tbuckley/cabot-search huggingface dataset:
Effect of nutritional support with highly purified, whey proteins for malnutrition and sarcopenia in patients affected with stage II-III colorectal or breast cancer: A blind, placebo controlled, randomized clinical trial.
Authors: Federica Mazzuca, Michela Roberto, Andrea Botticelli, Luca Marchetti, Elena Sarfati, Edoardo Crimini, Francesca Schipilliti, Marco Di Girolamo, Maurizio Muscaritoli, Paolo Marchetti
Journal: Journal of Clinical Oncology (2018)

TPS10129 Background: Malnutrition and sarcopenia may arise in both colorectal and breast cancer since the first visit. Previous studies demonstrate that malnourished cancer patients have a decreased quality of life and experience more chemotherapy-toxicity. Protein supplementations could prevent loss of lean body mass that goes along with malnutrition and sarcopenia. Therefore, the role of whey proteins takes a great deal of interest. We propose a randomized study, placebo-controlled, aimed at evaluating the activity and safe of a highly purified, whey protein nutritional support (PROLYOTIN) in cancer patients undergoing adjuvant chemotherapy (EudraCT n. 2018-000122-64). Methods: Patients with histological diagnosis of stage II/III according to AJCC system, breast or colorectal cancer, referred for adjuvant chemotherapy, with no metabolic disease, will be eligible. Obtained written informed consent, all patients will be blind-randomized with 1:1 ratio in two arms: A (PROLYOTIN) vs. B (placebo). Patients will be assessed before starting chemotherapy (T0), after 3 (T1) and 6 months (T2), with respect to a physico-nutritional examination, skeletal muscle mass calculation by CT scan and Body Impedance Assessment. Mini Nutritional Assessment, Malnutrition Universal Screening Tools and Quality of life by EORTC QLQ C-30 will be also done. At the same time frames (T0, T1, T2) detailed medical records, tumor characteristics, dietary practices and laboratory values (blood count, serum proteins, cholesterol, triglycerides, amylases, lipases, ESR, CRP, glucose, tumor markers, cortisol, insulin, vitamin D, LDH and CK) will be collected by a specialist team of medical oncologists and dieticians. The patient-adherence to protocol will be also monthly evaluated. Primary objective is to evaluate the nutritional status at baseline, T1 and T2 and the difference between the PROLYOTIN and placebo arms. Secondary, correlations between nutrtional status and clinicopathological parameters, and the quality of life will be analyzed. A total of 220 patients will be enrolled (95% CI, β 10%). Clinical trial information: 2018-000122-64.
NRAS-mutated melanoma patients have similar response rates to therapy with checkpoint inhibitors as other cohorts.
Authors: Michael Constantin Kirchberger, Selma Ugurel, Joanna Mangana, Markus Heppt, Thomas Eigentler, Carola Berking, Dirk Schadendorf, Gerold Schuler, Reinhard Dummer, Lucie Heinzerling
Journal: Journal of Clinical Oncology (2017)

e21035 Background: About 20% of metastatic melanomas harbor NRAS mutations which constitutively activate the MAPK pathway, driving cell proliferation and inhibiting apoptosis. The response of patients with NRAS-mutated melanoma to checkpoint inhibitor therapy is so far unknown. A previous study suggested a higher response rate of NRAS-mutated melanoma to anti-PD-1/anti-PD-L1 with an objective response in 7 out of 11 (64%) patients compared to 35% and 21% in BRAF wildtype or BRAF V600-mutated melanoma, respectively. Methods: In total, 224 patients with NRAS-mutated melanoma were analyzed. Of these, 180 patients received ipilimumab, 98 anti-PD1 monotherapy, and one patient combined ipilimumab and anti-PD1 therapy. We evaluated overall response rate (ORR), disease control rate, progression-free survival (PFS) and overall survival to checkpoint inhibitor therapy in these patients. Results: In this patient cohort with NRAS-mutated melanoma, 27% had brain metastases, 62% an elevated LDH and 22% an ECOG &gt; = 1. ORR was 15% for treatment with ipilimumab and 34% for anti-PD1 therapy. Disease control rates were 27% for ipilimumab and 52% for anti-PD1 therapy. PFS was 4.5 months for ipilimumab and 11.4 months for anti-PD1 therapy. Overall survival of all patients was 29 months. Conclusions: The efficacy data of ipilimumab or anti-PD1 therapy in NRAS-mutated melanoma patients were similar to the known response rates of NRAS wildtype melanoma patients.
Basal subtype of head and neck cancer to define response to EGFR inhibitor treatment.
Authors: Konrad Friedrich Klinghammer, Raik Otto, Jan D Raguse, Iduna Fichtner, Andreas Albers, Ulrich Keilholz, Jens Hoffmann
Journal: Journal of Clinical Oncology (2016)

e17512 Background: Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (SCCHN). Predictive biomarkers have not been established in the clinical setting and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment Methods:: From our patient derived xenograft platform of head and neck cancer, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al.,CCR 2015. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after three weeks of treatment (RTV). Results: Treatment results were heterogeneous with best response for single agent docetaxel. Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs BA 0.78 (MS vs BA, unpaired t test p0,0002). Cetuximab responser were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the 3 subtypes. No association was observed between initial tumor site and subtyp. Conclusions: Basal subtype was a strong predictor for response to EGFR directed therapy in head and neck squamous cell cancer patient derived xenografts, whereas activity of chemotherapy was homogenous between signature-defined subtypes. As no other predictive biomarker for EGFR directed therapy has previously been established for clinical use in SCCHN, our findings strongly suggest a validation study in a clinical setting
Phase 2, two-group, two-stage, open-label study of avelumab in patients with microsatellite stable, microsatellite instable and POLE-mutated recurrent or persistent endometrial cancer.
Authors: Panagiotis A. Konstantinopoulos, Joyce F. Liu, William Thomas Barry, Carolyn N. Krasner, Mary K. Buss, Michael J. Birrer, Sarah Farooq, Susana M. Campos, Elizabeth Stover, Susan Schumer, Alexi A. Wright, Jennifer Curtis, Ariana Peralta, Christin Whalen, Don S. Dizon, Richard T. Penson, Stephen A. Cannistra, Gini F. Fleming, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2017)

TPS5615 Background: The Cancer Genome Atlas project identified 2 groups of hypermutated endometrial cancers (ECs): an ultramutated group that harbored mutations in the exonuclease domain of polymerase e ( POLE), and a hypermutated group with microsatellite instability (MSI), the majority of which harbored MLH1 promoter methylation. We (Howitt, JAMA Onc 2015) and others have shown that POLE and MSI ECs are associated with higher number of predicted neoepitopes and tumor infiltrating lymphocytes, which is counterbalanced by overexpression of PD-1/PD-L1, suggesting that they may be excellent candidates for PD-1/PD-L1 blockade. Anti-PD-1 therapy has also demonstrated promising activity in mismatch repair deficient colorectal cancers and collectively in non-colorectal cancers (Le, NEJM 2015). Methods: This is an open-label, two-cohort, two-stage, phase 2 trial, of avelumab, a fully human IgG1 antibody directed against PD-L1, in two cohorts: i) a MSI/ POLE cohort including ECs with immunohistochemical (IHC) complete loss of expression of at least one of the mismatch repair (MMR) proteins and/or documented mutation in the exonuclease domain of POLE and ii) a MSS cohort including ECs with normal IHC expression of all MMR proteins. Key eligibility criteria include measurable disease, no upper limit of prior therapies, and any EC histology. Co-primary objectives include objective response rate and rate of progression-free survival at 6 months. Avelumab is administered at 10 mg/kg as 1-hour IV infusion every 2 weeks until disease progression or unacceptable toxicity; therapy may continue at the investigator’s discretion while awaiting radiologic confirmation of disease progression 4 weeks later. Maximum target enrollment is 70 patients (35 for each cohort). In the first stage, 16 patients will be enrolled in each cohort; if there are at least two objective responses or two patients progression-free at 6 months, accrual will continue to the second stage where 19 more patients will be enrolled for each cohort. Thus far, 16 patients have been enrolled, 13 on the MSS cohort and 3 on the MSI/ POLE cohort. Clinical trial information: NCT02912572.
Tumor bulk as an independent marker of anti-EGFR therapeutic benefit in metastatic colorectal cancer.
Authors: Jeremy D. Kratz, Noelle K. LoConte, Sam Joseph Lubner, Daniel Mulkerin, Kristina Matkowskyj, Nataliya Volodymyrivna Uboha, Meghan G. Lubner, David H. Kim, Perry J. Pickhardt, Dustin A. Deming
Journal: Journal of Clinical Oncology (2017)

e15054 Background: Molecular testing and location of the primary tumor (right-sided (R) versus (vs) left-sided (L)) are useful in predicting the clinical benefit of the anti-epidermal growth factor receptor (EGFR) antibodies, cetuximab (cet) and panitumumab (pan), in metastatic colorectal cancer (mCRC). We hypothesized that tumor bulk might also be predictive of treatment benefit given the potential for increased intra-tumor heterogeneity and reduced penetration of antibodies into bulkier lesions. Methods: A single institution retrospective cohort of 69 patients (pts) with KRAS wild-type mCRC were identified who received either cet or pan in the late-line setting +/- chemotherapy. Metastatic sites were cataloged including independent review of CT imaging prior to initiation of anti-EGFR therapy. Disease bulk was defined categorically as single metastatic lesion with diameter measuring &gt; 3.0 cm. Results: This cohort represents a diverse group having received varying prior lines of therapy and having assorted disease sites including mediastinal, pulmonary, hepatic, omental, and osseous lesions. When treated with anti-EGFR therapies, pts with pre-treatment metastases ≤3.0 cm in diameter had significant improvement in median progression free survival (mPFS) (6.2 months (mos)) vs pts with metastases &gt; 3.0 cm (3.9 mos, p &lt; 0.01). A trend towards improvement in overall survival was observed for pts with non-bulky (15.8 mos) vs bulky disease (8.6 mos, p = 0.08). A trend towards increased mPFS existed in L (5.1 mos) vs R cancers (2.5 mos, p = 0.11). In R cancers, no significant difference in mPFS was noted between bulky (2.5 mos) and non-bulky disease (2.9 mos, p = 0.53). Non-bulky L cancers had a significantly improved mPFS of 7.5 mos compared to 3.9 mos with L bulky disease (p &lt; 0.01). Non-bulky L cancers trended towards improved overall survival of 17.0 mos compared to 9.6 mos with L bulky disease (p = 0.08). Conclusions: Despite limited small sample size, these data indicate that tumor bulk is a potential predictor of the therapeutic benefit of anti-EGFR agents in left-sided mCRCs across a heterogeneous pt population. Disease bulk deserves further evaluation in larger datasets of mCRC across targeted therapeutics.
Genomic analysis of circulating tumor DNA in 442 patients with carcinoma of unknown primary: Implications for targeted therapeutics.
Authors: Shumei Kato, Nithya Krishnamurthy, Kimberly Banks, Kirstin Anne Williams, Casey B. Williams, Brian Leyland-Jones, Richard B. Lanman, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2017)

11511 Background: Carcinoma of unknown primary (CUP) is a rare, difficult-to-treat malignancy. To further understand the genomic landscape of CUP, next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from patient plasma was performed. To our knowledge, this is the largest cohort of patients with CUP interrogated by liquid biopsy. Methods: We evaluated the molecular alterations of 442 patients with CUP using clinical-grade NGS of ctDNA isolated from patient plasma. The test detects single nucleotide variants in 54-70 genes, as well as copy number amplifications, fusions and indels in selected genes. Results: Eighty percent of patients (353/442) had ctDNA alterations with 66% (290/442) harboring at least one characterized alteration; 43.9% (194/442) ≥ 2 characterized alterations. TP53-associated genes were most commonly altered (37.8% [167/442]) followed by genes involved in the MAPK pathway (31.2% [138/442]), PI3K signaling (18.1% [80/442]) and the cell cycle machinery (10.4% [46/442]). Among patients harboring at least one characterized alteration, most (87.9% [255/290]) had distinct genomic profiles, and 99.7% (289/290) had alterations theoretically targetable with either an FDA-approved or investigational agent. The mean number of potentially actionable alterations per patient was 1.7 (range, 0 to 10). Illustrative patients who had dynamic changes in ctDNA content during the course of therapy and responding patients matched on the basis of ctDNA to targeted therapies or immunotherapy will be presented. Conclusions: Evaluation of ctDNA was feasible among individuals with CUP. Most patients harbored a unique somatic profile. The majority of patients had potentially actionable alterations. Serial ctDNA showed dynamic changes in molecular alterations in response to therapy, and several patients have attained responses to targeted or immune therapies chosen on the basis of ctDNA findings. The current report suggests that non-invasive liquid biopsies merit investigation in next generation clinical trials.
Phase I trial study of bendamustine, ofatumumab, and pentostatin (BOP) as salvage regimen for patients with relapsed or refractory non-Hodgkin’s lymphoma or chronic lymphocytic leukemia.
Authors: Colin Thomas, Sameh Gaballa, Martina DiMeglio, Seyfettin Onder Alpdogan, Matthew H. Carabasi, Andrew E. Chapman, Neal Flomenberg, John L. Wagner, Joanne Filicko, Mark Adam Weiss
Journal: Journal of Clinical Oncology (2017)

e19005 Background: No standard salvage regimen exists for patients (pts) with relapsed or refractory (RR) NHL or CLL. Bendamustine, pentostatin and ofatumumab have activity in pts with CLL and NHL, but have not been combined as a single regimen. We conducted a phase I trial to assess the safety of this regimen. Methods: Pts with RR B-NHL or CLL were eligible. The design was a standard 3+3 using escalating doses of Bendamustine (50, 70, or 90 mg/m2 D1-2), Pentostatin (4 mg/m2 D1), and Ofatumumab (cycle 1: 300 mg D1; cycle 2-6: 1000 mg D2) every 28 days. Responses were assessed after cycle 3. Results: Ten pts were enrolled (6M/4F). Median age was 56 (range 37-65). Pts had follicular (FL) NHL (n = 2), CLL or SLL (n = 6), primary mediastinal B-cell lymphoma (PMBL) (n = 1), and extra-nodal marginal zone (MZL) NHL (n = 1). Pts had relapsed (n = 7) or refractory disease (n = 3) and received a median of 3 prior lines of therapy (range 1-4). Two CLL pts had high risk cytogenetics: 11p (n = 1) and 17p (n = 1). Most NHL pts (3/4) had stage 4 disease and all were refractory to rituximab. The ORR was 90% (PR = 5 pts: FL = 2, CLL/SLL = 3; CR = 4; CLL = 3, MZL = 1). One pt with PMBL progressed on treatment and died. One pt with CLL relapsed after 6 months. After a median follow up of 17 mo, the OS was 90% and PFS was 80%. Two pts (FL and CLL/SLL) subsequently underwent allogeneic stem cell transplant. DLT was not reached. Grade 3-4 toxicities included electrolyte imbalance (50%), neutropenia (30%), thrombocytopenia (30%), tumor lysis (20%), neutropenic fever (20%), and infusion reactions (10%). Common grade 1-2 toxicities were hyperglycemia (90%), thrombocytopenia (80%), nausea (80%), edema (80%), fatigue (80%) and neutropenia (70%). Conclusions: The BOP regimen is well tolerated and safe in pts with RR B-NHL or CLL. No DLT toxicity was reached at the highest bendamustine dose of 90mg/m2. Targeted therapies have largely supplanted the role of chemo-immunotherapy in the salvage setting. This trial was initiated in the pre-ibrutinib era and accrual to the planned phase II portion is on hold as pts now receive targeted therapy as salvage therapy. BOP might be an option for pts refractory to other strategies. Clinical trial information: NCT01352312.
Phase I bridging study of ch14.18/CHO long-term infusion in recurrent or refractory neuroblastoma patients in Japan.
Authors: Yoshiyuki Takahashi, Atsushi Narita, Nikolai Siebert, Nobuhiro Nishio, Yinyan Xu, Hideki Muramatsu, Asahito Hama, Takehiko Kamijo, Atsuko Nakazawa, Hajime Hosoi, Yoshiaki Kinoshita, Shinobu Shimizu, Katsuyoshi Kato, Masaaki Mizuno, Hans Loibner, Tatsuro Tajiri, Akira Nakagawara, Ruth Ladenstein, Holger N. Lode, Seiji Kojima
Journal: Journal of Clinical Oncology (2016)

10568 Background: The primary objective of this study was to assess safety and toxicity of anti-GD2 antibody ch14.18/CHO continuous long term infusion (LTI) used as single agent in Japanese pediatric neuroblastoma patients (pts). The secondary objective was to evaluate pharmacokinetic parameters (PK) to bridge between Japanese and European results. Anti-tumor activity was assessed in patients with evaluable diseases. Methods: Ch14.18/CHO (100 mg/m2/cycle; 3.3mg/kg/cycle below 12 kg body weight) was administered over 10 consecutive days every 5 weeks. If toxicity was acceptable, pts without progression could receive up to five cycles. Blood samples were collected for PK assessment, HACA response, immunophenotype, ADCC, CDC, biochemistry, Fc gamma receptor polymorphisms, and MRD assessment. Results: Ten pts with recurrent/refractory neuroblastoma were enrolled between September 2014 and July 2015. Nine pts (5 boys and 4 girls) were eligible and evaluable for toxicity and response. The median age was 4 (range 2-9) years. Grade 3 or higher toxicities were seen including anemia, leukopenia, neutropenia, elevation of hepatic transaminases, hyponatremia, and urticalia, but all these toxicities were reversible until the next scheduled cycle. No unexpected toxicities were seen. The supportive care guidelines allowed all pts to continue treatment at the same dose level. The PK of ch14.18/CHO in the Japanese pts was not significantly different from that observed in Caucasian pts. Three of nine pts had partial responses evaluated by MIBG scan or tumor marker. One patient progressed with brain metastases after 2 cycles.Eightpatients are alive with stable disease without further chemotherapy (median follow-up period 10 months (range 7-17) from enrollment). Conclusions: Japanese pts receiving ch14.18/CHO LTI for high risk neuroblastoma had similar PK, tolerability and objective response compared to Caucasian patients. These results allow bridging to data of ch14.18/CHO obtained in Caucasian patients for application in front of Asian authorities.
Somatic DNA mutations, tumor mutational burden (TMB), and MSI Status: Association with efficacy in patients (pts) with metastatic colorectal cancer (mCRC) of FIRE-3 (AIO KRK-0306).
Authors: Volker Heinemann, Nicole Kraemer, Hannes Buchner, Ludwig Fischer von Weikersthal, Thomas Decker, Alexander Kiani, Ursula Vehling-Kaiser, Salah-Eddin Al-Batran, Tobias Heintges, Christian A. Lerchenmuller, Christoph Kahl, Frank Kullmann, Markus H. Moehler, Werner Scheithauer, Swantje Held, Dominik Paul Modest, Jens Neumann, Andreas Jung, Thomas Kirchner, Sebastian Stintzing
Journal: Journal of Clinical Oncology (2018)

3591 Background: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wt mCRC patients (pts). Methods: Tumor DNA was profiled by next-generation sequencing to explore molecular markers of prognosis. The biomarker evaluable subpopulation (n = 373) was representative of the ITT population. Treatment efficacy was determined in the quadruple wild-type (wt) population (RAS, BRAF, AKT, PI3K = "MAPK/mTOR wt"). Kaplan-Meier estimation and log-rank tests were employed for overall survival (OS). Hazard ratios (HR) were estimated using the Cox proportional hazard method. P-values were not adjusted for multiple testing Results: Overall frequencies were (%,n): MSI-h 2.7% (10); BRAFmut 12.1% (45); RASmut 32.7% (122); quadruple wt: 47.7% (178); TMB > 8: 15% (56). RAS, BRAF, MSI-h and quadruple-wt status were prognostic. Pts with low-frequent RAS mutations (RASmut < 5%) had a significantly longer OS when compared to pts with higher RAS mutational frequency. Conclusions: NGS analysis revealed distinct subgroups of mCRCs with different prognosis. MSI status had prognostic impact, but TMB could not be validated as a prognostic or predictive marker. Overall survival. N Events N (% ) Median [ 95%CI ] N Events N (%) Median [ 95%CI ] HR [ 95%CI ], p-value MSI MSI-H 10 10 ( 100) 18.8 [ 2.5, 24.5 ] MSS 343 298 ( 87) 25.4 [ 23.1, 27.6 ] 1.92 [ 1.02, 3.62 ], 0.0432 TMB status 1 high 10 9 ( 90) 19.8 [ 2.5, 25.2 ] intermediate 114 100 ( 88) 25.7 [ 21.5, 29.1 ] 1.28 [ 0.65, 2.54 ], 0.4725 high 10 9 ( 90) 19.8 [ 2.5, 25.2 ] low 236 206 ( 87) 23.8 [ 21.4, 26.7 ] 1.16 [ 0.60, 2.27 ], 0.6568 intermediate 114 100 ( 88) 25.7 [ 21.5, 29.1 ] low 236 206 ( 87) 23.8 [ 21.4, 26.7 ] 0.91 [ 0.71, 1.15 ], 0.4186 TMB status 2 < = 8 304 268 ( 88) 23.8 [ 21.8, 26.1 ] > 8 56 47 ( 84) 27.5 [ 18.7, 31.1 ] 1.23 [ 0.90, 1.68 ], 0.1924 BRAF wt 328 289 ( 88) 26.4 [ 23.9, 28.8 ] Mut 45 39 ( 87) 15.9 [ 10.9, 19.1 ] 0.57 [ 0.41, 0.80 ], 0.0012 RAS wt 251 212 ( 85) 27.9 [ 24.7, 31.9 ] Mut 122 116 ( 95) 20.6 [ 17.4, 23.6 ] 0.62 [ 0.49, 0.78 ], 0.0000 MAPK wt 178 151 ( 85) 30.8 [ 26.4, 35.2 ] mut 195 177 ( 91) 20.8 [ 18.5 , 23.7 ] 0.64 [ 0.51, 0.79 ], 0.0001
Benefit of Extended Maintenance Therapy for Venous Thromboembolism with Dabigatran Etexilate Is Maintained Over 1 Year of Post-Treatment Follow-up
Authors: Sam Schulman, David Baanstra, Henry Eriksson, Samuel Z. Goldhaber, Ajay Kakkar, Clive Kearon, Sebastian Schellong, Jeffrey Friedman
Journal: Blood (2012)