bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolerability and efficacy of a biweekly docetaxel, fluorouracil, leucovorin, oxaliplatin regimen (TFOX) in previously advanced metastatic gastric and oesogastric junction (AGC) adenocarcinoma.
Authors: Pernot Simon , Mitry Emmanuel , Samalin Emmanuelle , Dahan Laetitia , Turki Hajer , Mazard Thibault , Ychou Marc , Seitz Jean Francois , Rougier Philippe , Taïeb Julien
Published: March 2020

4087

Background: The DCF regimen is superior to 5-FU-Cisplatin in term of response rate (RR) and overall survival (OS) in advanced gastric cancer, but is also more toxic. Oxaliplatin is better tolerated and can effectively replace cisplatin in AGC patients (pts). We hypothesize that incorporating Docetaxel into a simplified FOLFOX regimen should be a tolerable and efficient option, and could facilitate the use of this drug in 1st line in AGC. Methods: TFOX regimen was given biweekly as follow: Docetaxel (50mg/m2), oxaliplatin (85mg/m2), leucoverin (400mg/m2) and 5FU continuous infusion 48h (2400mg/m2). Main inclusion criteria were: pts with histollogically proven metastatic or locally advanced gastric or oesogastric junction adenocarcinoma, previously untreated, PS≤2. Using Fleming design the primary end point was response rate, needing a sample size of 40 pts. Results: Between 02/2008 and 07/2011, 41 pts with AGC were enrolled (oesogastric junction: 17 pts, diffuse type: 22 pts, metastatic: 37 pts); mean age was 53.5 years (31-73), 26 pts were male. PS 0/1/2: 11/24/6 pts, 14 pts had a relapse after a R0 resection. The total number of cycles administered was 310 (mean 7.6 cycles/pts) and 90% of pts received at least 4 cycles. No toxic death occurred. Grade 3-4 toxicities were observed in 20 pts (48%). Grade 3-4 toxicities were neutropenia (29%) febrile neutropenia (7%), neurotoxicity (10%), asthenia (10%). ORR was 63% (n=26) [IC95% 48-78], with 2 complete responses. Disease control rate (CR+PR+SD) was 78% (n=32) [IC95% 65-90]. Median progression free survival and overall survival were 6.5 months [IC95% 5.02-10.85] and 12.1 months [IC95% 7.25-15.28], respectively. Conclusions: TFOX is effective with a manageable toxicity profile in first line treatment for AGC pts. Tolerability of this regimen compares favourably with DCF reported tolerability. TFOX may be an alternative option for intensive 1st line treatment and should now be evaluated in randomized trials.
Prognostic value of lemur tyrosine kinase-3 (LMTK3) polymorphism in Japanese (J) patients (PTS) with localized gastric adenocarcinoma (GAC).
Authors: Barzi Afsaneh , Wakatsuki Takeru , Zhang Wu , Yang Dongyun , Loupakis Fotios , Ning Yan , El-Khoueiry Rita , Labonte Melissa Janae , Azuma Mizutomo , Bohanes Pierre Oliver , Benhaim Leonor , Gerger Armin , Koizumi Wasaburo , Watanabe Masahiko , Stebbing Justin , Giamas Georgios , Lenz Heinz-Josef
Published: March 2020

4088

Background: LMTK3 is an estrogen receptor α (ERα) regulator. Recent studies show that [rs808419(r8) and rs9989661(r9)] and LMTK3 expression are prognostic in breast and colon cancers. Our group demonstrated that r9AA is associated with shorter time to recurrence in Caucasian(C) and Hispanic(H) females(F) with GAC. We investigated the significance of LMTK3 polymorphism in J PTS with GAC. Methods: Blood or tissue samples of 169 J PTS who had surgery with/without adjuvant chemotherapy (ACT) were analyzed. Genomic DNA was extracted using the QIAmp kit; all samples were analyzed using PCR-based direct DNA-sequencing. The endpoints of the study were disease-free survival (DFS) and overall survival (OS). Kaplan-Meier curves and log-rank test were used for univariate analysis. Multivariate analysis was performed to test the interaction between polymorphism and gender adjusting for other variables. Results: 60 F and 109 males were enrolled in this study, 17% stage(s) IB, 31% s II, 36% s III, 17% s IV (AJCC-6). The median age was 67(31-88). 65% of PTS received S-1 based ACT. Median follow-up was 4 years(ys). Prognosis was worse in men with r9 AA than AG/GG, at 1 year 67% (95% CI 40-83%) with AA vs 99% (95% CI 91-99%) of AG/GG were alive (p= 0.039). Median survival was not reached in the AG/GG group; in the AA group median DFS and OS was 1yr (p= 0.03) and 2ys (p= 0.039) respectively. In the multivariate analysis adjusting for s, age, and ACT, males carrying AA had increased risk of disease recurrence (HR 3.84 95%CI 1.86-7.92, p< 0.001) and dying (HR 3.47 95%CI 1.58-7.62 p=0.002) compared to those with AG/GG (HR=1, reference). Conclusions: r9 AA was associated with significantly worse DFS and OS in J male with GAC. These results confirm our previous findings that LMTK3 is an independent prognostic factor for localized GAC; interestingly the relationship between gender and prognostic significance is the opposite in J vs. C/H. The gender disparity can be due to the differences in the etiology (histological subtypes), management strategies, allele frequency, and degree of estrogen exposure in the two populations. Additional studies are warranted to identify the underlying biological mechanism.
Two-year follow-up of a phase II study on catumaxomab as part of a multimodal approach in primarily resectable gastric cancer.
Authors: Bokemeyer Carsten , Ridwelski Karsten , Atanackovic Djordje , Arnold Dirk , Woell Ewald , Büchler Markus W. , Krueger Colin , Schuhmacher Christoph
Published: March 2020

4095^

Background: Perioperative chemotherapy (CT) has demonstrated as survival benefit in locally advanced gastric cancer (GC) in randomized trials. However, the overall cure rate is 30-40% and a significant number of patients are not able to receive the postoperative part of their CT regimen. In Europe, the trifunctional antibody catumaxomab is approved for the treatment of malignant ascites based on a pivotal trial which also included GC patients. A new multimodal approach combining neoadjuvant CT, followed by gastrectomy and intraperitoneal (i.p.) immunotherapy with catumaxomab was assessed in a single-arm multicenter phase II study. We here report 2-year follow-up data. Methods: GC pts (T2/T3/T4, N+/–, M0) received 3 cycles of neoadjuvant fluoropyrimidin/platinum-based CT followed by ’en-bloc’ R0-gastrectomy. Catumaxomab was administered i.p. as intraoperative bolus (10 µg) followed by 4 consecutive 3-hour infusions of 10-150 µg. Primary safety endpoint was the rate of predefined postoperative complications observed during 30 days after surgery. Key efficacy endpoints included disease-free (DFS) and overall survival (OS). Results: The original study data presented at the WCGC in 2011 (Schuhmacher et al.,Ann Oncol (2011) 22(suppl. 5)) showed that the primary endpoint was met and the described application regimen is safe. At time of surgery, 27.8% of patients were stage I, 27,8% of patients were stage II, 22,3% of patients were stage III and 14,8% of patients were stage IV as assessed according to pTNM measures. At 24 months 39/54 (safety analysis set) patients were still alife,14/54 were dead, (one patient lost to follow-up), 24/37 had no progression, only 13/37 patients relapsed (for 2 patients disease status was not recorded). At the 2 year cut off DFS was 56.4% (95% CI: 41–69%), OS was 75% (95% CI: 60–85%). Conclusions: Catumaxomab as part of a multimodal therapy in primarily resectable GC is a feasible option. The 2-year follow up efficacy results show promising data for DFS and OS in a cohort of locally advanced gastric cancer pts.
A prospective cohort study using a Japanese nationwide survey to evaluate the therapeutic effects of surgery and percutaneous ablation for hepatocellular carcinoma.
Authors: Hasegawa Kiyoshi , Kokudo Norihiro , Makuuchi Masatoshi , Izumi Namiki , Ichida Takafumi , Kudo Masatoshi , Ku Yonson , Sakamoto Michiie , Nakashima Osamu , Matsui Osamu , Matsuyama Yutaka ,   Liver Cancer Study Group of Japan
Published: March 2020

4104

Background: Which is the best treatment for less advanced hepatocellular carcinoma (HCC) with good liver function remains one of the most important and unsolved problems. To solve this problem, we conducted this study and evaluated the therapeutic impacts of surgical resection (SUR), percutaneous ethanol injection (PEI), and radiofrequency ablation (RFA) on long-term outcomes in patients with HCC. Methods: A large-scale database constructed by a Japanese nationwide survey was used for this study. Between 2000 and 2005, 28,510 patients with HCC were treated by SUR, PEI, or RFA, among whom we identify 12,968 patients with no more than 3 tumors (≤3cm) and liver damage of class A or B. The patients were divided into SUR group (n=5,361), RFA group (n=5,548), and PEI group (n=2,059). Rates of overall and recurrence-free survival were compared among them. Results: Median follow-up was 2.16 years. Overall survival rates at 3 and 5 years were respectively 85.3%/71.1% in the SUR group, 81.0%/61.1% in the RFA, and 78.9%/56.3% in the PEI. Recurrence-free survival rates at 3 and 5 years were 56.7%/36.2%, 42.8%/28.3%, and 35.7%/23.1%, respectively. On multivariate analysis, the hazard ratio for death was significantly lower in the SUR group than in the RFA (SUR vs. RFA:0.84, 95% confidence interval, 0.74-0.95; p=0.006) and the PEI (SUR vs. PEI:0.75, 0.64-0.86; p=0.0001). The hazard ratios for recurrence were also lower in the SUR group than in the RFA (SUR vs. RFA:0.74, 0.68-0.79; p=0.0001) and the PEI (SUR vs. PEI:0.59, 0.54-0.65; p=0.0001). Conclusions: Surgical resection would provide longer overall and recurrence-free survival than either RFA or PEI in patients with HCC.
Blood signatures for early liver cancer detection in patients with chronic hepatitis B.
Authors: Liew Choong-Chin , Omar Haniza , Lim Chun Ren , Bong Chin Wei , Ooi Edie Jian Jiek , Lee Michelle Mei Lin , Yu Choon Geok , Tan Soek Siam , Hassan Muhammad Radzi Abu , Menon Jarayam , Muthukaruppan Raman , Singh Mandeep , Abdullah Nik Azim Nik , Ooi Boon Phoe , Ding Robert Phooi Huat , Low Eng Joo , Tan Francis , Chao Samuel , Yang Hengxuan , Merican Ismail
Published: March 2020

4106

Background: Some 20-30% of patients with chronic hepatitis B (CHB) eventually develop hepatocellular carcinoma (HCC), a disease with poor prognosis and high mortality unless detected early. Ultrasound and/or alpha-fetoprotein (AFP) are widely used for HCC surveillance. However these technologies are operator-dependent, have low sensitivity and are considered inadequate for screening. This study describes a blood-based gene-expression signature prognostic for HCC in CHB patients. Methods: PaxGene was used to extract RNA from whole blood samples taken from more than 1,000 Malaysian patients (matched HCC, CHB, healthy controls). Complementary DNA was generated from isolated RNA via reverse transcription and analyzed using Affymetrix U133Plus 2.0 with MAS 5.0 normalization. To minimize bias we developed a novel algorithm based on SentinelPair regression analysis to identify biomarker panels. A Monte Carlo search identified pair combinations that could differentiate between cancer and controls. Twelve genes were selected for qRT-PCR Cohort 1 verification (n=139). Six genes were then short-listed for qRT-PCR Cohort 2 verification using independent samples (n=150). Results: Multivariate quantitative microarray analysis of 147 samples (HCC=47; CHB=50; controls=50) identified 12 probe sets differentially expressed between HCC patients and controls and CHB (ROC AUC=0.90). These genes were evaluated using qRT-PCR on the same cohort (ROC AUC=0.86). Six genes were subsequently short listed for qRT-PCR Cohort 2 verification. The AUC of the 6-gene-combination of Cohort 2 (HCC=50; CHB=50; controls=50) was 0.80. Importantly, of the thirteen HCC with low AFP (<15ng/ml), 9 were predicted as “positive.” Conclusions: Blood RNA biomarkers identified in this study may form the basis of a test that can be used in patients with CHB for detection of early HCC, potentially improving prognosis for this cancer. This blood-based test would represent a significant clinical alternative to ultrasound and/or AFP.
Clinical, pharmacodynamic (PD), and pharmacokinetic (PK) evaluation of cediranib in advanced hepatocellular carcinoma (HCC): A phase II study (CTEP 7147).
Authors: Zhu Andrew X. , Ancukiewicz Marek , Supko Jeffrey G. , Blaszkowsky Lawrence Scott , Meyerhardt Jeffrey A. , Abrams Thomas Adam , McCleary Nadine Jackson , Bhargava Pankaj , Fuchs Charles S. , Ryan David P. , Jain Rakesh K. , Duda Dan G.
Published: March 2020

4112

Background: Sorafenib remains the only approved systemic therapy in HCC. We performed a phase II study of cediranib (AZD2171)—a more potent and selective pan-VEGF receptor inhibitor—in advanced HCC patients (pts). Methods: Eligibility criteria included unresectable or metastatic measurable HCC, ECOG PS ≤2, CLIP score ≤3, and adequate organ function. Patients received cediranib at 30 mg po qd continuously (4-wk cycle). The primary endpoint was progression free survival (PFS). We also assessed overall survival (OS) and response rates, steady-state PK of cediranib, and blood circulating biomarkers. Results: Since 6/16/09, we have enrolled the targeted 17 pts required for the first stage of the planned study: ECOG 0/1/2=5/11/1, CLIP 1/2/3=6/4/7, Child A/B=14/3, BCLC C=17. Nine pts had prior sorafenib. The best response was stable disease in five pts (29%). The median PFS was 5.3 months (95% CI: 3.5-9.7). The median OS was 11.7 months (95% CI: 7.5-13.6). Grade 3 toxicities included hypertension (29%), hyponatremia (12%), elevated SGOT (12%) and one pt each (6%) in SGPT, fatigue, hyperbilirubinemia, cardiac ischemia, and proteinuria. Grade 4 pulmonary embolism and brainstem hemorrhage occurred in 1 pt each. Steady-state PK parameters (mean±SD) were, Cmin, 22±21 ng/mL; Cmax, 55±33 ng/mL; AUCτ, 887±503 ng*h/mL. Plasma levels of VEGF and PlGF increased and sVEGFR1, sVEGFR2 and Ang-2 decreased significantly after cediranib treatment (p<0.05). PFS was inversely correlated with baseline levels of bFGF, sVEGFR2 and VEGF, and OS was inversely correlated with baseline levels of sVEGFR1, Ang-2, TNF-alpha and CD34+CD133+ hematopoietic progenitor cells (p<0.05). Conclusions: Cediranib at 30 mg daily is associated with high frequency of grade 3 hypertension and shows preliminary evidence of antitumor activity in advanced HCC pts. Exploratory studies confirmed potential PD and response biomarkers of anti-VEGF therapy. Cediranib exhibits similar PK in HCC pts as in those with other tumor types and normal/near normal hepatic function. This study was stopped by AstraZeneca after discontinuation of cediranib development for unrelated factors.
Merkel cell polyomavirus in gastrointestinal neuroendocrine tumors.
Authors: Renne Salvatore Lorenzo , Fumagalli Caterina , Fazio Nicola , Viale Giuseppe , Barberis Massimo
Published: March 2020

4120

Background: Cutaneous Merkel cell carcinoma (MCC) is a high grade neuroendocrine carcinoma potentially induced by Merkel Cell Polyomavirus (MCPyV), a clonally integrated host in the tumor cell genome. Integration of viral DNA and truncating mutations in the helicase domain of the large T (LT) antigen, a protein implicated in the viral life cycle, have been detected in all MCPyV associated MCCs. These results suggest a role of the virus in tumor pathogenesis according to a two step model: a necessary but not sufficient integration of viral DNA followed by LT antigen premature truncations. Gastrointestinal neuroendocrine tumors (GI-NETs) share common phenotypical features with MCCs, therefore we evaluated whether MCPyVs may be present in GI-NET. Methods: Formalin–fixed and paraffin-embedded samples from 14 cases of liver metastases of G2 GI-NETs, 9 small cell lung cancer (SCLCs) and 4 MCCs of the skin were screened for MCPyV-DNA positivity using two PCR primer sets mapping the LT antigen gene. Then to confirm the putative pathogenetic role of the virus, we seeked for premature truncation of LT antigen by sequencing the helicase portion using seven amplicons mapping 1356-2210 region of the MCPyV complete genome (RefSeq: NC_010277.1). Results: Viral DNA was detected in 7/14 GI-NETs, in 0/9 SCLCs and in 4/4 MCCs. We found a premature stop codon truncating the helicase domain in two GI-NETs. Both the patients had a rapid disease progression. We also found previously not reported alterations in MCCs: a single aminoacid deletion in 3 cases and a point mutation causing a single aminoacid substitution in another case. Conclusions: For the first time the potential tumorigenic signature of MCPyV has been detected in GI-NETs, suggesting a possible role in pathogenesis. The study is ongoing to confirm these observations that could support new diagnostic and therapeutical perspectives of a subset of GI NETs. Moreover we have shown that the clonal integration of MCPyV in MCCs produces different genetic alterations with unknown effects on cell biology.
A multi-institutional phase II open-label study of AMG 479 in advanced carcinoid and pancreatic neuroendocrine tumors.
Authors: Kulke Matthew , Chan Jennifer A. , Ryan David P. , Meyerhardt Jeffrey A. , Fuchs Charles S. , Abrams Thomas Adam , Regan Eileen , Brady Rachel , Weber Jill M. , Campos Tiffany , Kvols Larry , Strosberg Jonathan R.
Published: March 2020

4125

Background: The IGF pathway is thought play an important role in neuroendocrine tumor progression. We therefore investigated AMG 479, a human monocolonal antibody against IGF1-R, in patients with metastatic progressive carcinoid and pancreatic neuroendocrine tumors (NETS). Methods: This open-label phase II study enrolled patients (≥18 yrs) with metastatic low and intermediate-grade carcinoid and pancreatic NETs. Key inclusion criteria included evidence of progressive disease (by RECIST) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160mg/dL. Prior treatments were allowed, and concurrent somatostatin analog therapy was permitted as long as patients remained on a stable dose. The primary endpoint was objective response rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: 60 patients (30 carcinoid, 30 pancreatic NET) were treated with AMG 479 18mg/kg every 3 weeks and 54 patients were evaluable for response. There were no objective responders by RECIST. When best response to therapy was evaluated, 10/27 (37%) evaluable carcinoid patients and 8/26 (31%) evaluable pancreatic NET patients experienced 1-29% tumor shrinkage, while 17/27 (63%) of the carcinoid patients and 15/26 (58%) of the pancreatic NET patients appeared to experience continued tumor growth. Median PFS was 6.3 months (95% CI 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients and 4.2 months for pancreatic NET patients. The OS rate at 12 months was 70% (55%-81%) for the entire cohort. Median OS has not been reached. Treatment related grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%) and infusion reaction (1%). Conclusions: While well-tolerated, single-agent AMG 479 was not found to result in major tumor responses among patients with metastatic low-intermediate grade carcinoid or pancreatic NET. Subgroup analysis to identify characteristics of patients who may have benefited from therapy with AMG 479 is ongoing.
Bevacizumab, pertuzumab, and sandostatin for patients (pts) with advanced neuroendocrine cancers (NET).
Authors: Firdaus Irfan , Shih Kent C. , Zakari Ahmed , Lang Evan Z. , McCleod Michael , Alguire Kathryn B. , Peacock Nancy Walker , Flora Douglas B. , Ruehlman Peter , Earwood Chris , Bendell Johanna C.
Published: March 2020

4127

Background: Targeted agents are used to treat well-differentiated NET. Octreotide binds somatostatin receptors and improves time to progression (TTP) of carcinoid tumors, and VEGF pathway targeting improves TTP of pancreatic NET. HER2 overexpression is reported in NET, and pertuzumab blocks HER2 receptor dimerization. This phase II trial combined bevacizumab, pertuzumab, and octreotide LAR for pts with advanced NET. Methods: Pts with advanced well-differentiated NET were enrolled. Pts had ECOG 0-1, and normal end-organ function, including left ventricular ejection fraction (LVEF) ≥50%. Pts received bevacizumab 15 mg/kg IV, pertuzumab 420 mg IV (following an 840 mg loading dose) day 1 of a 21 day cycle, and octreotide LAR 30 mg IM every 28 days. Primary endpoint was objective response rate (ORR). Results: Between 6/10 and 4/11, 43 pts enrolled. 22 M/21 F, med age 62 (33-88), 32 (74%) carcinoid, 11 (26%) PNET. 26% had prior sandostatin, 72% prior surgery, 19% prior radiation, 23% with > 2 previous systemic therapies. Treatment-related grade 3 toxicities included: hypertension (28%), LVEF dysfunction (9%) (reversible with trial drug hold), and diarrhea (7%). No grade 4 toxicity was reported. Median treatment duration was 38 weeks (range: 0 – 76). Chromogranin A values were elevated in 27 pts; 59% had decreases during treatment. Seven pts (16%) achieved objective response [CR: 1 carcinoid (2%), PR: 6 (4 carcinoid, 2 PNET) (14%)]. ORR for carcinoid pts was 15.6%. Median PFS for the entire group was 8.2 months (95% CI: 6.3 – NA). PFS for carcinoid pts was 8.5 months (95% CI: 6.3 – NA); PFS for PNET pts was 6.4 months (95% CI: 3.9 – NA). Median OS has not been reached at 14.3 months followup. Conclusions: The ORR of the combination of bevacizumab, pertuzumab, and octreotide LAR in NET pts was encouraging. Particularly the response rate in carcinoid pts appears higher than historical data, warranting further investigation of this regimen in these pts.
Patients with carcinoma of unknown primary and “colon cancer profile”: Clinicopathologic features and survival data.
Authors: Varadhachary Gauri R. , Karanth Siddharth , Hainsworth John D. , Wang Huamin , Carlson Heather R. , Lenzi Renato , Abbruzzese James L. , Raber Martin N. , Greco Frank A.
Published: March 2020

4130

Background: We have previously proposed a “colon cancer profile” (CCP-CUP) favorable subset. CCP-CUP is ~ 8% of all CUP with features resembling lower gastroinestional cancers. Distinguishing this entity from other CUP pts is of significance given the progress in the treatment of metastatic colorectal cancer (CRC). Additionally, emerging data suggests a high level of agreement between histology+IHC and tissue of origin profiling for CCP-CUP. Methods: The retrospective cohort includes 74 pts from MD Anderson (50) and Sarah Cannon (24) Cancer Centers from 2004 -2010. Pts with CDX2+ tumors and pathology suggesting a "GI profile" were chosen. All pts met the definition of CUP and most had a negative colonoscopy. Results: 2 cohorts were created - Cohort 1 (34 pts), labeled “consistent with lower GI profile” [CDX2+, CK20+, CK7-] and Cohort 2 (40 pts), labeled “probable lower GI profile” [CDX2+, irrespective of CK7/CK20 status]. Most pts had a good PS; 58% women, median age 59 yrs; 20 (27%) pts had ascites on presentation and the predominant sites of metastases included liver (30%), carcinomatosis (50%), and nodes (51%). 53 pts received first line CRC regimens (FOLFOX or FOLFIRI based), 15 pts received gemcitabine or taxane based and 3 ‘other’ regimens. OS was 37 mo (C.I 22- 52). 6 of these were "outliers" (Stage 4 NED or indolent pathology). Excluding these, cohorts 1 and 2 had 32 and 36 pts - their OS were 37 and 21 mo respectively. There was no difference in OS of pts with or without ascites on presentation. Kras data was available for 17; 12 were Kras mutant. On multivariate analysis, the factors found to negatively influence survival were age, PS (of 2) and 3 or more sites of disease. Conclusions: Survival of IHC defined CCP-CUP pts (which may include colorectal, appendiceal and small bowel profile) exceeds historical control and illustrates a new "favorable" subset. IHC is not without its limitations – nonetheless, pts with CDX2 + tumors and CUP should undergo evaluation for GI cancers and likely best served with an armamentarium of drugs used for CRC. Since carcinomatosis and liver mets are predominant sites, all patients with abdominal CUP should undergo optimal IHC (CDX-2, CK7, and CK20) testing to rule out a CCP-CUP.
Mutation profling in patients with carcinoma of unknown primary using the Sequenom MassARRAY system.
Authors: Hale Katherine Stemke , Wang Huamin , Karanth Siddharth , Raber Martin N. , Carlson Heather R. , Lenzi Renato , Abbruzzese James L. , Mills Gordon B. , Varadhachary Gauri R.
Published: March 2020

4131

Background: CUP management may be viewed as an epitome of personalised medicine as we apply our understanding of biological markers to this heterogeneous disease. There is a significant interest in evaluating actionable mutations in various signaling pathways, receptors and downstream effectors in CUP that may help us understand its biology and serve as the basis for unique targeted therapeutic approaches. Sequenom (SQM) Massarray platform enables rapid mutation profiling in solid tumors which we applied to CUP. Methods: 83 CUP samples were sent for DNA mass array analysis. Sequenom was run on 60 samples; 23 samples lacked sufficient quantity or quality of DNA. Data on clinicopathological features was collected. Results: Of the 60 patient samples run on SQM, 16 patients had changes including 11 mutations and 6 polymorphisms . The 6 polymorphisms were in MET . The mutations reported were :RAS (7; 6 KRAS, 1 NRAS), IDH1 (2), PI3K (1) and MET (1). Atleast 50% of the tumors were poorly differentiated. Interestingly, the 2 patients with IDH1 mutations presented with osseous predominant metastatic disease. Of the 6 patients with KRAS mutations, 4 presented with a gastrointestinal profile ( CDX2+ or CK20+) on IHC; in all 4, the DNA sequencing analysis results matched the sequenom results. Conclusions: The (all-comers) overall mutation rate in a heterogenous CUP population is low (11/60, 18%). No "new" low frequency mutations were found using the current panel (Table). Rare and potentially targetable mutations may be identified with a larger panel. Focusing on CUP subsets using this approach may also provide a higher mutational yield. [Table: see text]
Final results of a phase Ib study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.
Authors: Eskens Ferry , Oldenhuis Corina N. , Loos Walter J. , Esteves Brooke , van Doorn Leni , Cotreau Monette M. , Bhargava Pankaj , Zhang Joshua , Strahs Andrew Louis , den Hollander Martha Willemine , Gietema Jourik A.
Published: March 2020

4132

Background: Tivozanib is a potent, selective, oral small-molecule tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1, 2 and 3 with a long half-life. A Phase I study found tivozanib's maximum tolerated dose (MTD) to be 1.5 mg/d and responses were observed in pts with colorectal cancer (CRC) and other tumors. Tivozanib has shown additive anti-tumor activity with 5-fluorouracil in a preclinical breast tumor model. FOLFOX6 is a standard chemotherapy for GI cancers. This open-label, Phase Ib study (NCT00660153) sought to determine the MTD, dose-limiting toxicities (DLTs), pharmacokinetics (PK), and anti-tumor activity of escalating doses of tivozanib combined with a modified (m) FOLFOX6 regimen (85 mg/kg2 oxaliplatin) in pts with advanced GI tumors. Methods: Tivozanib was administered once daily in 4-week cycles (3 weeks on, 1 week off) with mFOLFOX6 administered on Days 1 and 15 of each cycle. Pts also received a single dose of tivozanib on day -5 for PK analysis. Pts were allowed to continue tivozanib following discontinuation of mFOLFOX6. Results: Twenty two pts (14:8 male:female; median age 58 years; 91% Caucasian) received tivozanib 0.5 mg (n=9), 1.0 mg (n=3), or 1.5 mg (n=10) and mFOLFOX6. Pts received a median of 5.2 (range 0.0 to 25.1) months of treatment. DLTs were observed in 2 pts on tivozanib 0.5 mg (reversible Grade [Gr] 3 diarrhea and Gr 3/4 transaminase elevations) and in 2 pts on tivozanib 1.5 mg (Gr 3 seizure and reversible Gr 3 vertigo). Other Gr 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n=2 each). Eight pts discontinued treatment due to AEs. The MTD for tivozanib with mFOLFOX6 was 1.5 mg. The disease control rate was 63% (<1% complete response, 27% partial response, 36% stable disease). Preliminary PK data showed no interaction between tivozanib and mFOLFOX6. Eight additional pts enrolled at the 1.5 mg dose level are currently being evaluated. Final results will be presented. Conclusions: Tivozanib can be combined at its recommended dose of 1.5 mg/day with mFOLFOX6 for pts with advanced GI tumors. The combination was tolerable and showed encouraging anti-tumor activity. A Phase II study of this combination for mCRC is ongoing.
Axitinib for first-line metastatic renal cell carcinoma (mRCC): Overall efficacy and pharmacokinetic (PK) analyses from a randomized phase II study.
Authors: Rini Brian I. , Grünwald Viktor , Fishman Mayer N. , Melichar Bohuslav , Ueda Takeshi , Karlov Petr A , Bair A H. , Chen Ying , Kim Sinil , Jonasch Eric
Published: March 2020

4503

Background: Axitinib is a potent, selective, second-generation inhibitor of vascular endothelial growth factor receptors with efficacy in mRCC. Due to PK and pharmacodynamic variability, some patients have sub-optimal drug exposures at the standard 5-mg twice daily (BID) dose. Prior analyses indicated higher drug exposure enhanced efficacy; thus, dose titration based on individual tolerability may optimize exposure and improve outcomes. A randomized phase II trial evaluated the efficacy and safety of axitinib dose titration from 5 mg BID to a maximum of 10 mg BID in first-line mRCC. Methods: Patients with treatment-naïve mRCC received axitinib 5 mg BID for a 4-week lead-in period (cycle 1). Then, patients with 2 consecutive weeks of blood pressure (BP) ≤150/90 mmHg, no axitinib-related toxicities >grade 2, no dose reductions, and ≤2 antihypertensive medications were randomized in a double-blind fashion to axitinib 5 mg BID + dose titration with either axitinib (arm A) or placebo (arm B); those ineligible for randomization continued with same dose (arm C). Primary endpoint is objective response rate (ORR). Serial 6-hr PK sampling and 24-hr ambulatory BP monitoring (ABPM) were performed on cycle 1 day 15 in a subset of patients. Results: In all, 203 patients were accrued; 112 randomized to arms A or B, and 91 in arm C. As of July 1, 2011, ORR (95% confidence interval [CI]) was 40.2% (31.0, 49.9) in A+B (blinded pooled analysis) and 56.0% (45.2, 66.4) in C. Median progression-free survival (mPFS) (95% CI) was 13.7 mo (9.2, not estimable [NE]) in A+B and 12.2 mo (8.6, 16.7) in C. Patients with drug exposure above therapeutic threshold (AUC24 ≥300 ng·h/mL; n=27) on cycle 1 day 15 had longer mPFS and higher ORR than those with sub-therapeutic exposure (n=25) (mPFS [95% CI]: 13.9 mo [12.2, NE] vs 8.3 mo [5.5, NE]; ORR: 59% vs 48%). Patients with mean increases of diastolic BP (ΔdBP) ≥15 mmHg (n=18) per ABPM had higher ORR than those with ΔdBP <15 mmHg (n=36) (61% vs 53%). Conclusions: Axitinib is effective in first-line treatment of mRCC, with high ORR and mPFS >1 yr. Preliminary results suggest therapeutic drug exposure and ΔdBP ≥15 mmHg on cycle 1 day 15 may be associated with better outcomes.
Biomarker analysis and final results of INT70/09 phase II proof-of-concept study of pazopanib (PZP) in refractory urothelial cancer (UC).
Authors: Necchi Andrea , Zaffaroni Nadia , Mariani Luigi , Schwartz Lawrence H. , Nicolai Nicola , Giannatempo Patrizia , Crippa Flavio , Morosi Carlo , Gianni Alessandro M. , De Braud Filippo G. , Salvioni Roberto
Published: March 2020

4507

Background: Discouraging results have been achieved with standard and novel compounds in refractory UC. The final results with biomarker analysis of INT70/09 trial with pazopanib are presented. Methods: Pts failing ≥ 1 chemotherapy regimen for metastatic disease underwent PZP 800 mg once daily until PD or unacceptable toxicity. CT scan and PET scan were planned at baseline and q4weeks thereafter. Independent review of all CT scans was made and ≥ 5 RECIST CR+PR were required to conclude for activity according to Simon’s 2-stage design. 50 mL of EDTA blood samples were collected at baseline and q4wks in all pts to analyze plasma VEGF, sVEGFR-1,-2 and -3, c-Kit, IL-6, 8 and 12 by multiplex ELISA plates. Results: 41 pts were enrolled from 02/2010 to 07/2011. 15 pts (37%) had UC of the upper urinary tract. 20/41 pts were treated in 3rd line or beyond. 19 pts (46%) were CDDP-refractory and 22 (54%) had hepatic metastases. 27 (66%) had ECOG PS 1-2. 7 pts (17%) had a confirmed PR, 24 had a SD (76% clinical benefit). 20 pts (49%) had a confirmed necrotic evolution of metastases and/or a decreased SUV at PET consistent with PR. Median PFS and OS (95% CL) were 2.6 (1.7-3.7) and 4.7 mos (4.2-7.3), respectively but 7 pts (17%) had long-term cure for >10mos (4/7 beyond 2nd line). G3 hypertension occurred in 2 pts, diarrhoea in 5, anemia and hand-foot syndrome in 3 pts each. Significant increase from T0 (baseline) to T1 (+4wks) level was observed for VEGF (p<0.0001), IL6 (p<0.0129) and IL8 (p<0.0013) and decrease for VEGFR2 and c-Kit (p<0.0001 each). Rising IL8T1 levels significantly associated with RECIST progression at covariance analysis (p=0.0104). Elevated IL8T1 levels (IQ range, HR=2.11), liver mets (HR=2.33), PS (HR=3.73) and upper tract UC (HR=0.33) were significant variables for OS at multivariate Cox analysis. Conclusions: This is the 1st trial ever presented to meet the primary endpoint with a targeted drug in UC. A role for antiangiogenesis in UC has been set. Increasing levels of IL8 were associated with PD and worse outcome and may be included in a new prognostic model. Future investigation should aim at targeting IL8 to improve efficacy results by prolonging responses.
Primary, secondary, and quality-of-life endpoint results from the phase III AFFIRM study of MDV3100, an androgen receptor signaling inhibitor.
Authors: De Bono Johann Sebastian , Fizazi Karim , Saad Fred , Taplin Mary-Ellen , Sternberg Cora N. , Miller Kurt , Mulders Peter , Chi Kim N. , Armstrong Andrew J. , Hirmand Mohammad , Selby Brian , Scher Howard I. ,   for the AFFIRM Investigators
Published: March 2020

4519^

Background: MDV3100, a novel androgen receptor signaling inhibitor (ARSI), inhibits: 1) binding of androgens to AR, 2) AR nuclear translocation, and 3) association of AR with DNA. MDV3100 was active in a phase I-II trial enrolling pre- and post-docetaxel castration-resistant prostate cancer (CRPC) patients. The AFFIRM trial evaluated whether MDV3100 could provide benefit to men with post-docetaxel CRPC. Methods: In this double-blind, multinational phase III study, patients who had received docetaxel-based chemotherapy were randomized 2:1 to MDV3100 160 mg/day or placebo. Treatment with corticosteroids was allowed but not required. Patients were stratified by baseline ECOG and mean brief pain inventory score. The primary endpoint was overall survival (OS). Other efficacy endpoints included radiographic progression-free survival (rPFS), time to PSA progression (TTPP), soft tissue objective response (PR+CR), PSA response, and quality of life (QoL) response (FACT-P). Results: 800 patients were randomized to MDV3100 and 399 to placebo with respective median treatment durations of 8.3 and 3.0 months.Based on a planned interim analysis at 520 deaths, the Independent Data Monitoring Committee recommended the study be unblinded and placebo patients offered MDV3100. Efficacy results are presented (Table). The most common MDV3100 events with an incidence higher than placebo were fatigue (34% vs 29%), diarrhea (21% vs 18%), and hot flush (20% vs 10%). Grade >3 events of interest were cardiac disorders (0.9% MDV3100 vs 2% placebo), fatigue (6% MDV3100 vs 7% placebo), seizure (0.6% MDV3100 vs. 0% placebo), and LFT abnormalities (0.4% MDV3100 vs 0.8% placebo). Conclusions: MDV3100, a novel ARSI, is well-tolerated and significantly prolongs OS, slows disease progression, and improves QoL in men with post-docetaxel CRPC. [Table: see text]
Effect of neoadjuvant abiraterone acetate (AA) plus leuprolide acetate (LHRHa) on PSA, pathological complete response (pCR), and near pCR in localized high-risk prostate cancer (LHRPC): Results of a randomized phase II study.
Authors: Taplin Mary-Ellen , Montgomery Robert B. , Logothetis Christopher , Bubley Glenn J. , Richie Jerome P. , Dalkin Bruce L. , Sanda Martin G. , Loda Massimo F. , True Lawrence D. , Troncoso Patricia , Genega Elizabeth M. , Balk Steven P. , Nelson Peter , Xie Wanling , Haqq Christopher M. , Tran Namphuong , Liu Cameron S. , Kheoh Thian San , Molina Arturo , Kantoff Philip
Published: March 2020

4521

Background: LHRPC is infrequently cured with prostatectomy (RP). To date neoadjuvant androgen deprivation therapy (ADT) has not improved outcomes and residual intra-prostatic androgens remain. AA lowers serum testosterone (T) and DHT to < 1 ng/dL and has improved survival in advanced PC. Methods: We conducted a neoadjuvant, phase II trial of AA/LHRHa in LHRPC. The primary aim was to evaluate intra-prostatic T/DHT with LHRHa vs LHRHa/AA. We report secondary endpoints of PSA, pCR and near pCR ([≤ 5mm residual tumor]) and safety. Eligibility: ≥ 3 positive biopsies and either Gleason ≥ 7 (4+3), T3, PSA ≥ 20 ng/mL or PSA velocity > 2 ng/mL/year. For the first 12 wks men were randomized to LHRHa or LHRHa/AA/prednisone (P) 5mg qd. After 12 wks, a prostate biopsy was done to measure T/DHT. Men received 12 more wks of LHRHa/AA/P followed by RP. Results: 58 men enrolled: 28 to initial LHRHa and 30 to initial AA/LHRHa. 2 withdrew prior to RP (1/group). Median age was 58 (50-75). pCR/near pCR was 14/56 (25%). Grade 3 AEs included elevated AST/ALT 5/58 (9%) and hypokalemia 3/58 (5%). No grade 4 mineralocorticoid-related AEs were observed. Conclusions: Neoadjuvant ADT with AA was well tolerated in LHRPC. PSA (<0.2) declines were high and achieved earlier on AA/LHRHa compared to LHRHa. The pCR/near pCR rates were higher for 24 wks AA (34%) than 12 wks AA (15%). No new safety signals were seen with AA used with P 5 mg. These results support further evaluation of aggressive ADT as neoadjuvant/adjuvant therapy for LHRPC. [Table: see text]
Five years into the national second-opinion project of the German Testicular Cancer Group (GCTSG): Impact on guideline implementation and the quality of care for testicular cancer patients.
Authors: Zengerling Friedemann , Hartmann Michael , Heidenreich Axel , Krege Susanne , Albers Peter , Karl Alexander , Wagner Walter , Bedke Jens , Schmelz Hans U. , Retz Margitta , Kliesch Sabine , Winter Eva , Kuczyk Markus , Schrader Mark ,   on behalf of the German Testicular Cancer Study Group (GTCSG), supported by the German Cancer Aid
Published: March 2020

4530

Background: The diagnosis and therapy of testicular germ cell tumors are subject to constant change. Numerous national and international guidelines have been published since the 1990s in order to meet this challenge. It is questionable, however, whether mere publication of guidelines will lead to their implementation. The aim of the present project of the GTCSG was to establish a national second-opinion network in order to improve the implementation of guidelines and the quality of care. Methods: Before determining the primary therapy, participating urologists could communicate with one of 30 second-opinion centers (SOC) via an internet-based platform. The data set comprised the primary clinical, radiological and pathohistological findings, the therapy planned by the advice seeker (first opinion), the therapy recommended by the SOC (second opinion), and the applied therapy as well as the 2-year follow-up data. Primary end points of the study were congruence between the first and second opinion, treatment changes based on the second opinion, and relapse-free 2-year survival. Results: A total of 1722 SOC requests have been submitted since November 2006. At the time of our data analysis 927 cases were evaluated. The response rate was 75.8% for treatment data and 74.4% for 2-year follow-up data. Advice seekers and SOC had discrepant treatment concepts in 43.3% of the cases; this discrepancy was independent of tumor histology and increased in advanced tumor stages (clinical stage ≥IIa: 52.3% vs. <IIa: 34%; p<0.001, Pearson Χ2 test). The SOC request led to reduction of the applied therapy in 11.4% and intensification in 9.5% of the cases. Progression-free 2-year survival was 92% (112/122) for stage I, 90% (17/19) for stage IIa-IIb, and 65% (17/26) for stage ≥IIc. Conclusions: Guidelines for the treatment of germ cell tumors are inadequately implemented, particularly in advanced tumor stages. Every fifth second opinion resulted in a relevant change in the scope of therapy. Patients whose treatment was congruent with the second opinion had a relapse rate comparable to that of study results in the literature.
Serum tumor marker (STM) decline rates during high-dose chemotherapy (HDCT) to predict outcome for germ cell tumor (GCT) patients (pts).
Authors: Feldman Darren Richard , Voss Martin Henner , Jia Xiaoyu , Van Alstine Lindsay Joy , Patil Sujata , Fischer Patricia , Sheinfeld Joel , Bosl George J. , Motzer Robert John
Published: March 2020

4532

Background: STM decline rates predict outcome for GCT pts during 1st-line conventional-dose chemotherapy. We investigated the importance of STM decline rates during salvage HDCT. Methods: HDCT included an initial low dose (LD) portion (1-2 cycles of paclitaxel plus ifosfamide [TI] + G-CSF) for stem cell collection followed by a high-dose (HD) portion (3 cycles of carboplatin + etoposide or TI + carboplatin). Eligible pts had elevated STM (AFP >15 and/or HCG >2.2) at the start of LD and completed ≥1 HD cycle. Slope and t1/2 were calculated for HCG and AFP for cycles 1-2 of LD and HD starting with the peak value during days (d) 1-6 of LD and HD to avoid interference from lysis. T1/2 for AFP ≤7d and HCG ≤3.5d were categorized as satisfactory (SAT); normalization within 7d was also considered SAT, regardless of t1/2. Pts with elevated AFP and HCG had to have adequate decline in both to be considered SAT. Progression-free (PFS) and overall survival (OS) were compared for SAT vs. unsatisfactory (UNSAT) pts using the log-rank test. Results: Of 117 pts (115 male, 105 nonseminoma), the most common primary sites were testis (81) and mediastinum (26). 93, 19, and 5 pts completed 3, 2, and 1 HD cycles, respectively. Overall, 19/117 had SAT decline during LD (19/77 for HCG; 7/57 for AFP). For LD, there was no significant difference in PFS or OS for SAT vs. UNSAT decline. For HD, 17/96 had SAT decline (11/59 for HCG; 9/47 for AFP). SAT overall decline (HCG and AFP) during HD predicted superior PFS (p=0.0025) and OS (p=0.0046) with 2-year (yr) PFS 0.88 (0.59, 0.97) vs. 0.37 (0.26, 0.47) and 3yr OS 0.82 (0.55, 0.94) vs. 0.37 (0.26, 0.48). SAT HCG decline alone also predicted superior PFS (p=0.0018) and OS (p=0.004) with 2yr PFS 0.91 (0.51, 0.99) vs. 0.32 (0.19, 0.46) and 3yr OS 0.91 (0.51, 0.99) vs. 0.35 (0.22, 0.50) whereas only a non-significant trend for improved PFS (p=0.14) and OS (p=0.16) was seen for AFP alone. Conclusions: STM decline rates during the HD portion of salvage HDCT predicts favorable PFS and OS, mostly driven by HCG. However, UNSAT STM decline does not exclude long-term PFS/OS. STM decline rates during the initial LD portion of HDCT programs do not predict outcome; thus, UNSAT LD decline should not prohibit subsequent HDCT.
PFS to predict long-term OS after first-line treatment for advanced renal cell carcinoma (aRCC): Correlation and power analysis of randomized trials (RCT).
Authors: Milella Michele , Massari Francesco , La Russa Francesca , Maines Francesca , Felici Alessandra , Vaccaro Vanja , Porta Camillo , Bracarda Sergio , Cognetti Francesco , Giannarelli Diana , Tortora Giampaolo , Bria Emilio
Published: March 2020

4541

Background: Targeted agents (TA) have become standard 1st line aRCC treatment based on evidence of PFS advantage. Retrospective series indicatePFS as a reliable intermediate end-point in this setting; however, correlation, surrogacy testing, and validation are required. Methods: RCT evaluating the efficacy of TA as 1st line treatment for aRCC were eligible. PFS/OS Response/Disease Control rates (ORR, DCR) and HR were extracted from papers/updated presentations. Correlations between 6-, 9-, and 12-mo PFS and OS rates according to parametric (Pearson’s r) and non-parametric (Spearman’s Rho and Kendall’s Tau) coefficients (with 95% CI) were analyzed to avoid lead-time biases. Regression analysis (parametric R2) and a power-analysis-model to determine patients’ sample necessary to detect 3%, 5% and 10% OS gain were developed. Results: Six RCT (4096 pts) were gathered. The best overall correlation between PFS and OS at concurrent timepoints was found at 9 mos. With regard to overall rates, 3- and 6-mo PFS significantly correlated with 9-mo OS, as shown in the table below. Pearson’s coefficients for the correlation between 3-mo PFS and 6- and 12-mo OS were 0.70 (p=0.01) and 0.67 (p=0.01); the correlation between 6-mo PFS and 12-mo OS was also significant (Pearson 0.74, p=0.005; Spearman 0.83, p=0.005; Tau 0.71, p=0.001). The regression equation was: Y=0.391861 + 0.4914X [R2 0.44, p(slope)=0.01]; based on this model, the demonstration of a 3-mo PFS absolute difference of 6%, 10% and 21% (corresponding to a 9-mo OS benefit of 3%, 5% and 10%) would require 2043, 696 and 155 patients, respectively. A significant correlation was also found between DCR and OS. Conclusions: Early PFS is an acceptable intermediate end-point for OS in the context of 1st line TA for aRCC. Individual patient data analysis to verify Prentice criteria would be required for definitive confirmation. [Table: see text]
A phase I study of the androgen signaling inhibitor ARN-509 in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Rathkopf Dana E. , Morris Michael J. , Danila Daniel Costin , Slovin Susan F. , Steinbrecher Jill Elise , Arauz Gabrielle , Curley Tracy , Rix Peter J. , Chow Maneval Edna , Chen Isan , Fleisher Martin , Landa Jonathan , Fox Josef J. , Larson Steven M. , Scher Howard I.
Published: March 2020

4548

Background: ARN-509 is a novel small molecule AR antagonist that impairs AR nuclear translocation and binding to DNA, inhibiting tumor growth and promoting apoptosis, with no partial agonist activity. (Clegg et al., 2012) We conducted a phase I trial to assess safety, pharmacokinetics (PK), and determine the recommended phase II dose (RP2D). Methods: Eligible patients with mCRPC received ARN-509 orally on a continuous daily dosing schedule. Seven doses (30, 60, 90, 120, 180, 240, and 300 mg) were tested using standard 3x3 dose escalation criteria. Once drug concentrations were achieved that met or exceeded optimal levels predicted preclinically, an additional 2 dose levels were tested to further confirm the safety margin of ARN-509 (390 and 480 mg). Anti-tumor activity was assessed by PSA, radiographic responses, and FDHT-PET imaging. Results: Thirty patients were enrolled. The most common grades 1-2 treatment-related adverse events were fatigue (38%), nausea (29%), and pain (24%). There was only 1 treatment-related grade 3 adverse event (abdominal pain) at 300 mg, possibly related to a higher pill burden. PK was shown to be linear and dose-dependent. At 12 weeks, 42% of patients have had ≥ 50% PSA declines. Eleven (37%) patients have discontinued the study due to progression, with the longest patient still on study for more than 16 months. FDHT-PET imaging demonstrated AR blockade at 4 weeks across multiple dose levels. Conclusions: In this phase I study, ARN-509 was shown to be safe and well tolerated with linear PK. Based on promising activity across all dose levels and pharmacodynamic evidence of AR antagonism, an optimal biologic dose of 240 mg daily was selected for phase II investigation. DOD/PCF PCCTC trial sponsored by Aragon Pharmaceuticals.