bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of temsirolimus (CCI-779), carboplatin, and paclitaxel in patients (pts) with advanced solid tumors: NCIC CTG IND 179
Authors: Oza A. M. , Kollmannsberger C. ,   NCIC Clinical Trials Group, Hirte H. , Welch S. , Siu L. , Mazurka J. , Sederias J. , Doyle L. A. , Eisenhauer E. 
Published: August 2020

3558 Background: Temsirolimus (T) has encouraging activity in many malignancies, including endometrial cancer and a combination with carboplatin and paclitaxel would logical regimen for further development. This trial was designed to assess the safety and tolerability of this combination and expand experience at the recommended dose in pts with endometrial and ovarian cancers. Methods: A 3+3 dose escalation Phase I study has been conducted in pts with advanced solid malignancies suitable for carboplatin and paclitaxel chemotherapy who had not received more than 2 prior lines of chemotherapy. To date, 31 eligible pts with a median age of 59 have been treated and 27 are evaluable for toxicity. Pts were entered in 6 dose levels, with the first two levels administering T on Days 8 and 15 and the next 4 levels switching to a D1, 8 administration. Eighteen had received prior chemotherapy and 15 prior radiation. Results: Day 8, 15 administration of T was not feasible due to myelosuppression on day 15. The combination of carboplatin and paclitaxel on day 1 with T on D1 and 8 has been well tolerated, and patients have received a median of 5 cycles of therapy. At dose level 6 (T 25 mg D1 and 8, paclitaxel 175 mg/m2 D1, carboplatin AUC 6 D1) dose limiting toxicity (DLT) was seen in one of 6 pts treated to date (Gr 4 thrombocytopenia) and a second pt had a possible DLT ( Gr 3 fatigue in presence of baseline fatigue). This dose level is being expanded in 4 endometrial and ovarian cancer pts. The regimen is active: of the 26 patients with follow-up data, there have been 10 with partial response (38.5%; med. duration 7.1 mo [1.0–12.7]) and 12 with stable disease (46%; med. duration 6.9 mo [1.3- 7.8]). One patient had progressive disease and three were inevaluable. Conclusions: The results indicate this combination is well tolerated and requires additional assessment in a Phase II setting. The recommended Phase II dose will be dose level 6 provided no further DLTs are observed in the additional 4 patients entered. [Table: see text] No significant financial relationships to disclose.
Evaluation of ALK-1 expression in circulating endothelial cells (CECs) as an exploratory biomarker for PF-03446962 undergoing phase I trial in cancer patients
Authors: Mancuso P. , Shalinsky D. R. , Calleri A. , Quarna J. , Antoniotti P. , Jilani I. , Hu-Lowe D. , Jiang X. , Gallo-Stampino C. , Bertolini F. 
Published: August 2020

3573 Background: ALK-1 is a member of the TβRI family & a novel target for antiangiogenic therapy (Rx). PF- 03446962 (PF) is a fully human mAB (IgG2, κ) generated against ALK-1 with dose-dependent preclinical antiangiogenic activities (Hu-Lowe et al, Proc AACR, 2009). This study's objectives were to determine whether: 1) CECs in cancer patients express ALK-1; and 2) whether therapy with PF against ALK-1 will modulate ALK-1 expression or CEC function in an ongoing Ph I trial. Methods: The human mAb was conjugated with alexa fluor 647. ALK-1 expression was assayed by a standardized multicolor flow cytometry assay (Mancuso et al, CCR 2009). Results: ALK-1 expression was characterized on human vascular (HUVEC) & lymphatic (HDLC) endothelial cells; HUVEC & HDLC cells highly express ALK-1 (>99% of these cells are ALK- 1+). ALK-1 expression was assessed in healthy controls (n=17) & cancer patients after normalizing for CEC viability. Patients with advanced malignancies had increased numbers of ALK-1+ CECs: Patients with breast ca (n=12), melanoma (n=8), NSCLC (n=11), & CRC (n=4) had 16±12, 39±23, 50±30, & 62±25 ALK-1+ CECs/mL, respectively, vs 7±6 ALK-1+ CECs/mL in controls. In contrast, ALK-1 expression was minimally or not expressed in pts with hematologic malignancies; ALK-1 was absent in CD117+ or CD34+ bone marrow cells. In the Ph I trial, preliminary evidence suggests that PF may alter CEC function; ALK-1+ CECs were markedly reduced in the 1st two pts studied at EIO after 22 days on Rx. Conclusions: ALK-1 is expressed in CECs. Flow cytometry enables rapid assay of ALK-1 expression in cancer patient blood. ALK-1 is expressed in an increased number of CECs/mL in cancer pts with solid malignancies vs controls. ALK-1 expression in CECs in pts with NSCLC & CRC may correspond to high ALK-1 expression observed in corresponding nonmatched tumor microarrays in addition to other malignancies such as sarcoma, SCLC & neuroendrocine pancreatic ca (Fiedler, Proc ASCO, 2009). Additional preliminary Ph I results will be reported as part of assessing whether CECs may have any role as biomarkers to potentially detect patients with ALK-1+ solid malignancies or monitor anti-ALK-1 therapy. [Table: see text]
Functional imaging of neoadjuvant chemotherapy response in women with locally advanced breast cancer using diffuse optical spectroscopy
Authors: Soliman H. , Gunasekara A. , Rycroft M. , Zubovits J. , Dent R. , Spayne J. , Jong R. , Yaffe M. , Czarnota G. 
Published: August 2020

3591 Background: Functional imaging with tomographic near infrared diffuse optical spectroscopy (DOS) can quantitatively measure tissue parameters such as the concentration of deoxy-hemoglobin (Hb), oxy-hemoglobin (HbO2), percent water (%water), and scattering power (SP). The purpose of this study was to evaluate the correlation between DOS functional parameters with pathologic outcomes. Methods: Patients with locally advanced breast cancer undergoing neoadjuvant chemotherapy or chemoradiotherapy were recruited to this study (n=10). Five scans were conducted per patient: a baseline scan taken up to 3 days prior to treatment and at 1 week, 4 weeks, 8 weeks, and after neoadjuvant treatment prior to surgery. Pulsed near-infrared laser light was used to scan the suspended breast at four different wavelengths and data was used for tomographic reconstruction. Volume-of-interest (VOI) weighted tissue Hb, HbO2, %water, and SP corresponding to the tumour was calculated and compared to pathological response as determined from full mount mastectomy specimens. Results: For all 10 patients the tumour-based VOI was significantly different than background tissue for all functional parameters (p<0.001). Five patients had a good pathologic response. Four patients were considered non-responders. One patient initially had a poor clinical response to chemotherapy but after a change in chemotherapy had a good clinical response. Responders and non-responders were significantly different for all of the functional parameters (p<0.05) at the 4 week scan. In the 5 patients with a good response the mean drop in Hb, HbO2, %water, and SP from baseline to the 4 week scan was 70.4% (SD=18.6), 66.5% (SD=24.5), 59.6% (SD=30.9), and 60.7% (SD=29.2), respectively. In contrast, the 4 non- responders had a mean drop of 17.7% (SD=9.8), 18.0% (SD=20.8), 15.4% (SD=11.7), and 12.6% (SD=10.2), for Hb, HbO2, %water and SP, respectively. Conclusions: Functional imaging using tomographic DOS parameters of Hb, HbO2, %water and SP could be used as an early detector of final pathologic tumour response. This could be evaluated in the future to assess response and potentially adjust chemotherapy regimens. No significant financial relationships to disclose.
Correlation of insulin-like growth factor 1 (IGF-1) expression and clinical outcome in K-RAS wild-type colorectal cancer patients treated with cetuximab-irinotecan
Authors: Scartozzi M. , Bearzi I. , Mandolesi A. , Loupakis F. , Zaniboni A. , Berardi R. , Pierantoni C. , Masi G. , Falcone A. , Cascinu S. 
Published: August 2020

4017 Background: K-RAS wild type colorectal tumors show an improved response rate to anti-EGFR monoclonal antibodies. Nevertheless 70% to 40% of these patients still does not seem to benefit from this therapeutic approach. Recent data suggested that in presence of IGF-1 system altered activation colorectal cancer cells may escape anti-EGFR mediated cell death. The interaction between IGF-1 expression and K-RAS mutational analysis was tested in order to verify the ability of IGF-1 to identify a sub-group of patients more likely to benefit from EGFR-targeted antibodies treatment. Methods: IGF-1 expression and K-RAS mutational status was assessed in advanced colorectal cancer patients receiving irinotecan/cetuximab. Results: Sixty-two patients were analyzed. IGF-1 was negative in 21 patients (34%). and overexpressed in the remaining 41 cases (66%). In IGF-1 negative and IGF-1 positive tumors we observed progressive disease in 6 (29%) and 26 (63%) patients respectively (p = 0.01). Median time to progression was 7.7 months in patients showing IGF-1 negative tumors and 2.3 months for IGF-1 expressing tumors (p = 0.005). Among K-RAS wild type patients, IGF-1 negative and positive tumors showed a partial response to cetuximab-irinotecan in 7 (50%) and 1 (5%) cases respectively (p = 0.004). Median time to progression in IGF-1 negative tumors was 11 months and 3.2 months in IGF-1 positive colorectal cancers (p = 0.03). Conclusions: IGF-1 proved to be a reliable predictive factor for resistance to anti-EGFR monoclonal antibodies in K-RAS wild type colorectal cancer. Combined IGF-1 and K-RAS analysis may represent an effective strategy for a better selection of responding colorectal tumors in this setting. No significant financial relationships to disclose.
International randomized phase III study of capecitabine (Cap), bevacizumab (Bev), and mitomycin C (MMC) in first-line metastatic colorectal cancer (mCRC): Final results of the AGITG MAX trial
Authors: Tebbutt N. C. , Gebski V. , Wilson K. , Cummins M. , Chua Y. , Robinson B. , Broad A. , Cunningham D. , Simes J. , Price T. 
Published: August 2020

4023 Background: The addition of Bev to oxaliplatin or irinotecan based doublet chemotherapy has shown benefit in mCRC. Cap± MMC are alternate chemotherapy regimens suitable for patients (pts) who are either unfit for or who do not require initial oxaliplatin/irinotecan. This phase III study compared Cap with Cap Bev and Cap Bev MMC. The aim was to develop a low toxicity regimen suitable for a broad population of pts with mCRC. Methods: Previously untreated pts with unresectable mCRC considered suitable for Cap monotherapy were randomised to arm A Cap (Cap 2000mg/m2/d or 2500mg/m2 d1–14 q21d), arm B Cap Bev (Bev 7.5mg/kg q3w) or arm C Cap Bev MMC (MMC 7mg/m2 q6w). Primary endpoint: PFS, secondary endpoints: RR, toxicity, OS, QoL . Randomisation was stratified by age, PS, centre and Cap dose. Response was assessed every 6w. The study was designed to detect an increase in the median PFS from 5.5m (arm A) to 8m (arm B or C) at p<0.025 with 80% power. Results: A total of 471 pts were randomised from July 2005-June 2007. Outcomes were evaluated on an intention to treat basis and included 15 ineligible pts. Baseline demographics were well balanced between arms with median age 67y (range 31–86y). Toxicity was reported: ASCO 2008 abstr 4029. The most common grade 3/4 toxicities were PPE (16%, 26%, 28%) and diarrhoea (11%, 17%, 16%) for arms (A,B,C). However, adjusted rates per cycle were similar as arms B & C received more cycles of Cap (A8.3, B10.8, C10.5). Other toxicity rates were generally <10%. The study achieved its primary endpoint with a highly significant improvement in PFS for arms B & C. RR and OS are summarized ( Table ). Conclusions: All treatment regimens were well tolerated in a relatively elderly patient cohort. The addition of Bev±MMC to Cap significantly improved PFS without significant additional toxicity. OS was similar for all arms. Cap Bev±MMC is an active, low toxicity regimen that may be considered as a treatment option for pts with mCRC. [Table: see text] [Table: see text]
Definition of oxaliplatin sensitivity in patients with advanced colorectal cancer previously treated with oxaliplatin-based therapy
Authors: de Gramont Lesparre A. H. , Chibaudel B. , Bourges O. , Perez-Staub N. , Tournigand C. , Maindrault-Goebel F. , André T. , Larsen A. K. , Afchain P. , Louvet C. 
Published: August 2020

4024 Background: Oxaliplatin combined with fluoropyrimidines is standard adjuvant therapy in stage III colon cancer and first-line therapy in stage IV colorectal cancer. Oxaliplatin can be reintroduced either at relapse, or after maintenance or after chemotherapy holidays. In this study we defined the sensitivity to oxaliplatin reintroduction based on the oxaliplatin-free interval. Methods: Stage IV pts entered in the OPTIMOX1 and 2 studies (FOLFOX4, FOLFOX7 followed by maintenance without oxaliplatin or chemotherapy holidays) and pts having relapsed after metastases surgery and neoadjuvant or adjuvant FOLFOX for resectable stage IV were eligible if they were rechallenged with FOLFOX. Endpoints were: survival from reintroduction according to interval between the last cycle of oxaliplatin first-line and reintroduction, survival and response at reintroduction according to first FOLFOX response and PFS. Results: 330 pts were included: male 60%, colon/rectum/both 62%/35%/2%, resectable/unresectable: 14%/86%, PS 0–1 / >1: 90%/10%, sites 1/>1: 57%/43%. 23 pts had adjuvant and 22 pts had neoadjuvant chemotherapy. 58 pts (18%) had FOLFOX reintroduction before progression. PFS/OS from reintroduction according to induction FOLFOX response were 8.7/19.5 mths if CR, 4.6/15.2 mths if PR, and 3.2/9.7 mths if SD (P=.0019/.01). PFS/OS from reintroduction according to induction FOLFOX PFS were 2.9/9.3 mths if PFS<6 mths, 4.6/14.7 mths if PFS 6–12 mths and 8.5/23.7 if PFS=12 mths. Table shows results according to intervals. There was no difference between 0–3 and 3–6 mths or 6–9 and 9–12 mths intervals. Conclusions: A prolonged interval between two FOLFOX therapies or a prolonged PFS at first-line FOLFOX predict the efficacy of oxaliplatin reintroduction. The interval between two FOLFOX therapies does not identify a completely refractory population. Resistance (PD rate) is divided by two at each 6 month intervals. [Table: see text] No significant financial relationships to disclose.
Randomized phase II study of picoplatin in combination with 5-fluorouracil and leucovorin (FOLPI) as a neuropathy-sparing alternative to modified FOLFOX-6 as first-line therapy for colorectal cancer (CRC)
Authors: Earhart R. , Cheporov S. , Gladkov O. , Biakhov M. , Breitz H. , De Jager R. 
Published: August 2020

4026 Background: Picoplatin (Pico) was designed to overcome platinum resistance and has the potential for improved safety compared to other platinum agents. FOLFOX (5-FU, LV, oxaliplatin [oxali]) treatment for advanced CRC has dose-limiting oxali- related neurotoxicity. The incidence of grade (G) 3–4 neurotoxicity with single-agent Pico across studies was <2%, suggesting that Pico may provide a neuropathy-sparing alternative to oxali. A Phase I trial identified the Pico MTD at 150 mg/m2 when infused Q4W with Q2W FU/LV. The present study evaluates Pico when administered Q4W with Q2W FU and LV (FOLPI) vs. modified (m) FOLFOX-6 (FOLFOX) as 1st line treatment for patients (pts) with advanced CRC. Methods: Each pt received LV and infusional FU per mFOLFOX-6 Q2W. Pts with no prior chemotherapy for advanced CRC received Pico Q4W (150 mg/m2) or oxali Q2W (85 mg/m2). Tumor response was assessed by RECIST using CT scans. Adverse events (AEs) were assessed with CTCAE. Neuropathy was assessed using the FACT-Neurotoxicity questionnaire and by a neurologist blinded to treatment. Results: 101 pts were randomized (50 to FOLPI, 51 to FOLFOX). Pts have received 213 (median 4, max 11) 4-week cycles of FOLPI and 414 (median 8, max 21) 2-week cycles of FOLFOX. Median dose intensity of Pico = 28 mg/m2/wk (range 19–44); mean relative dose intensity = 77%. Median dose intensity of oxali = 36 mg/m2/wk (range 28–43); mean relative dose intensity = 86%. Neurotoxicity was observed in 65% of pts on FOLFOX (10% G 3/4) and 28% of pts on FOLPI (no G 3/4). Most frequent G 3/4 AEs on FOLPI were neutropenia (60%), thrombocytopenia (40%) and anemia (14%). In the FOLFOX arm, other than neuropathy, the most frequent G 3/4 AEs were neutropenia (20%) and thrombocytopenia (12%). Disease control (CR+PR+SD) was 76% for FOLPI and 76% for FOLFOX. In the FOLPI arm there were 1 CR (2%) and 11 PR (22%). In the FOLFOX arm there were no CRs and 13 PR (26%). Conclusions: In this ongoing trial, FOLPI with Pico Q4W shows comparable disease control as measured by RECIST compared to FOLFOX. Neurotoxicity was less frequent and less severe in the FOLPI arm compared to the FOLFOX arm. Pico therefore may be a neuropathy-sparing alternative to oxaliplatin in CRC. [Table: see text]
KRAS mutation, cancer recurrence, and patient survival in stage III colon cancer: Findings from CALGB 89803
Authors: Fuchs C. , Ogino S. , Meyerhardt J. A. , Irahara N. , Niedzwiecki D. , Hollis D. , Saltz L. B. , Mayer R. J. , Bertagnolli M. M. 
Published: August 2020

4037 Purpose: KRAS mutation in stage IV colorectal cancer predicts resistance to anti-EGFR targeted treatment (cetuximab or panitumumab). However, whether the presence of KRAS mutation independently predicts the survival of colon cancer patients remains uncertain. Methods: We conducted a prospective observational study of 508 cases identified among 1264 patients with stage III colon cancer who enrolled in a randomized adjuvant chemotherapy trial (5-fluorouracil, leucovorin with or without irinotecan) between April 1999 and May 2001 (CALGB 89803; Saltz et al. J Clin Oncol 2007). KRAS mutations were detected in 178 tumors (35%) by Pyrosequencing. Kaplan-Meier and Cox proportional hazard models were used to assess the significance of KRAS mutational status and adjusted for potential confounders including age, sex, tumor location, T stage, N stage, performance status, adjuvant chemotherapy arm and microsatellite instability (MSI) status. Results: When compared to patients with wild-type KRAS, those with a mutation in KRAS did not experience any difference in disease-free (DFS), recurrence-free (RFS), or overall survival (OS) (log-rank P>0.56 for DFS, RFS, and OS). Five-year DFS was 62% for KRAS-mutated and 63% for KRAS-wild-type patients. Five-year RFS was 64% for KRAS-mutated and 66% for KRAS- wild-type patients. Five-year OS was 74% for KRAS-mutated and 73% for KRAS-wild-type patients. The effect of KRAS mutation on patient survival did not differ according to clinical features, chemotherapy arm or MSI status, and the effect of adjuvant chemotherapy assignment on outcome did not differ according to KRAS status. Conclusions: In this large clinical trial of chemotherapy in patients with stage III colon cancer, KRAS mutational status was not associated with any significant influence on disease-free or overall survival. No significant financial relationships to disclose.
Analysis of prognostic (prog) Web-based models for stage II and III colon cancer (CC): A population-based validation of Numeracy (NUM) and ADJUVANT! Online (ADJ!)
Authors: Gill S. , Loprinzi C. , Kennecke H. , Grothey A. , Nelson G. , Woods R. , Speers C. , Alberts S. , Bardia A. , Sargent D. 
Published: August 2020

4044 Background: To aid in decisions regarding adjuvant therapy (AT) for resected high-risk CC, two prog models are in common use: the Mayo Clinic NUM calculator developed from a pooled data analysis of 7 randomized 5FU-based AT trials, and ADJ! developed using SEER data. This study examines the accuracy of NUM and ADJ! utilizing a cohort of patients (pts) referred to the BC Cancer Agency (BCCA). Methods: Demographic, disease and treatment data for pts with stage II/III CC referred to the BCCA from 1995–1996 + 1999–2003 were collected. Observed (obs) 5-year relapse free survival (RFS) and overall survival (OS) were compared to predicted estimates (pred) using NUM and ADJ!, both overall and for all prog subgroups with ≥ 10pts, as stratified by T stage, N stage, tumor grade and age. Data are presented in a descriptive manner and using confidence intervals. Results: Median follow-up was 5.6 yrs for 2,033 pts - 53% male, median age 68y, 40% N0. The mean percentages of 5 year pred outcomes for each of the two models and the actual Kaplan Meier mean survivals are presented in the table . The percentage correct predictions of 5 y status is also presented, with correctness deemed accurate if the pt was alive and predicted to be alive by ≥ 50% as determined by each model or dead while the respective tool predicted < 50% possibility of being alive. For surgery alone pts, ADJ!pred were more often closer to what was observed, as compared to NUMpred, in the prog subgroups (for RFS 56%, OS 88%). For surgery + 5-FU pts, within these subgroups, NUMpred were more often closer to what was observed, as compared to ADJ!pred, for RFS (62%) and for OS (55%). Conclusions: In this independent population-based validation, NUM and ADJ! have acceptable and similar reliability with modest over-estimations of 5y RFS and OS. Both models thus appear to be useful adjuvant decision-aids. [Table: see text] No significant financial relationships to disclose.
Wt Kras and gene expression levels of VEGFR2, EGFR, and ERCC-1 associated with progression-free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC) treated with first-line 5-FU or capecitabine with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Authors: El-Khoueiry A. B. , Pohl A. , Danenberg K. , Cooc J. , Zhang W. , Yang D. , Singh H. , Shriki J. , Iqbal S. , Lenz H. J. 
Published: August 2020

4056 Background: While wild type (wt) Kras is associated with improved outcome to anti-EGFR therapy in pts with mCRC, there are no identified predictors of outcome for FOLFOX/BV. We evaluated Kras status and expression of genes involved in angiogenesis, DNA repair and 5-FU metabolism in 68 patients treated with FOLFOX/BV or XELOX/BV. These genes included VEGF, VEGF-receptor 2 (KDR), Cox-2, IL 6 and 8, chemokine-receptors 1 & 2, EGFR and ERCC-1. Methods: Tissue samples from 68 patients with mCRC were analyzed. mRNA was extracted from laser-capture-microdissected tumor tissue. cDNA was prepared by reverse transcription and quantitation of the candidate genes was performed using a fluorescence- based real-time detection method (TaqMan). Allele specific RT-PCR was performed to determine Kras mutation status in codons 12 and 13. Results: There were 68 pts (38 males, 30 females), median age: 56 years (range 29–81). All received first line 5FU, oxaliplatin and BV (28 FOLFOX/BV, 40 XELOX/BV). Radiologic response: 1 CR, 39/68 (57%) PR, 27/68 (40%) SD, and 1 PD. Median OS is not reached. At a median follow-up of 32.0 months (mo) (range: 2.3–47.8 mo), the median PFS was 12.4 mo (95% CI: 9.8–15.2). Kras mutation was identified in 39 pts (57%). RR was 64% in pts with wt Kras and 52% in pts with mutant Kras (p=0.33). PFS was significantly longer for pts with wt kras compared to pts with mutant kras (13.7 mo [95% CI: 6.9–13.2] versus 8.3 mo [95%CI: 6.9–13.2], P=0.039). High EGFR (median PFS: 15.2 mo; 95% CI 11.7–16.5 mo), high VEGFR2 (median PFS: 13.9 mo; 95% CI 11.0–16.5 mo), and low ERCC1 (median PFS: 12.4 mo; 95% CI 10.9–16.4 mo) were associated with longer PFS compared to low EGFR (median PFS: 7.9 mo; 95% CI 6.9–11.0 mo, P=0.040), low VEGFR2 (median PFS: 7.2 mo; 95% CI 6.5–8.1 mo, P=0.032), and high ERCC1 (median PFS: 9.6 mo; 95% CI 5.8–15.2 mo, P=0.045). Conclusions: To our knowledge, this is the first report of a potential association between Kras status as well as gene expression levels of VEGFR2, ERCC-1 and EGFR and clinical outcome to FOLFOX/BV therapy in pts with mCRC. Prospective clinical trials are needed to validate these results. [Table: see text]