thrombocytopenia and splenomegaly as clinical end-points indicative of bevacizumab mediated modulation of oxaliplatin-induced hepatic toxicity. Methods: We performed a retrospective review of metastatic colorectal cancer patients treated at M D Anderson Cancer Center from 1/2003 to 1/2010 with ≥ 3 months of frontline fluoropyrimidine and oxaliplatin (FOLFOX) with or without bevacizumab. Patients with prior liver disease, liver surgery or absence of spleen were excluded. Splenic volumes pre, during and post FOLFOX therapy were determined with CT scans and correlated with platelet counts and treatment. Results: A total of 184 patients [Bev cohort: FOLFOX/Bev (n =138); Non-Bev cohort: FOLFOX alone (n = 46)] were identified. Baseline characteristics (age, gender, spleen size and platelet counts) were similar in both groups. Median number of oxaliplatin cycles for each cohort was 9.00 (p = 0.9). The median total oxaliplatin dose did not differ between the two cohorts (p = 0.9). Development of splenomegaly (volume increase ≥ 30%) was more common in the Non-Bev cohort (48% vs. 32%; p = 0.013). The median time to develop splenomegaly was significantly longer in the Bev cohort (7.6 vs. 5.5 months; p = 0.023). Splenomegaly correlated with a higher rate of thrombocytopenia (defined as platelets < 150K) at 3 months (40% vs. 16%, p = 0.0005) and beyond (during 3 to 6 months of treatment, p < 0.0001). Correspondingly, bevacizumab therapy was associated with lower rates of thrombocytopenia at 3 months (24% in Bev cohort vs. 43% in Non-Bev cohort, p = 0.006) and beyond (p = 0.003). Conclusions: In our cohort, addition of bevacizumab to oxaliplatin chemotherapy reduces the occurrence of splenic enlargement, which correlates with a decreased rate of thrombocytopenia. Further studies to understand the potential hepato-protective mechanism of anti-VEGF therapy are needed.
First European phase II trial of intravenous (iv) cetuximab (Cet) and hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin in patients with unresectable liver metastases from wt KRAS colorectal cancer (CRC) after systemic therapy failure (OPTILIV, NCT00852228).
Authors: Levi Francis , Ducreux Michel , Hebbar Mohamed , Rougier Philippe , Focan C. N. J. , Guimbaud Rosine , Carvalho Carlos , Tumolo Salvatore , Innominato Pasquale F. , Ajavon Yves , Castaing Denis , De Baere Thierry , Karaboué Abdoulaye , Lepere Celine , Boige Valerie , Proux Laetitia , Adam Rene , Bouchahda Mohamed ,   on behalf of ARTBC International
Published: March 2020

3547 Background: HAI of chronomodulated (Chrono) irinotecan (I), 5-Fluorouracil (F) and oxaliplatin (O), or flat O combined with iv F-leucovorin allowed secondary metastases resections and prolonged survival in patients (pts) with CRC liver metastases despite prior chemotherapy failure (Bouchahda, Cancer 2009; Goere, Ann Surg 2010). Purpose: To prospectively evaluate safety and efficacy of combining iv Cet with HAI of IFO in pts with CRC liver metastases. Methods: This Phase II trial involved previously treated pts with unresectable CRC liver metastases. Pts received iv Cet (500 mg/m²) and Chrono or conventional HAI of I (180 mg/m²), F (2800 mg/m²), and O (85 mg/m²) q2 weeks. Liver metastases were resected if adequately downstaged. Results: Planned accrual of 60 pts was reached on 01/24/2012. 3 pts were not treated, 9 are ongoing. 48 consecutive treated pts (18F, 30 M; aged 32-76 years) are fully assessed and monitored. They had PS 0-1 (98%), bilobar liver lesions (69%), a median of 8 metastases (1-50; largest diameter, 57 mm – 15-172). Prior chemotherapy involved one (43%), or two or three (57%) lines. A median of 5 protocol courses (1-13) was given. Main grade 3-4 toxicities per pt were neutropenia (40%), abdominal pain (15%), fatigue (15%), nausea (15%), diarrhea (13%) and sensory neuropathy (4%). Objective response rate was 44% [30-58], with 6% radiological complete responses. Disease control rate was 85%. Secondary liver surgery was performed in 15 pts (31.3%).One pt with 25 metastases (1-6 cm) in all liver segments had pathologic complete response in 24 lesions removed through three-stage hepatectomy. She currently has an off treatment disease-free survival of 17+ months.With a follow up of 4 to 47 months, median progression-free survival is 14.2 months [9.7-18.8], 1- and 2-year survival rates are 92.8% and 59.2% respectively. Conclusions: OPTILIV offers a safe and unusually effective treatment option for patients with CRC liver metastases after failure of systemic chemotherapy within a coordinated medico-surgical strategy.
Plasma concentrations of YKL-40 in chemo-naive patients with metastatic colorectal cancer treated with FLOX with or without cetuximab: Results from the NORDIC VII study.
Authors: Tarpgaard Line Schmidt , Guren Tormod Kyrre , Glimelius Bengt , Pfeiffer Per , Kure Elin , Yilmaz Mette K. N. , Sorbye Halfdan , Keldsen Nina , Skovlund Eva , Johansen Julia S. , Tveit Kjell Magne 
Published: March 2020

3548 Background: KRAS status is presently the best biomarker to select patients with metastatic colorectal cancer (mCRC) for therapy with EGFR inhibition even though not confirmed in all phase III studies. In the NORDIC VII study a survival benefit of adding cetuximab to the Nordic FLOX regimen could not be confirmed. Identification of new predictive and prognostic biomarkers is essential. Plasma concentration of YKL-40 is emerging as a new biomarker in patients with cancer and inflammatory diseases. We tested the hypothesis that high plasma YKL-40 associates with short progression free survival (PFS) and short overall survival (OS) in patients included in the NORDIC VII Study. Methods: 566 patients with mCRC were randomized to: A) Nordic FLOX; B) FLOX + cetuximab; and C) FLOX for 16 weeks + cetuximab continuously. Plasma samples were available from 510 patients (90%). Pretreatment plasma YKL-40 was determined by ELISA (Quidel), and the plasma YKL-40 concentration was dichotomized according to the age-corrected 95% YKL-40 level in 3130 healthy subjects. Results: Plasma YKL-40 was elevated in 204 patients (40%) and the median plasma YKL-40 was higher in the study group compared to healthy subjects (120 mg/l vs. 40 mg/l, p<0.001). Elevated plasma YKL-40 was associated with short PFS (HR=1.25, 95% CI 1.04-1.51, p=0.02). This relationship was demonstrated only in patients treated with FLOX chemotherapy alone (HR=1.42, 1.02-1.98, p=0.04). High plasma YKL-40 was associated with short OS in all patients (HR=1.55, 1.25-1.92, p<0.001) and in the different treatment groups (A: HR=1.54, 1.05-2.26, p=0.03; B: HR=1.40, 0.97-2.01, p=0.07; C: 1.79, 1.23-2.60, p=0.002). Multivariate analysis (YKL-40, performance status, number of metastatic sites) demonstrated that elevated plasma YKL-40 was an independent biomarker of short OS (HR=1.46, 1.17-1.81, p=0.001). Conclusions: Plasma YKL-40 may be a new prognostic biomarker in patients with mCRC treated with 1st line FLOX chemotherapy, with or without cetuximab. The predictive value of plasma YKL-40 is not yet clarified.