tbuckley/cabot-search huggingface dataset:
Second-line chemotherapy by FOLFIRINOX with unresectable pancreatic cancer (phase I, II study).
Authors: Noritoshi Kobayashi, Motohiko Tokuhisa, Ayumu Goto, Itaru Endo, Yasushi Ichikawa
Journal: Journal of Clinical Oncology (2016)

297 Background: The purpose of this study was to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLT), and efficacy of the second-line chemotherapy (after gemcitabine based chemotherapy) by FOLFIRINOX with unresectable pancreatic cancer. Methods: The subjects were histopathologically proven unresectable pancreatic cancer patients. The schedule was oxaliplatin 85mg/m 2 on day1, irinotecan on day1, leucovorin 400mg/m 2 on day 1 followed by FU 400mg/m 2 as a bolus on day 1 and 2400mg/m 2 as 46-hour continuous infusion biweekly. We were planned the dose of oxaliplatin, leucovorin and FU were fixed and the dose of irinotecan was defined as follows: level 0: 100mg/m 2 , level 1: 125mg/m 2 , level 2: 150mg/m 2 , and level 3: 180mg/m 2 . We started level 1 and at least three patients were enrolled at same dose two cycles. If DLT was observed two patients in six or three patients, we suspected the level was MTD. We also evaluated this study as phase II. Primary end point was response rate (RR). We also evaluated progression free survival (PFS), overall survival (OS) and adverse event (AE). Results: Eighteen patients were enrolled in this study (man: n = 11, woman: n = 7). We evaluated initial eight patients as phase I study. One patient had neutropenia and another one patient had hyperglycemia and severe infection. We decided level 1 was MTD and recommended dose was level 0. According to phase II study, RR was 22.2% (CR: n = 0, PR: n = 4, SD: n = 7, PD: n = 7) and disease control rate (DCR) was 61.1%. PFS was 2.8 (0.7-11.7) months and OS was 9.8 (2.4-14.4) months. The most common severe AE was neutropenia (66.7%). Fibril neutropenia was occurred one (5.6%) case. Conclusions: Recommended dose was oxaliplatin 85mg/m 2 on day1, irinotecan 100mg/m 2 on day1, leucovorin 400mg/m 2 on day 1 followed by FU 400mg/m 2 as a bolus on day 1 and 2400mg/m 2 as 46-hour continuous infusion. RR was 22.2% and major AE was neutropenia but FN was rare. Second-line FOLFIRINOX is marginally effective treatment for gemcitabine-base chemotherapy failure cases.
Sequential treatment of advanced or metastatic renal cell carcinoma (mRCC): What is effective? Data from the German RCC registry.
Authors: Lothar Mueller, Peter J. Goebell, A. Lueck, Friedrich Overkamp, Michele Vogt, Norbert Marschner
Journal: Journal of Clinical Oncology (2014)

499 Background: In addition to Bevacizumab+Interferon, current treatment options of mRCC imply two major intracellular modes of action and thus classes of therapies: the four approved tyrosine kinase inhibitors (TKI) Sunitinib, Sorafenib, Pazopanib, Axitinib and the two inhibitors of the mammalian target of rapamycin (mTOR) Temsirolimus, Everolimus (EVE). With their availability efficacy of sequential treatment has become a central question of clinical research. While clinical trials recruit highly selected patients (pts) and usually focus on a single line of therapy, collected data of clinical registries may represent all patients and all sequential therapies. Methods: Starting in 12/2007 the registry aims to enrol a total of 1500 patients from more than 120 oncology and urology outpatient centres collecting data on all systemic treatments, outcome, patient and tumour characteristics. Here, the effectiveness of two 1 st – 2 nd -line sequential treatments, TKI–TKI vs TKI–EVE, was investigated with a multivariate cox proportional hazards model considering potential confounding variables (age, comorbidity, body mass index (BMI), duration of 1 st -line therapy, Motzer’s score and type of sequential treatment). Results: At the time of analysis, 481 pts had received sequential 1 st - and 2 nd -line treatment between 2007 and 2012. In total, 70% of pts received 1 st -line TKI-treatment. 46% of these pts received the sequential treatment TKI–TKI, 25% received TKI–EVE. In the multivariate analysis, high BMI (HR 0.946, 95% CI 0.9018-0.9923, p&lt;.05) and a long duration of 1 st -line-therapy (HR 0.9967, 95% CI 0.9956-0.9979, p&lt;.001) had a significant positive impact on OS, whereas high risk Motzer`s score (HR 8.9992, 95% CI 2.4231-33.4228, p&lt;.01) had a significant negative impact on OS. However, the type of sequential treatment had no impact on OS (HR 1.0658, 95% CI0.6463-1.7576, p=0.802). Conclusions: The RCC Registry provides an overview of the current treatment reality in routine medical practice. TKI are the most frequently applied 1 st -line treatments, followed by TKI or mTOR inhibitors. Our data show no difference concerning the effectiveness of the sequential treatment TKI–TKI vs TKI–EVE.
Proteomic signatures of colorectal cancer to identify distinct and reproducible subgroups independent of oncogenic mutations.
Authors: Michael Sangmin Lee, Callisia Clarke, Zhi-Qin Jiang, Ganiraju C. Manyam, Feng Tian, Yiling Lu, Jeffrey Morris, Bradley McIntosh Broom, David Menter, Eduardo Vilar Sanchez, Imad Shureiqi, Kanwal Pratap Singh Raghav, Cathy Eng, George J. Chang, Iris Simon, Rene Bernards, Gordon B. Mills, Michael J. Overman, Dipen M. Maru, Scott Kopetz
Journal: Journal of Clinical Oncology (2015)

580 Background: While colorectal cancer (CRC) has classically been categorized on the basis of oncogenic mutations such as KRAS and BRAF, proteomic analyses directly elucidate the functional state of the cancer cell’s protein signaling, as recently described in a pan-cancer cohort and with mass-spectroscopy in a small CRC cohort. We performed an antibody-based proteomic analysis (reverse-phase protein array; RPPA) of a large cohort at MD Anderson (MDACC) and The Cancer Genome Atlas (TCGA) to determine patterns of protein expression in CRC. Methods: 725 archived CRC tumor samples (263 MDACC discovery set, and 462 TCGA validation set) underwent protein extraction and RPPA at MDACC to determine levels of 127 proteins. With unsupervised hierarchical clustering, samples dichotomized with distinct patterns of protein expression. The proteins with highest discriminatory utility were identified by LIMMA in the discovery set and confirmed in the validation set. Clinical variables and DNA sequencing results were available for correlation. Results: Among the top 30 discriminant proteins for the dichotomized groups in each dataset, 18 were common to both and tended to correlate with each other. One group was notable for high EMT (high fibronectin and collagen VI, low E-cadherin), while the other group was notable for high Akt/TSC/MTOR (high AKT, MTOR, Tuberin), and high RTK pathway components (high BRAF, HER2, HER3). This latter group also was notable for elevated beta-catenin and low CHK1, implicating differential activation of Wnt and cell cycle pathways, and intriguingly had elevated phospho-AMPK and phospho-NFkB. In the MDACC cohort, this latter group was more likely to have mucinous histology (p=0.009 by Fisher’s exact test) and lack lymphovascular invasion (p=0.026). When both TCGA and MDACC cohorts were examined, there was no significant difference in microsatellite instability, PIK3CA, KRAS, or BRAF mutations between the two proteomic groups. Conclusions: CRCs appear to be classifiable into distinct subsets by proteomic features. These findings reflect distinct differences in cellular signaling that are independent of common oncogenic driver mutations.
Predictive and prognostic markers of recurrence after resection of primary or metastatic colorectal cancer.
Authors: Jeffrey Bryan VanDeusen, Joshua Uronis, Michael Morse, Michael L. Gatza, Michael B. Datto, Christopher Mantyh, H. Kim Lyerly, Joseph R. Nevins, Bryan M. Clary, Shiaowen David Hsu
Journal: Journal of Clinical Oncology (2012)

447 Background: Current biomarkers for colorectal cancer sub-classify tumors based on single mutations, such as KRAS; however, studies of single mutations belie the molecular complexity of colorectal cancer in which an average of 14 key genes per tumor is dysregulated. We hypothesize that colorectal cancer may be molecularly sub-classified based on an oncogenic pathway prediction model in which tumors are grouped based on patterns of oncogenic pathway dysregulation/expression. Methods: Affymetrix microarray data from 850 patients with primary colorectal cancer from publically available datasets were combined using Bayesian factor regression modeling normalization. The activity of 19 separate oncogenic pathways was predicted among tumors to generate patterns of pathway activity for each sample. Mixture modeling was applied to these samples to identify subgroups of tumors with unique patterns of pathway dysregulation. Validation of subclasses was performed on a dataset of 133 primary and metastatic colorectal cancer samples of patients undergoing curative surgical resection at our institution. Tumors were subgrouped according to our previous model and recurrence free survival was calculated. In vivo validation was performed by treating NOD/SCID mice bearing patient derived tumors with everolimus with changes in tumor size calculated between day 0 and day 21. Results: Mixture modeling resulted in 6 individual subgroups of colorectal cancer based on pathway dysregulation. Kaplan Meier curves revealed that patients in subclass 4 had the poorest prognosis while patients in subclass 6 had the best prognosis (p=0.05). Further, tumors in subclass 4 were generally enriched for high mTOR pathway activation and patient derived explants from subclass 4 with high predicted mTOR activity were found to be sensitive to the MTOR pathway inhibitor everolimus. Conclusions: Prediction of oncogenic signaling pathway activity is a powerful tool that may be used to molecularly sub-classify colorectal cancer into biologically relevant subgroups. These subgroups have prognostic and predictive implications for recurrence following surgical resection and responsiveness to targeted therapy.
Variates of survival for stage IV uveal melanoma
Authors: P. Rietschel, K. Panageas, C. Hanlon, A. Patel, P. B. Chapman
Journal: Journal of Clinical Oncology (2005)

7536 Background: Systemic therapy of stage IV uveal melanoma (mel) is not thought to improve survival. In selected patients (pts), local therapy of metastases (mets) (e.g. surgery or intrahepatic therapy) can be associated with long-term survival. The natural history of stage IV mel is heterogeneous and not well-described. We were interested in describing the natural history and factors that correlate with long-term survival in the stage IV uveal mel pts seen at our institution. Methods: A retrospective analysis of the 119 stage IV uveal mel pts in the MSKCC mel database. We recorded dates of initial diagnosis, stage IV, last follow up, and death; site of 1st met, how the 1st met was discovered, treatment. Results: 40 pts were still alive at last follow up (median follow up of survivors = 8 months). Median overall survival was 12.5 months (95% CI 9.6–16.8). 22% were alive at 4 years. A novel observation was that 28% of the pts had lung/soft tissue only as the site of first metastasis. In a multivariate analysis, we found 3 variates that correlated independently with prolonged survival: Lung or soft tissue as only site of first metastasis (p=.03, HR 0.55, CI .32-.95), treatment with surgery or intrahepatic therapy (p=.005, HR 0.38, .22-.65), and time interval from diagnosis to stage IV uveal mel (p=.03). Whether stage IV mets were first discovered by screening tests (CT scans, blood tests routine physical exam) or by symptoms did not correlate with the likelihood of having surgery or with overall survival. Conclusions: Pts with lung/soft tissue only as the site of first metastasis, pts who are treated with local therapy (surgery or intrahepatic therapy), and pts with longer time interval from initial diagnosis to stage IV have longer survival after stage IV uveal mel is diagnosed. There appeared to be no survival advantage in discovering asymptomatic stage IV uveal mel. Hopefully this will change with improved systemic treatments. No significant financial relationships to disclose.
Activity of vorinostat (SAHA), cladribine (2-CdA), and rituximab in previously untreated mantle cell lymphoma: A phase I/II study.
Authors: S. E. F. Spurgeon, A. I. Chen, B. Ratterree, C. Okada, G. Palmbach, K. Diaz, N. Subbiah, C. Capper, E. E. Epner
Journal: Journal of Clinical Oncology (2011)

8023 Background: Epigenetic modifications are important to cancer pathogenesis and novel therapies that target the epigenome include hypomethylating agents and histone deacetylase inhibitors (HDACi). 2-CdA combined with rituximab (R) is an effective treatment for B cell malignancies and recent evidence suggests that 2-CdA inhibits DNA and potentially histone methylation via the transfer of methyl groups. Vorinostat (SAHA) is an HDACi that is FDA approved for use in cutaneous T cell lymphoma and has shown modest activity in B cell lymphoma. We initiated a Phase I/II trial combining SAHA, 2-CdA, and rituximab (SCR) for the treatment of B-cell non-Hodgkins Lymphoma (NHL). Methods: Phase I enrolled 10 patients with relapsed/refractory NHL. The MTD of vorinostat for the Phase I was 400 mg (D 1-14) combined with 2-CdA 5mg/m2 IV (D 1-5), and R 375 mg/m2 IV (weekly x 4 for cycle 1 and 1x/month) every 28 days for up to 6 cycles. Phase II eligibility includes relapsed NHL as well as previously untreated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL). Primary outcome is response rate (ORR). Scientific correlatives include analysis of CD20 expression, histone acetylation, gene microarray and methylation analysis, and Q-PCR of potential target genes. Results: 45 patients (Phase I/II) have been enrolled and 39 patients have been treated. The ORR in evaluable relapsed patients is 32% (7/22). Of the 14 previously untreated advanced MCL patients, 13 have completed ≥ 2 cycles and are evaluable for response. ORR is 100% (13/13) with 77% (10/13) complete responses (CR). Of these 13 patients, 5/6 (83%) who have completed 6 cycles have attained CR. Toxicities have primarily included reversible myelosuppression, 1 gr. 4 thrombo-embolic event (probably related), and 1 grade 5 pulmonary hemorrhage in a patient with relapsed pulmonary lymphoma. Conclusions: The SCR regimen shows activity across a number of low grade B-cell malignancies and shows particular therapeutic promise in patients with previously untreated mantle cell lymphoma. Correlative studies are ongoing. Future studies should continue to explore this regimen in previously untreated mantle cell lymphoma.
Survival trends and patterns of chemotherapy use in elderly metastatic colorectal cancer (mCRC) patients.
Authors: V. Shankaran, S. J. Beck, D. K. Blough, L. Koepl, Y. M. Yim, E. Yu, S. D. Ramsey
Journal: Journal of Clinical Oncology (2011)

6118 Background: Since 2002, several drugs (including bevacizumab (Bv), oxaliplatin (Ox), irinotecan (Iri)) have been approved for mCRC. The goals of this study are to examine patterns of newer chemotherapy (CTx) use and survival trends in older mCRC pts. Methods: Pts ≥ age 65 with mCRC diagnosis (dx) 2001–5 were identified from the SEER–Medicare database. Pts were excluded for Medicare HMO, lack of Medicare parts A and B, or second cancer. First–line (1L) CTx was identified within 3 mo of dx. Pts were categorized by dx year (2001–3 vs. 2004–5) and treatment (none, CTx, CTx + Bv.). A logistic regression model identified factors associated with 1L Bv use. A Cox proportional hazards regression model was used to assess association of various factors (age, comorbidity, hepatic resection (rsxn), CTx) with survival. Results: 5,725 pts (median age 77) met criteria, of whom 2,647 (46%) received 1L CTx. In 2004–5, 32% and 12% of treated pts received Ox and Iri (vs.1% and 34% in 2001–3). Following its approval in 2004, 25% of treated pts received Bv. Factors associated with 1L Bv use include age <75 (OR 1.43, p=0.02) and concurrent use of Ox (OR 10.11, p<0.001) or Iri (OR 5.82, p<0.001). In a Cox proportional hazards model, survival was greater in pts with lower comorbidity, age <75, hepatic rsxn, 1L CTx use, and dx 2004–5. Pts dx 2004–5 who used Bv had the greatest survival compared with untreated pts dx 2001–3 (HR 0.46, p<0.001, median OS 15 vs. 6 mo). Conclusions: In an elderly mCRC cohort, nearly half of pts received 1L CTx, many with regimens containing Iri, Ox, or Bv. Survival was greatest in pts dx 2004–5 who used Bv. Increased Ox use may also have improved survival in this period. Future SEER–Medicare analyses may help elucidate the relative benefit of other new agents in the elderly, a population under–represented in clinical trials. Cox proportional hazards model. Factor HR 95% CI P Age < 75 0.71 0.66 – 0.75 <0.001 Comorbidity (Klabunde) ≤ 1 0.75 0.70 – 0.80 <0.001 Hepatic rsxn 0.68 0.58 – 0.79 <0.001 Dx 2001-3 + 1L CTx 0.84 0.78 – 0.91 <0.001 Dx 2004-5 no 1L CTz 0.88 0.81 – 0.95 0.002 Dx 2004-5 + 1L CTx 0.63 0.57 – 0.69 <0.001 Dx 2004-5 + 1L CTx and Bv 0.46 0.39 – 0.55 <0.001 Reference: Age ≥ 75. Comorbidity >1, No hepatic rsxn, Dx 2001-3 no 1L CTx
Analysis of <i>KRAS/NRAS </i>mutations in phase 3 study 20050181 of panitumumab (pmab) plus FOLFIRI versus FOLFIRI for second-line treatment (tx) of metastatic colorectal cancer (mCRC).
Authors: Marc Peeters, Kelly S. Oliner, Timothy Jay Price, Andres Cervantes, Alberto F. Sobrero, Michel Ducreux, Yevhen Hotko, Thierry Andre, Emily Chan, Florian Lordick, Cornelis J. A. Punt, Andrew Strickland, Gregory Wilson, Tudor-Eliade Ciuleanu, Laslo Roman, Eric Van Cutsem, Ying Tian, Andre Scott Jung, Roger Sidhu, Scott D. Patterson
Journal: Journal of Clinical Oncology (2014)

LBA387 Background: Previously, this study showed significant improvement in progression-free survival (PFS) in pmab + FOLFIRI vs FOLFIRI (HR=0.73; 95% CI: 0.59-0.90; p=0.004) and a trend toward improved overall survival (OS; HR=0.85; 95% CI: 0.70-1.04; P=0.12; Peeters et al. JCO 2010). Recently, analysis from 1st-line mCRC PRIME study showed that mutations in RAS genes (KRAS/NRAS exons 2/3/4) predicted a lack of response to pmab (Douillard et al. NEJM 2013). Methods: The primary objective was to assess the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS based on RAS mutation status in the primary analysis population. Bidirectional Sanger sequencing was used to detect mutations in KRAS exons 3, 4 and NRAS exons 2, 3, 4 in patients (pts) with known WT KRAS exon 2 mCRC. Results: In this prospective retrospective analysis, overall RAS ascertainment rate was 85% (n=1008/1186). 18% of the WT KRAS exon 2 pts harbored additional RAS mutations (n=107/597). Efficacy is shown (Table). Tx HR for pts with WT RAS was 0.803 (95% CI: 0.629-1.024; P=0.077) for OS and 0.695 (95% CI: 0.536-0.903; P=0.006) for PFS. Conclusions: Improvements were observed in the tx effect of pmab + FOLFIRI vs FOLFIRI on OS and PFS in the WT RAS group vs the WT KRAS exon 2 group. Pts with MT RAS mCRC are unlikely to benefit by the addition of pmab to FOLFIRI, similar to pts with MT KRAS exon 2 mCRC in this study. These findings are consistent with previously reported outcomes by RAS status and support RAS testing to determine potentially appropriate pts for pmab tx. Clinical trial information: NCT00339183. [Table: see text]
Efficacy and safety of recombinant interleukin-21 (rIL-21) and rituximab in relapsed/refractory indolent lymphoma
Authors: J. M. Timmerman, J. C. Byrd, D. J. Andorsky, M. F. Siadak, T. A. DeVries, D. F. Hausman, J. M. Pagel
Journal: Journal of Clinical Oncology (2008)

8554 Background: IL-21 is a cytokine that activates NK and CD8+ T cells and can enhance antibody-dependent cellular cytotoxicity. This Phase 1, two-part dose-escalation study evaluated the combination of rIL-21 and rituximab in subjects with relapsed, indolent CD20+ B cell lymphomas who had received at least 1 prior course of systemic therapy. A dose of 100 μg/kg rIL-21 was selected for evaluation in an expanded cohort of 15 subjects in Part 2 of the study. Methods: Eligible subjects received weekly rituximab (375 mg/m2) on days -7, 0, 7, 14, and 21, and 100 μg/kg rIL-21 IV on days 0, 7, 14, and 21 of a 4-week treatment cycle. Safety, serum levels of rIL-21, and tumor response assessed by the investigator per Cheson criteria were evaluated. Subjects without disease progression at day 36 were eligible to receive a second cycle. Results: 15 subjects (5 follicular lymphoma, 9 small lymphocytic lymphoma/chronic lymphocytic leukemia, and 1 marginal zone lymphoma) were treated. The median number of prior regimens was 3 (range, 1–8); all subjects had prior rituximab (median number of prior courses, 2; range, 1–6). Last response to rituximab included CR in 2, PR in 6, SD in 2, PD in 3, and unknown in 2. Ten of 15 subjects completed 2 treatment cycles. Most adverse events (AEs) were Grade 1 or 2, and included flu-like symptoms, headache, and fatigue. Grade 3/4 AEs related to study drug consisted of Grade 4 chest pain in 1 subject with a history of cardiac disease who died secondary to stent restenosis, transient Grade 4 thrombocytopenia without bleeding in 1 subject, and Grade 3 rash in 1 subject. Lab abnormalities were generally Grade 1 or 2 and included anemia, thrombocytopenia, lymphopenia, neutropenia, hypoalbuminemia, and hypokalemia. Pharmacokinetic and immunogenicity assessments are in process. Overall best responses to date on study include 1 CR, 1 CRu, 3 PR (including 1 subject whose last response to rituximab lasted < 6 months), 8 SD, and 2 unevaluable, for an overall response rate of 33% [95% CI = (12–62%)]. Two subjects with SD are still on study. Conclusions: Combination treatment with rIL-21 plus rituximab for up to two 4-week cycles is well tolerated and associated with clinical response, even in subjects heavily pre-treated with rituximab. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ZymoGenetics ZymoGenetics