bluuebunny/crossref_metadata_2025 huggingface dataset:
Docetaxel pharmacogenetics: The influence of RXRα and HNF4α genetic variations on docetaxel disposition in Asian nasopharyngeal carcinoma patients.
Authors: Chew Sin Chi , Singh Onkar , Chen Xiangai , Lim Wan-Teck , Tan Eng-Huat , Lee Edmund Jon Deoon , Chowbay Balram
Published: March 2020

2598

Background: The transactivations of the metabolism enzymes (CYP3A4/5) and efflux transporters (ABCB1/ABCC2) involved in docetaxel disposition are regulated by the orphan nuclear receptors such as PXR, CAR, RXRα and HNF4α. This study aimed to explore the associations between the genetic variations present in the genes encoding the orphan nuclear receptors, RXRα and HNF4α, on docetaxel disposition. Methods: The DNAs from healthy Chinese, Malay and Indian subjects (n=56 each) were screened for RXRα and HNF4α SNPs in exons and intronic/exonic boundaries by direct sequencing. The high frequency SNPs (>1%) were profiled in a cohort of local nasopharyngeal cancer patients (n=54). Genotypic-phenotypic correlations were conducted using Mann-Whitney U-test and Kruskal-Wallis test. Results: Eighty-eight and sixty-nine SNPs were identified from the healthy screening of RXRα and HNF4α, respectively, across 3 populations. A total of 30 and 35 high frequency SNPs in RXRα and HNF4α, respectively, were profiled in the patients. Six RXRα SNPs [IVS2+33G>A (rs2234753), IVS7+70A>G (rs1536475),*846G>A (rs4240711), *+4458G>A (rs3132291), *+4768C>A (rs4842196) and *+4988A>G (rs4842198)] and 6 HNF4α SNPs [-728A>C (rs1800963), IVS2-278A>G (rs55934816), IVS6+141A>G (rs6103731), IVS7-88T>C (rs2273618), IVS9–145T>C (rs3746574) and IVS9-67C>G (rs3746575)] were significantly associated with higher clearance and lower AUC0-∞ and/or Cmax of docetaxel (P<0.05). Conversely, HNF4α SNP [IVS9+354G>T (rs3818247)] was associated with lower clearance and higher AUC0-∞ and Cmax of docetaxel (p<0.05). A high linkage pattern was observed among the abovementioned RXRα SNPs except for IVS2+33G>A (rs2234753) (D'≥0.74). Similarly, HNF4α SNPs were found to be highly linked, except for -728A>C (rs1800963) (D'≥0.62). Conclusions: The results highlight the contributions of RXRα and HNF4α pharmacogenetics in influencing the inter-individual variability in docetaxel disposition in Asian nasopharyngeal patients.
Biomarkers of vincristine neuropathy in Kenyan children.
Authors: Skiles Jodi L , Chiang ChienWei , Li Claire , Li Lang , Olbara Gilbert , Tallam Celestine , Njuguna Festus , Renbarger Jamie L.
Published: March 2020

2601

Background: In a U.S. population, cytochrome P450 (CYP) 3A5 high-expressers metabolize vincristine (VCR) more efficiently than low-expressers and vincristine-induced peripheral neuropathy (VIPN) is less common in African-Americans than Caucasians. We test the hypothesis that more children in Kenya are CYP3A5 high-expressers compared to U.S. children and as such experience less VIPN. Methods: This study was conducted in Kenyan children with cancer (n=78) being treated with VCR at Moi University AMPATH Oncology Institute in partnership with Indiana University. Saliva Oragene kits for DNA extraction and genotyping were obtained. Whole blood was collected via finger stick on Whatman protein saver dried blood spot cards for analysis of VCR concentrations. VIPN was assessed prospectively using two neuropathy assessment tools (Modified Total Neuropathy Score (TNS) and National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 4.0). Results: Compared to 14% in the U.S. sample, 94% of Kenyan subjects are CYP3A5 high-expressers (p<2.2x10-16). Kenyan children have significantly lower VCR plasma concentrations (11.15ng/ml/mg ± 1.051) compared to US (primarily Caucasian) children (13.26ng/ml/mg ± 2.897) one hour following the administration of VCR (p=0.011). By TNS VIPN assessment, 71% of Kenyan children developed VIPN compared to 100% of U.S. children (p=8.8x10-7). CYP3A5 high-expresser genotype is associated with lower TNS VIPN severity scores than low-expresser genotypes (p=0.006). TNS VIPN assessments show that height is positively correlated with severity of VIPN (p=0.025). CTCAE VIPN assessments also showed a positive correlation with height (p=0.036), but did not show any association with CYP3A5 genotype. Conclusions: Kenyan children are more likely to be CYP3A5 high-expressers than U.S. children and as such may metabolize VCR more efficiently. Supporting these data is that Kenyan children experience significantly less VIPN than U.S. children. CYP3A5 genotype and height are independent predictors of VIPN in Kenyan children with cancer. The CTCAE may lack sufficient sensitivity to detect VIPN for use in future studies aimed at optimizing VCR dosing strategies.
Bendamustine plus rituximab (B-R) versus CHOP plus rituximab (CHOP-R) as first-line treatment in patients with indolent and mantle cell lymphomas (MCL): Updated results from the StiL NHL1 study.
Authors: Rummel Mathias J. , Niederle Norbert , Maschmeyer Georg , Banat Andre G. , von Gruenhagen Ulrich , Losem Christoph , Kofahl-Krause Dorothea , Heil Gerhard , Welslau Manfred , Balser Christina , Kaiser Ulrich , Weidmann Eckhart , Duerk Heinz A. , Ballo Harald , Stauch Martina , Barth Juergen , Hinke Axel , Brugger Wolfram ,   Study Group Indolent Lymphomas (StiL)
Published: March 2020

3

The full, final text of this abstract will be available at abstract.asco.org at 12:01 AM (EDT) on Sunday, June 3, 2012, and in the Annual Meeting Proceedings online supplement to the June 20, 2012, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Phase I/II study of the investigational aurora A kinase (AAK) inhibitor MLN8237 (alisertib) in patients (pts) with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), breast cancer (BrC), head/neck cancer (H&N), and gastroesophageal (GE) adenocarcinoma: Preliminary phase II results.
Authors: Lee Peter , Alvarez Ricardo H. , Melichar Bohuslav , Adenis Antoine , Bennouna Jaafar , Schusterbauer Claudia , Zhang Bin , Benaim Ely , Rosen Peter J.
Published: March 2020

3010

Background: AAK is a key mitotic regulator that is amplified or overexpressed in multiple tumor types. MLN8237 is an investigational oral, selective AAK inhibitor being studied in both hematologic (phase III) and nonhematologic malignancies. In the phase 1 part of this study, MLN8237 was generally well tolerated in pts with solid tumors. The maximum tolerated dose was 50 mg BID for 7d + 2 wks rest in 21-d cycles; this dose was recommended for phase II evaluation. Here we report preliminary data from the 5-arm phase 2 part (NCT01045421). Methods: 20 pts each with one of 5 tumor types in the relapsed/refractory setting were enrolled in phase II for efficacy evaluation: NSCLC (inc. 8–10 pts with mainly squamous-cell histology), SCLC (inc. 8–12 chemotherapy refractory pts), BrC (inc. 8–10 pts with a basal-like intrinsic subtype, and 8–10 HER2+ pts), H&N (inc. 8–12 pts with tonsillar or base-of-tongue disease), or GE adenocarcinoma. Pts were aged ≥18 y, and had ECOG PS 0–1, measurable disease by RECIST, and ≤2 prior cytotoxic chemotherapy regimens (≤4 in BrC). Oral MLN8237 was administered as an enteric-coated tablet at 50 mg BID for 7d + 2 wks rest in 21-d cycles. The primary endpoint was overall response rate. Response was determined by RECIST v1.1. Each arm with ≥2 partial responses (PR) is being expanded with 25 additional pts. Results: In 100 efficacy-evaluable pts, median age was 59 y (range 33–88) and 89% were caucasian. Pts received a median of 3 cycles (range 1–9). PRs were observed in 11 pts: H&N, SCLC (each n=3), BrC, GE adenocarcinoma (each n=2), and NSCLC (n=1). 45 pts had a best response of stable disease. In the safety population (n=196), most frequent grade ≥3 drug-related AEs were neutropenia (37%), leukopenia (12%), fatigue, anemia, stomatitis, and thrombocytopenia (each 6%). Updated data will be presented. Conclusions: Preliminary phase II data suggest that oral MLN8237 is tolerable and has antineoplastic activity in a range of solid tumors studied. This study is currently ongoing to further evaluate MLN8237 in the expansion cohorts.
Molecular profiling of patients (pts) with colorectal cancer (CRC) and matched targeted therapy (MTA) in phase I clinical trials.
Authors: Dienstmann Rodrigo , Sanchez-Olle Gessami , Serpico Danila , Rodon Ahnert Jordi , Saura Cristina , Macarulla Teresa , Fernandez Maria Elena Elez , Alsina Maria , Perez-Garcia Jose Manuel , Capdevila Jaume , Argiles Guillem , Brana Irene , Cruz Cristina , Azaro Analia , Moreno-Fernandez Debora , Aura Claudia , Hernandez-Losa Javier , Vivancos Ana , Ramon y Cajal Santiago , Tabernero Josep
Published: March 2020

3014

Background: Molecular prescreening and biomarker enrichment strategies in Phase 1 trials with targeted therapies are anticipated to improve the outcomes of affected pts. Methods: As part of our personalized oncology program, tumors from pts with advanced chemorefractory CRC were analyzed for specific molecular aberrations (KRAS/ BRAF/ PIK3CA mutations [mut], PTEN and pMET expression) at the Vall d'Hebron Molecular Pathology and Genomics Labs. Those whose tumors were found to have a dysregulation were offered a Phase 1 trial with MTA. Results: During 2010 and 2011, tumor molecular analysis was performed in 254 pts: KRAS mut (80/254, 31.5%), BRAF mut (24/196, 12.2%), PIK3CA mut (15/114, 13.2%), KRAS+PIK3CA mut (9/114, 7.9%), PTEN low (97/183, 53.0% - HSCORE<50; 45/183, 24.6% - PTEN null), KRAS mut + PTEN low (38/138, 20.8%), pMET high (38/64, 59.4% with HSCORE>30). In total, 68 pts (median, age 63 yrs; prior therapies 3), received 82 different matched therapies. Type of MTA: PI3K pathway inh (if PIK3CA mut, n=10; or PTEN low, n=32), MEK+PI3K pathway inh (if KRAS mut, n=10; or BRAF mut, n=1), second-generation anti-EGFR mAbs (if KRAS wild-type, n=11), anti-HGF mAb (if pMET high, n=10), mTOR inh + anti-IGFR-1R mAb (if PTEN low, n=5) and BRAF inh (if BRAF mut, n=3). Median time to treatment failure (TTF) with MTA was 7.9 weeks (CI95%:7.6-8.1) vs. 16.3 weeks (CI95%:13.9-18.7) for their prior systemic antitumor therapy (p<0.001). If prior therapy non-standard (according to NCCN guidelines, n=39), TTF with MTA 7.9 weeks (CI95%:6.8-8.9) vs. TTF with prior therapy 8.7 weeks (CI95%:7.3-10.1). If an approved standard regimen (n=43), TTF with MTA 7.9 weeks (CI95%:7.6-8.1) vs. TTF with prior therapy 21.9 weeks (CI95%:15.0-28.7). Partial response was seen in one pt (1.2%, PI3K inh with PIK3CA mut) and stable disease > 16 weeks in 10 cases (12.2%). Clinical benefit, defined as a TTF ratio ≥ 1.3 (TTF on MTA/ TTF on prior therapy), was seen with 15.9% of the therapies (13/82). Conclusions: Preliminary results suggest that matching chemorefractory CRC patients with targeted agents in early clinical trials based on the current molecular profile does not result in longer TTF compared to their prior therapy.
A phase I, single-institution, open-label, dose escalation trial with an expansion cohort evaluating the safety and tolerability of AZD6244 and IMC-A12 in subjects with advanced solid malignancies.
Authors: Ahmed Shabina Roohi , Ball Douglas Wilmot , Cosgrove David , Scardina Angela , Petito Emily , Downs Melinda , Nelkin Barry , Chen Helen X. , Doyle Laurence A , Donehower Ross C. , Carducci Michael Anthony , Azad Nilofer Saba
Published: March 2020

3020

Background: Significant crosstalk exists between the PI3K and Raf/MEK/ERK pathways and treatment of select cell lines with a MEK inhibitor and an IGF1-R inhibitor has been shown to cause greater inhibition of growth than either agent alone. IMC-A12 (I) is a recombinant human monoclonal antibody directed IGFI-R; it blocks interaction between IGF-1R and its ligands, IGF-I and -II. AZD6244 (A) is a highly selective, non-competitive MEK ½ inhibitor. Methods: The study is a phase I, dose-escalation with a standard 3+3 design. Eligible patients had advanced solid tumor, good end organ function and performance status with exclusion for poorly controlled diabetes or growth hormone abnormalities. Part 1: open label, dose escalation. Pts were treated with A at 50 mg BID, then 75 mg BID; I at 12mg/kg q2wk held constant. DLTs were defined as grade (G) 3 or 4 toxicities during cycle 1. Part 2: expansion cohort of 15 pts for correlative endpoints and PK studies; serial tumor biopsies will be evaluated for changes in signaling in the IGF pathway, including p-ERK, p-Akt and RAS. Mutational analysis of RAS and RAF will be done to correlate with PD endpoints and disease response. Results: Part 1: 16 patients accrued with 6 treated at DL1 and 10 treated at DL2. Multiple tumor types were represented, including 4 colon, 2 thyroid, 2 pancreatic, and 1 breast. At 75 mg of A, there was 1 DLT of visual changes. G3 AEs included nausea/vomiting (n=2, 12%), visual changes/retinopathy (n=2, 12%), MRSA skin infection (n=1, 6%), (n=1, 6%), hyperglycemia (n=1, 6%), and stroke (n=1, 6%). Other common AEs included acneform rash (n=10, 63%), nausea/vomiting (n=6, 37%), anorexia (n=4, 25%), and diarrhea (n=3, 19%). Of 10 evaluable patients in Part 1, 1 had a partial response and 4 patients had stable disease (40%). Sustained responses of 10 and 14 months were seen in the DTC patients. 3 patients are currently enrolled in the expansion cohort. The RP2D is 50 mg of A, due to the visual changes seen with 75 mg, and 12mg/kg of I. Conclusions: A at 50 mg QD combines safely with I 12mg/kg. An expansion cohort is underway to determine if this combination warrants further investigation.
Phase I study of vandetinib in combination with gemcitabine and oxaliplatin in advanced solid malignancies.
Authors: Wang Peng , Owonikoko Taofeek Kunle , Lin Yan , Stoller Ronald G. , Petro Daniel P. , Park Deric M. , Ramanathan Ramesh K. , Chu Edward , Beumer Jan Hendrik , Appleman Leonard Joseph
Published: March 2020

3037

Background: Vandentinib (VAN) is a tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor-2 (VEGFR-2) and 3 (VEGFR-3) as well as epidermal growth factor receptor (EGFR) and RET (‘rearranged during transfection’). Combinations of VEGFR kinase inhibitors and cytotoxic agents have been studied with interest, but have been associated with increased toxicity. This phase I trial evaluated the safety, tolerability and maximum tolerated dose of VAN in combination with gemcitabine (GEM) and oxaliplatin (OX). Methods: Subjects with advanced solid malignancy, ≤ 2 prior regimens with adequate hematologic, hepatic and renal function were eligible. GEM and OX were administered intravenously at 1000 mg/m2 and 85 mg/m2 respectively every 14 days. VAN was administered orally at two dose levels: level 1 (200 mg) and level 2 (300 mg) once daily continuously. After a maximum of 6 cycles of GEMOX, non-progressing patients were allowed to continue VAN until progression or intolerance. A dose level was determined to be tolerable if <2 DLTs out of 6 evaluable subjects were observed. Response was assessed by restaging scan after every 2 cycles. Results: A total of 20 subjects were enrolled in the study; 15 male, 5 female. Median age 62 years (47-68). Nine subjects were enrolled on dose level 1 and 11 subjects on dose level 2. One subject in dose level 1 experienced a deep venous thrombosis in cycle 1 deemed a DLT. Thrombocytopenia (worst-grade 3) as well as diarrhea and rash (worst-grade 2) were observed in several patients, without dose-limiting toxicity in cycle 1. Reversible posterior leukoencephalopathy was observed in 1 subject following abrupt self-discontinuation of an antihypertensive mediation. The recommended phase 2 dose was established as GEM (1000mg/m2) OX (85mg/m2) and VAN (300mg). One subject with refractory small cell lung cancer had a confirmed partial response, and 10 subjects (pancreas-7, bladder-2 and biliary-1) achieved stable disease ≥12 weeks. Conclusions: VAN in combination with GEM/OX was well tolerated at full doses of each of the 3 agents. Preliminary anti-tumor activity seen in refractory solid tumors supports further evaluation of this regimen.
First-in-human phase I study of a selective VEGFR/FGFR dual inhibitor sulfatinib in patients with advanced solid tumors.
Authors: Xu Jian-Ming , Wang Yan , Shen Lin , Gong Jifang , Huang Cheng , Ye Chen Yang , Yang Li , Sai Yang , MU Hua
Published: March 2020

3040

Background: Sulfatinib is a highly selective oral small molecule tyrosine dual inhibitor of vascular endothelial growth factor receptors (VEGFR) and fibroblast growth factor receptors (FGFR). It demonstrated potent in vivo inhibitory effects on a variety of human tumor xenografts. Methods: This phase I dose-escalation study were to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, and preliminary antitumor activity, and to assess potential pharmacodynamics (PD) markers of sulfantinib when given orally in continuous cycles of 28 days, until disease progression or unacceptable toxicity. Results: Forty one patients (pts) have been enrolled and treated with doses of 50-300mg once or twice daily. Pts had a median age of 50 (36-70) yrs, with 63% male and 93% gastrointestinal tumors. Common adverse events (AEs) included fatigue, hypertension, vomiting, nausea, diarrhea, electrolyte disorder and elevated AST/ALT, mostly grade (G) 1/2. Three DLTs including a G3 coagulation disorders, upper gastrointestinal bleeding and impaired liver function were observed in the 50 and 265mg qd and 150mg bid cohorts, respectively. MTD has not been reached and the dose escalation is ongoing. Among 28 evaluable pts, 10 (36%) had stable disease (SD) for 8 weeks or longer, including liver and neuroendocrine cancer, GIST and solid-pseudopapillary tumor of pancreas. A patient with GIST had SD of 9 months at 265mg qd. There was a significant decrease in soluble VEGFR2 level and increase in FGF23 level after 4-week treatment comparing to the baseline at 265 mg or higher daily doses, indicating inhibition of both VEGFR2 and FGFR. PK analyses showed that sulfatinib was rapidly absorbed with Tmax 1.3~2.8h and half-life of 15.3~19.1h. Both Cmax and AUC displayed dose-proportional increases and no obvious accumulation occurred at day 28. Conclusions: Sulfatinib was well tolerated at doses up to 300 mg per day and demonstrated preliminary anti-tumor activity, especially in liver cancer and GIST. PD marker analysis indicates dual inhibition of VEGFR and FGFR. PK data suggests good dose proportionality in exposure without marked drug accumulation.
Phase Ib study of CNTO 888 (anti-CCL 2) in combination with chemotherapies for treatment of patients with solid tumors.
Authors: Calles Antonio , Brana Irene , LoRusso Patricia , Yee Lorrin , Puchalski Thomas , Seetharam Shobha , Balvers Melan , De Boer Carla , Elsayed Yusri A. , Calvo Emiliano , Tabernero Josep
Published: March 2020

3059

Background: CC-chemokine ligand 2 (CCL2) is expressed in various malignancies, implicated in angiogenesis, proliferation and metastasis. CNTO888 is a hIgG1κ mAb with selective high CCL2 binding affinity and showed preclinical antitumor activity. Methods: Primary objectives were safety and a recommended dose of CNTO 888 in combination with chemotherapy: Arm 1 - 15 mg/kg CNTO 888 + docetaxel 75 mg/m2 Q3W; Arm 2 - 15 mg/kg CNTO 888 + gemcitabine 1000 mg/m2 on D1 and 8 Q3W; Arm 3 - 15 mg/kg CNTO 888 + paclitaxel 175 mg/m2 and carboplatin AUC6 Q3W; Arm 4 - 10 mg/kg CNTO 888 Q2W + pegylated doxorubicin 50 mg/m2 Q4W. Two (Arms 1, 2, 3) or 4 (Arm 4) prior chemotherapies for advanced disease were allowed. Pharmacokinetic (PK) profile of CNTO 888 and chemotherapies, free and total CCL2, CTC/CEC count, and uNTX were evaluated. Adverse events (AE) and dose limiting toxicities (DLT) were evaluated after 6 subjects completed 1 cycle. Results: 53 subjects (22F/31M) were treated: Arm 1 n=15, Arm 2 n=12, Arm 3 n=12, Arm 4 n=14. Two DLTs occurred: a grade 4 febrile neutropenia (Arm 1) and a grade 3 neutropenia (Arm 2). All 4 combinations were found to be safe and tolerable and continued enrolment to a minimum of 12 subjects evaluable for safety and PK. Best overall response were partial response (PR) (1) and stable disease (18; 2 ≥ 4 months). One subject with pancreatic adenocarcinoma achieved PR, allowing for surgical resection. Most frequently reported (≥ 20%) related serious AEs are: Arm 1: Neutropenia, Stomatitis, Fatigue, Febrile neutropenia, Alopecia. Arm 2: Anemia. Arm 3: Thrombocytopenia, Alopecia, Neutropenia, Asthenia, Fatigue, Anemia, Arthralgia, Nausea, Vomiting. Arm 4: Stomatitis, Rash, Fatigue, Nausea, Anemia, Neutropenia. CNTO 888 did not affect the chemotherapy PK profile; similarly, chemotherapy did not affect the CNTO 888 PK profile. No subjects (n=38) tested positive for antibodies to CNTO 888. Free CCL2 declined 2 hrs post treatment and returned to baseline levels by 48 hrs and continued to increase with further administrations in all treatment arms. There were no consistent changes with other biomarkers. Conclusions: CNTO 888 in combination with standard chemotherapy was well tolerated but few objective responses were seen.
Open-label extension study of the RNAi therapeutic ALN-VSP02 in cancer patients responding to therapy.
Authors: Alsina Maria , Tabernero Josep , Shapiro Geoffrey , Burris Howard , Infante Jeffrey R. , Weiss Glen J. , Cervantes-Ruiperez Andres , Gounder Mrinal M. , Paz-Ares Luis , Falzone Rick , Hill Jamie , Cehelsky Jeffrey , Vaishnaw Akshay , Gollob Jared , LoRusso Patricia
Published: March 2020

3062

Background: ALN-VSP02 is an RNA interference (RNAi) therapeutic comprised of lipid nanoparticle-formulated small interfering RNAs targeting vascular endothelial growth factor (VEGF)-A and kinesin spindle protein (KSP). In a phase 1 trial, ALN-VSP02 administered as an iv infusion q2 wks was well-tolerated and showed evidence of anti-VEGF pharmacology and antitumor activity. Methods: Patients treated on the phase I trial with stable disease (SD) or better after 4 months (8 doses) were eligible to continue on an extension study until disease progression. Main objectives included continued evaluation of safety/tolerability and assessment of disease response. Results: Seven of 37 patients (18.9%) evaluable for response went onto the extension study, including 1 of 7 (14.2%) at 0.4 mg/kg, 2 of 5 (40%) at 0.7 mg/kg, and 4 of 11 (36.3%) at 1.0 mg/kg. All had progressed after one or more prior therapies. Tumor types included head and neck squamous cell carcinoma, angiosarcoma, endometrial cancer, renal cell carcinoma (RCC, N=2), and pancreatic neuroendocrine tumor (PNET, N=2). At the time of enrollment, 6 had SD and one (endometrial cancer with multiple liver metastases) had an unconfirmed partial response (PR). The average length of time on treatment (including phase I and extension studies) was 9.5 months (range 5-19). As of January 2012, 3 patients remain on study, including the endometrial cancer patient with an ongoing PR who has had >80% tumor regression after 19 months of treatment at 0.7 mg/kg and two patients with RCC and PNET with continued SD after nearly 1 year of treatment at 1.0 mg/kg. The other patients with RCC and PNET at 1.0 mg/kg with SD came off after 8.5 and 5.5 months, respectively, for adverse events that included fatigue or elevated alkaline phosphatase. A decrease in spleen volume, likely an on-target effect and not associated with any adverse events, occurred to a greater degree on the extension study than on the phase I trial and was most pronounced in patients receiving ≥ 12 doses. Conclusions: ALN-VSP02 has preliminary activity against endometrial cancer, RCC and PNET and a favorable safety profile that permits chronic dosing. Phase II trials are warranted in these and other VEGF-overexpressing tumors.
ME-143, a novel inhibitor of tumor-specific NADH oxidase (tNOX): Results from a first-in-human phase I study.
Authors: Kurkjian Carla , Pant Shubham , Burris Howard A. , Bendell Johanna C. , Jones Suzanne Fields , Moore Kathleen N. , Moreno Ofir , Mass Robert D. , Infante Jeffrey R.
Published: March 2020

3067

Background: ME-143, a second generation isoflavone-derived compound, specifically binds tNOX, shifting the ceramide-S1P equilibrium and resulting in prompt apoptosis via pleotrophic caspase activation. A first generation compound, phenoxodiol (PXD), showed promising phase II activity with cisplatin in ovarian cancer. ME-143 is broadly active against human cancers in both in vitro and in vivo models, with IC50’s 1-2 logs lower than PXD. Toxicology studies up to 140mg/kg (human dose equivalent ~23mg/kg) showed no STD level. The only significant findings were dose dependent hypospermia and testicular atrophy in rats. We report clinical and PK results from the first-in-human phase I study. Methods: A 3+3 dose escalation design was used with 4 dose cohorts: 2.5, 5, 10, and 20mg/kg IV over 30 minutes weekly times 3, followed by a 1 week break, and then continuous weekly dosing in patients with advanced solid tumors. Dense PK sampling was performed at 0, 5, 10, 20, 30, 60, 90, 120, 180, 240, 300, 360 minutes, and 24 hours post-infusion day 1 and 15 of the first treatment cycle. Results: To date, 9 patients have been enrolled, 3 in each of the first 3 cohorts. Median time on treatment is 56 days (range 6 to 62). Five patients have discontinued protocol therapy, all due to PD. No DLT’s have been observed. Related AE’s include grade 1: myalgia (1), anorexia (1), fatigue (2), headache (1), diarrhea (1), vomiting (1) and grade 2: fatigue (1). Preliminary PK analyses in the first 2 cohorts is shown in table below. Conclusions: ME-143 appears to be well tolerated when administered IV. Preliminary PK data suggest that drug levels achieve target concentration extrapolated from pre-clinical studies (AUC0-t ~10mg*hr/mL) and exceed levels obtained with IV PXD in the phase II study (AUC0-t ~2mg*hr/mL) . Updated clinical data from all planned dose cohorts, including the final pharmacokinetic analysis and planned phase II dose, will be presented. [Table: see text]
CD30 expression in nonlymphomatous malignancies.
Authors: Sharman Jeff Porter , Goldschmidt Jerome H. , Burke John M. , Hellerstedt Beth A. , McIntyre Kristi , Yasenchak Christopher A. , Boyd Thomas E. , Ruxer Robert L. , Patel-Donnelly Dipti , Braiteh Fadi S. , Forero-Torres Andres , Savin Michael A. , Albertson Tina Marie ,   McKesson Specialty Health/US Oncology Research
Published: March 2020

3069

Background: CD30 is commonly expressed in Hodgkin lymphoma (HL), anaplastic large cell lymphoma (ALCL), and testicular embryonal carcinoma. Expression of CD30 in other solid tumors and non-lymphomatous malignancies has been reported but not investigated systematically. CD30 is the target of brentuximab vedotin (Adcetris), an antibody drug conjugate (ADC) that is approved for the treatment of patients with relapsed HL and systemic ALCL after failure of other therapies. A study was initiated to determine the incidence of CD30 expression in non-lymphomatous malignancies and to identify patients who may be candidates for treatment with brentuximab vedotin. Methods: Patients with non-lymphomatous malignancies were eligible for screening if they were relapsed or refractory to previous therapy or had no effective treatment options available. Archived tissue from solid tumors was tested for CD30 expression by immunohistochemistry (IHC); fresh bone marrow or blood samples from multiple myeloma or leukemia patients were tested by flow cytometry. Patients were considered CD30 positive and eligible for a companion treatment protocol with brentuximab vedotin if ≥10% of malignant cells stained positive by IHC or ≥20% by flow cytometry. Results: At this interim analysis, a total of 875 patients have been tested for CD30 expression: 95% had solid tumors, 3% had leukemia, and 2% had multiple myeloma. Twenty-two patients (2.5%) were CD30 positive, including 7 of 94 patients with ovarian cancer (7%), 5 of 20 with melanoma (25%), 2 of 5 with mesothelioma (40%), 1 of 4 with skin squamous cell carcinoma (25%), 2 of 41 with triple negative breast cancer (5%), 1 of 37 with pancreatic cancer (3%), 1 of 26 with small cell lung cancer (4%), and 1 of 3 with anal cancer (33%), and thyroid carcinoma (33%). One patient was identified with CD30-positive mast cell leukemia. In positive patients, the percent of CD30-positive malignant cells varied between 10 and 80%. Conclusions: CD30 expression was observed in multiple types of non-lymphomatous malignancies, thereby identifying additional populations who may be candidates for treatment with a CD30-targeted ADC, such as brentuximab vedotin. A companion clinical trial with brentuximab vedotin is currently ongoing.
Targeted therapies for the treatment of non-small cell lung cancer: Bull’s eye or missed target?
Authors: Malik Shakun M. , Johnson John R , Bijwaard Karen , Becker Robert , Keegan Patricia , Pazdur Richard
Published: March 2020

3074

Background: Targeted drugs approved for advanced non-small cell lung cancer (NSCLC) include bevacizumab [(monoclonal antibody directed against vascular endothelial growth factor-A (VEGF-A)], erlotinib [(an epidermal growth factor receptor kinase (EGFR) inhibitor)] and crizotinib [(an anaplastic lymphoma kinase (ALK) inhibitor)]. The development programs for erlotinib and bevacizumab did not prospectively employ in vitro diagnostic tests to select patients (pts). Post-hoc exploratory analyses for bevacizumab based on VEGF-A levels have not identified subgroups with differential treatment effects: however for erlotinib, pts with activating EGFR mutations had greater improvement in overall response rates (ORR) and progression-free survival. Crizotinib is the first targeted therapy for NSCLC in which pts were selected using an analytically validated investigational test for ALK translocations. Crizotinib received accelerated approval on August 26, 2011 for the treatment of pts with locally advanced or metastatic ALK-positive NSCLC as detected by an FDA-approved test (Vysis ALK Break Apart FISH Probe Kit) that was approved by FDA on the same day. Methods: NDA file for crizotinib was examined. Results: Two single arm trials assessing efficacy of crizotinib monotherapy in ALK positive pts showed ORR of 61% and 50%. At FDA’s request, a cohort of 23 pts that tested negative for the ALK translocation evaluated showed ORR of 26%. Two additional pts had a single assessment and, if confirmed, the response rate would be 37% in this “marker negative” subgroup. Further exploration of this subgroup is a postmarketing commitment. Conclusions: Evaluation of target status (positive or negative) in all pts provides optimal information to guide clinical practice. As observed with crizotinib, responses may be observed in the “marker negative” subgroup. This unexpected finding may reflect the drug’s activity via alternate pathways, selection of a suboptimal biomarker for assessing ALK activation, or selection of a suboptimal cut-point for positive/negative. Accurate diagnostic tests will facilitate drug development with possible greater observed treatment effect and potentially smaller clinical trials.
Phase I and pharmacokinetic study of farletuzumab in solid tumors.
Authors: Sasaki Yasutsuna , Miwa Keisuke , Yamashita Keishi , Fujiwara Keiichi , Katsumata Noriyuki , Fujiwara Yasuhiro , Namiki Masayuki , Koyanagi Nozomu
Published: March 2020

3084

Background: Farletuzumab (F) is a humanized monoclonal antibody against folate receptor α (FRA). Expression of FRA is reported to be 90% and 40% in ovarian cancer (OC) and gastric cancer (GC), respectively. The purpose of the study is to assess tolerability, pharmacokinetic profile and preliminary antitumor effect in solid tumors. Methods: Patients with OC or FRA expressing solid tumor who are resistant to standard treatments are eligible in the study. After pharmacokinetic (PK) run-in, F was administered by IV injection repeating every week until disease progression. PK profile was analyzed on day1 to day 10 in PK run-in and on day 22 to 29 in cycle 1. Dose limiting toxicities (DLTs) were defined as G4 hematological and G3/4 non-hematological toxicities by NCI-CTCAE. Dose escalation was planed in 4 cohorts (50, 100, 200 and 400mg/m2). Results: Sixteen patients (14 OC and 2GC) received F infusion. Neither DLTs nor G3/4 toxicities were reported in all cohorts. As adverse events, G1/2 infusion reaction (44%), headache (44%), cytokine release syndrome (38%), nausea (31%) and appetite loss (31%) were observed and medically managed. AUC and Cmax.were increased dose-dependently and linear PK profiles were identified with median clearance between 6.02 and 10.54 mL/hr/m2 in each cohort. No tumor shrinkage was recorded, but long-term disease stabilization for 22+ mos. and 10+ mos. were observed in one patient with clear cell OC (100mg/m2) and one patient with GC (400 mg/m2), respectively. No cumulative toxicities were observed in these 2 patients. Conclusions: The toxicities of F in Japanese patients were manageable with similar PK profile as compared with the US population (Konner et al. Clin Cancer Res 2010: 16; 5288-95). Long term disease stabilization is observed in subpopulation of clear cell OC and GC.
Phase I study of sirolimus plus gemcitabine in patients with advanced solid tumors: A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Martin Liberal Juan , Gil Marta , Jimenez Laura , Ochoa de Olza Maria , Munoz Carmen , Gonzalo Nuria , Rigo Raul , Colom Helena , Sainz Jaspeado Miguel , M. Tirado Oscar , Garcia del Muro Xavier
Published: March 2020

3096

Background: In preclinical studies, combination of sirolimus with gemcitabine enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. Methods: Patients with advanced solid tumors, age 18-70 years, no prior mTOR inhibitor or gemcitabine, ECOG PS 0-1, and adequate hematological, renal and hepatic function, were enrolled in this phase I study to assess safety, tolerability, pharmacokinetics (PK), and to identify the dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended dose (RD) of the combination of sirolimus and gemcitabine. A 3+3 dose escalation design with cohorts of 3-6 patients was used. Sirolimus was given po continuously. Gemcitabine was given iv 10mg/m2/minute on days 1 and 8 every 3 weeks. Dose levels 1, 2 and 3 corresponded to sirolimus 2, 2 and 5mg/24h plus gemcitabine 800, 1000 and 1000mg/m2 respectively. After observing DLTs at higher dose level and poorer mTOR signaling inhibition at lower doses, a new cohort of sirolimus 5mg/24h plus gemcitabine 800 mg/m2 was added. Skin biopsies pre and post treatment were performed to assess the inhibition of mTOR pathway. Results: 19 patients were enrolled: median age 51 years (36-70); gender 12M, 7F. Median number of cycles was 4. Patients were treated at 4 dose levels, the MTD was reached at level 3 and the RD was: sirolimus 5mg/24h and gemcitabine 800mg/m2. 3 DLTs were observed, 1 at dose level 2 and 2 at dose level 3: transaminitis grade 3, thrombocytopenia grade 3 and thrombocytopenia grade 4. Other toxicities grade 1-2 included anemia, neutropenia, asthenia, mucositis and high cholesterol levels. 2 patients achieved partial response (1 uterine cervix cancer and 1 colon cancer). Immunohistochemistry of pS6 in skin biopsies showed significative inhibition of mTOR pathway at RD. PK parameters estimated were in agreement with those previously reported in the literature. No influence of sirolimus administration on gemcitabine clearance was found. Conclusions: Combination of sirolimus and gemcitabine is feasible and safe, allowing administration of active doses of both agents and achieving mTOR signaling inhibition. A phase II study to assess the activity of this combination in sarcomas is ongoing.
A phase I study of the gamma-secretase inhibitor RO4929097 and capecitabine in refractory solid tumors.
Authors: LoConte Noelle K. , Tevaarwerk Amye , Kolesar Jill , Holen Kyle D. , Lubner Sam Joseph , Mulkerin Daniel , Schelman William R. , Razak Albiruni R.A. , Siu Lillian L. , Eickhoff Jens C. , Carmichael Lakeesha , Wilding George , Ivy S. Percy , Liu Glenn
Published: March 2020

3101

Background: RO4929097 is a oral inhibitor of gamma-secretase, which results in Notch signaling inhibition. Prior work has demonstrated that Notch-signaling inhibition enhances chemosensitivity of colon cancer cells. This study sought to combine RO4929097 with capecitabine (cape) and determine maximum tolerated dose (MTD), toxicities and efficacy. Preclinical and prior phase I work demonstrated possible autoinduction of RO4929097, so pharmacokinetic (PK) evaluation of RO4929097 and cape was planned. Methods: Adult patients with refractory solid tumors were eligible and received RO4929097 and cape at a fixed dose of 1000 mg/m2 BID with escalating doses of RO4929097 on a 21-day cycle according to a 3+3 design. Cape was administered for 14 days and the RO49029097 once daily, 3 days per week. RO4929097 plasma concentrations were evaluated by LC/MS/MS on days 3 and 10 of cycle 1, and PK parameters analyzed with WinNonLin version 5.2. Results: 4 dose levels have been completed (20, 30, 45 and 68 mg); 18 of 19 patients are evaluable for toxicity and PK data is available for 11 patients. One DLT has been observed (intolerable grade 2 fatigue) at 68 mg. There have been 2 confirmed partial responses: fluoropyrimide-refractory colon cancer (for 12 cycles) and cervical cancer (for 6 cycles). The half-life, Cmax and AUC of RO4929097 all significantly decreased on day 10 compared to day 3, with an increase in clearance for all doses. The half-life was significantly shorter in dose level 3 (p=0.0012) and dose level 4 (p=0.0126) compared to dose level 1. Conclusions: RO4929097 plus cape was well tolerated. Activity was seen in cervical and colon cancer. Autoinduction of RO4929097 was seen both with increasing cycle number and increasing dose. However, all plasma concentrations of RO4929097 were above those needed for Notch inhibition (1.9 ng/mL based on prior studies). Dose level 1 (cape 1000 mg/m2 BID and RO4929097 20 mg daily) is the recommended phase II dose. [Table: see text]
Phase I trial to assess the safety and pharmacokinetics of afatinib and weekly vinorelbine in patients with advanced solid tumors.
Authors: Hollebecque Antoine , Bahleda Rastislav , Berge Yann , Massard Christophe , Uttenreuther-Fischer Martina Maria , De-Montserrat Helene , Tschoepe Inga , Soria Jean-Charles , Delord Jean-Pierre
Published: March 2020

3104

Background: Afatinib (A) is an oral, irreversible ErbB Family Blocker with activity in a wide range of tumor cell lines dependent on ErbB signaling. Vinorelbine (VNR) interferes with tubulin polymerization and spindle formation during metaphase. Additive or supra-additive activity of A or EGFR TKI with VNR has been demonstrated in preclinical models. Methods: This dose-escalation Phase I study established the safety profile, MTD and PK of A with i.v. and p.o. VNR using a modified 3+3 design. Eligible patients (pts) were ≥18 years with refractory advanced or metastatic tumors, an ECOG PS 0–1, and adequate organ and bone marrow function. VNR i.v. (25 mg/m2)/oral (60 mg/m2 with escalation to 80 mg/m2 after 3 weeks) was administered weekly on Days 1, 8, 15 and 22 with escalating oral daily doses of A 20 mg, 40 mg and 50 mg in 28-day treatment courses. Results: The study treated 55 pts: 30 pts for MTD determination and 25 pts in the PK expansion cohort (24 M/31 F), median age 54 years (range 34–72). 28/27 pts were included in the VNR i.v./p.o. cohorts, respectively. Patients had NSCLC, breast, pancreatic (n=13/5/3), head and neck, stomach or colorectal cancer (n=2 each group); 28 pts had other cancers. At 20 mg A, no DLTs occurred in the VNR i.v./p.o. cohorts; whereas, at 50 mg A, 4/6 pts and 3/5 pts experienced DLTs. At 40 mg A and VNR i.v./p.o., 1/6 pts included for MTD determination experienced DLT, as did 7/13 pts and 2/12 pts in the VNR i.v./p.o. PK expansion cohorts, respectively. Main DLTs were diarrhea and febrile neutropenia. Median treatment duration (snapshot date 9 Dec 2011) across all dose groups was 80 days (range 10–687), with 98 and 58 days in the MTD cohorts of VNR i.v./p.o., respectively. Related AEs observed in most patients were diarrhea, asthenia, nausea, vomiting, neutropenia, decreased appetite, mucositis and rash. Five pts had a PR, confirmed in 2 pts. Preliminary PK analyses suggest no drug–drug interaction between A and i.v. VNR. Conclusions: Afatinib in combination with weekly i.v./p.o. VNR is tolerated, with manageable, reversible, target-related side effects and promising signs of clinical activity in heavily pretreated patients. The MTD for A for both combinations is 40 mg daily.
Final analysis of the phase III randomized trial of cetuximab (CET) plus either brivanib alaninate (BRIV) or placebo in patients (pts) with chemotherapy refractory, K-RAS wild-type (WT), metastatic colorectal carcinoma (mCRC): The NCIC Clinical Trials Group and AGITG CO.20 trial.
Authors: Siu Lillian L. , Shapiro Jeremy David , Jonker Derek J. , Karapetis Christos Stelios , Zalcberg John Raymond , Simes John , Couture Felix , Moore Malcolm J. , Price Timothy Jay , Siddiqui Jehan , Nott Louise M. , Charpentier Danielle , Liauw Winston S. , Sawyer Michael B. , Jefford Michael , Magoski Nadine M , Haydon Andrew Mark , Walters Ian B. , Tu Dongsheng , O'Callaghan Christopher J.
Published: March 2020

3504

Background: The anti-EGFR monoclonal antibody CET has improved survival in pts with chemotherapy refractory, K-RAS WT mCRC. BRIV is a potent inhibitor of multiple receptor tyrosine kinases including both VEGFR and FGFR. The combination of CET and BRIV targets tumor growth and angiogenesis and demonstrated encouraging activity in an early phase clinical trial. Methods: Pts with mCRC previously treated with combination chemotherapy were randomized 1:1 to receive CET 400 mg/m2 IV loading dose followed by weekly maintenance of 250 mg/m2 plus either BRIV 800 mg PO daily (Arm A) or placebo (Arm B). Pts may have had 1 prior anti-VEGF, but no prior anti-EGFR therapy. Primary endpoint was overall survival (OS). Results: From 02/2008 to 02/2011, 750 pts were randomized (376 in Arm A and 374 in Arm B). Demographics: median age=64 (range 27-88); male=64%; ECOG 0:1:2 (%)=32:58:10; >3 prior chemotherapy regimens=92%; prior anti-VEGF therapy=41%; K-RAS WT=97%. Primary analysis was conducted per protocol after 536 deaths were observed, with median OS of 8.8 months in Arm A and 8.1 months in Arm B, hazard ratio (HR)=0.88; 95% CI=0.74 to 1.03; p=0.12. Median progression-free survival (PFS) was 5.0 months in Arm A and 3.4 months in Arm B, HR=0.72; 95% CI=0.62 to 0.84; p<0.0001. Incidence of any ≥grade 3 adverse event (AE) was 78% in Arm A and 53% in Arm B. Time to deterioration of physical function was shorter and global quality of life scores were lower in Arm A vs Arm B. Planned subgroup analyses revealed no statistically difference in treatment effects on OS based on pre-specified factors of age, gender, ECOG and race. Likewise, no difference was detected based on exploratory subgroup analyses of LDH and prior anti-VEGF therapy. Conclusions: Despite positive effects on PFS, the combination of CET+BRIV did not significantly improve OS in pts with chemotherapy refractory, K-RAS WT mCRC. Final updated results based on 20-25% additional events for a total of nearly 700 deaths, as well as further exploratory subgroup analyses, will be presented.
EORTC liver metastases intergroup randomized phase III study 40983: Long-term survival results.
Authors: Nordlinger Bernard , Sorbye Halfdan , Glimelius Bengt , Poston Graeme John , Schlag Peter M. , Rougier Philippe , Bechstein Wolf , Primrose John Neil , Walpole Euan Thomas , Mauer Murielle E. , Gruenberger Thomas ,   For the EORTC GI Group, CR UK, ALMCAO, AGITG, Nordic Group, and FFCD.
Published: March 2020

3508

Background: This study evaluates the benefit of combining peri-operative chemotherapy and surgery for patients with liver only metastases from colorectal cancer (LM) deemed resectable on pre-operative imaging. The PFS results, the primary endpoint, were reported (ASCO 2007). We now report on the secondary endpoint overall survival (OS) results, after a median follow-up of 8.5 years. Methods: Between September 2000 and July 2004, 364 patients (pts) with up to 4 LM were randomized between peri-operative FOLFOX4 (oxaliplatin 85mg/m² and LV5FU2), 6 cycles before and 6 cycles after surgery, (CT arm), and surgery alone (S arm). OS was compared between arms using a 2-sided non-stratified log-rank test at the 0.05 level of significance (intent-to-treat analysis). Results: 182 pts were randomized in each arm (CT arm and S arm) of which 171 were eligible (CT and S) and 152 underwent resection (CT and S). In the CT arm, 171 received preop CT and 115 received postop CT. At a median follow-up of 8.5 years, 221 deaths were reported (61 % of all randomized pts). Causes of death in CT arm were cancer relapse (85 pts), complication of surgery (2 pts), other causes (16 pts) and unknown cause (4 pts), and in S arm, cancer relapse (99 pts), complication of surgery (2 pts), other causes (11 pts) and unknown cause (2 pts). Observed median OS was higher in CT arm: 61 months (CT) vs. 54 months (S) in all randomized pts and 64 months (CT) vs. 55 months (S) in eligible pts. The 5 year OS rate was 51.2% (CT) vs. 47.8% (S) (all randomized) and 52.4% (CT) vs. 48.3% (S) (eligible pts). There was no significant difference in OS between arms (HR=0.88, 95% CI 0.68-1.14, p=0.34) (all randomized). After progression, second line treatment with chemotherapy was given in 59 % (CT) and 77% (S) of the pts with cancer progression and repeat surgery in 46% (CT) and 40% (S), respectively. Conclusions: Peri-operative chemotherapy with FOLFOX4 improves PFS but does not significantly improve OS over surgery alone. A potential benefit may have been diluted by second treatment lines and by more deaths unrelated to cancer in the CT arm.
Prognostic impact of BRAF and KRAS mutations and their relationship to DNA mismatch repair (MMR) status in 2,686 stage III colon cancer patients (pts) treated in a phase III study of adjuvant FOLFOX with or without cetuximab: NCCTG N0147.
Authors: Sinicrope Frank A. , Mahoney Michelle R. , Smyrk Thomas C. , Thibodeau Stephen N. , Goldberg Richard M. , Nelson Garth D. , Sargent Daniel J. , Alberts Steven R. ,   North Central Cancer Treatment Group
Published: March 2020

3514

Background: Activating mutations in the BRAF oncogene (mutBRAF) are associated with deficient MMR (dMMR) in sporadic colon cancers and are mutually exclusive with KRAS mutations (mutKRAS). We evaluated BRAF and KRAS in relation to MMR and disease-free survival (DFS) in stage III pts treated with adjuvant FOLFOX +/-cetuximab; study was amended mid-way to require prospective KRAS testing (Alberts SR, ASCO 2010). Methods: Extracted DNA from archival tumors was analyzed for BRAF exon 15 (V600E) and KRAS exon 2 mutations by allele specific RT-PCR. Tumors with loss of any MMR protein (MLH1, MSH2, MSH6) were categorized as dMMR vs proficient (pMMR). DFS was censored at 4 yrs; median follow-up was 3.1 yrs. Results: Among 2,686 pts, 12% (314/2580) of tumors were dMMR; 28% (716/2579) had mutKRAS, and 14% (346/2515) had mutBRAF of which 43% (150/346) were dMMR. mutBRAF was associated with high grade, proximal site, T3-4, >4 LNs, and dMMR (all p<0.002); mutKRAS with low grade, proximal, <3 LNs, and pMMR (all p<0.02). Among dMMR tumors, mutKRAS was more frequent in distal vs proximal cancers (28% vs. 8%, p=0.0004). Both mutKRAS (HR=1.42, p=0.0001) and mutBRAF (HR=1.34, p=0.02) were associated with worse DFS and remained significant after adjustment for treatment, MMR, grade, site, T stage and LNs. mutBRAF (p=0.003) and mutKRAS (p=0.003) were each prognostic for DFS in pMMR, but not dMMR tumors (KRAS, p=0.79; BRAF, p=0.60). While MMR was not significant univariately, proximal dMMR tumors had favorable DFS [HR 0.8, 95% CI (0.6-1)] and distal dMMR tumors had poor DFS [HR 2 (1.1-3.4)] after adjusting for KRAS, BRAF, grade, T stage and LNs (pinteraction=0.02). pMMR/mutBRAF (p=0.027) and pMMR/mutKRAS (p<0.001) had worse DFS vs pMMR/bothWT. Conclusions: mutBRAF and mutKRAS were significantly associated with worse DFS independent of treatment, covariates, and each other, with the DFS impact restricted to pMMR tumors. Prognostic impact of MMR was dependent upon tumor site after adjusting for covariates. Support: NIH Grant CA 25224, NCI K05CA 142885, Bristol-Myers Squibb, ImClone, Sanofi-Aventis, and Pfizer.