tbuckley/cabot-search huggingface dataset:
Randomized multicenter double-blind phase II trial: The immunological adjuvant OPT-821 with or without a trivalent ganglioside vaccine in metastatic sarcoma patients following metastasectomy.
Authors: Richard D. Carvajal, Rashmi Chugh, Mohammed M. Milhem, Christopher W. Ryan, Suzanne George, Bartosz Chmielowski, Mark Agulnik, Eve T. Rodler, Anthony D. Elias, G. Thomas Budd, Hussein Tawbi, Sujana Movva, Brian Andrew Van Tine, Mark Andrew Dickson, Martee Leigh Hensley, Mary Louise Keohan, William D. Tap, Cathryn M. Bennett, Robert G. Maki, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2012)

TPS10103 Background: The gangliosides GM2, GD2, and GD3 are strongly expressed in sarcoma and represent novel antitumor targets. We have demonstrated the safety and immunogenicity of individual monovalent ganglioside conjugate vaccines when administered with OPT821, a synthetic saponin adjuvant that augments the T-cell response. Antitumor effects are observed with anti-ganglioside antibodies in preclinical models, with greatest benefit seen in the micrometastatic setting. Patients (pts) with metastatic sarcoma rendered disease-free by surgery are at high risk for disease recurrence, with no therapy demonstrated to improve outcomes. Therefore, this population is ideally suited to test the efficacy of vaccine induced anti-ganglioside antibodies. We thus initiated this randomized double-blind phase II study of OPT821 with or without a trivalent ganglioside vaccine composed of GM2, GD2 lactone and GD3 lactone conjugated to KLH, an immunogenic carrier protein. Methods: A total of 134 pts will be randomized on a 1:1 basis stratified by disease state (relapsed disease vs metastasis at time of diagnosis), disease-free interval and number of relapses. Key inclusion criteria include stage IV sarcoma (locoregional recurrence is not sufficient) rendered disease-free following surgery or multi-modality therapy, no more than 8 weeks since surgery, and no continuous use of anti-inflammatory medications. Pts with Ewings sarcoma, GIST and rhabdomyosarcoma (except pleomorphic/anaplastic) are ineligible. Eligible pts will receive 10 subcutaneous injections in the outpatient setting over 84 weeks. The primary endpoint is progression-free survival (PFS). Secondary objectives include overall survival (OS) and 1- and 3-year PFS rate. Exploratory objectives include correlation of serologic response to outcome, comparison of tumor ganglioside expression at baseline and at recurrence, and analysis of circulating tumor cells. Enrollment began in July 2010. As of January 1, 2012, 83 patients had been recruited from 12 participating sites. Clinicaltrials.gov#: NCT01141491. Funded by Mabvax Therapeutics and NIH (R21CA13386).
Nintedanib (N) plus best supportive care (BSC) versus placebo (P) plus BSC for the treatment of patients (pts) with colorectal cancer (CRC) refractory to standard therapies: Subanalysis of the phase III LUME-colon 1 study in pts by prior regorafenib (R) treatment.
Authors: Heinz-Josef Lenz, Takayuki Yoshino, Guillem Argiles, Timothy Iveson, Javier Sastre, Mark Harrison, Howard John Lim, Niall C. Tebbutt, Marc Peeters, Taroh Satoh, Christian Dittrich, Mouna Sassi, Arsene-Bienvenu Loembe, Eric Van Cutsem
Journal: Journal of Clinical Oncology (2017)

660 Background: N is a triple angiokinase inhibitor (including VEGFR, PDGFR and FGFR). LUME-Colon 1 (NCT02149108) evaluated the efficacy and safety of N in pts with metastatic CRC (mCRC) after failure of standard therapies and showed a statistically significant improvement in progression-free survival (PFS) (HR [95% CI]: 0.58 [0.49–0.69]; p &lt; 0.0001) but no difference in overall survival (OS) (HR: 1.01 [0.86–1.19]; p = 0.8659). Here, we report results of a prespecified subanalysis in pts by prior R treatment. Methods: Eligible pts (aged ≥ 18 years; ECOG PS 0–1; mCRC adenocarcinoma refractory to standard treatments, including oxaliplatin, irinotecan, fluoropyrimidines, anti-VEGF and anti-EGFR in RAS wt) were randomised 1:1 to N (200 mg bid) + BSC or P (bid) + BSC. Prior R treatment was a stratification factor. Co-primary endpoints were PFS by central review and OS. Results: 768 mCRC pts were randomised; 285 (37%) had received prior R (N, n = 141; P, n = 144) and 483 (63%) were R naïve (N, n = 245; P, n = 238). Baseline characteristics were similar between the groups (pretreated vs naïve) except: race (Asian: 39% vs 19%), time from first diagnosis ( ≥ 36 months [m]: 67% vs 48%), time from onset of metastatic disease ( ≥ 24 m: 85% vs 64%). Median PFS (N vs P) was 1.5 vs 1.4 m (HR: 0.61 [0.47–0.79]) in prior R pts and 1.5 vs 1.4 m (HR: 0.62 [0.51–0.76]) in R-naïve pts (interaction p-value = 0.9245). Median OS (N vs P) was 6.5 vs 4.6 m (HR: 0.90 [0.69–1.17]) in prior R pts and 6.3 vs 6.6 m (HR: 1.09 [0.89–1.33]) in R-naïve pts (interaction p-value = 0.2529). N was tolerable in both subgroups; AEs leading to discontinuation (N vs P) occurred in 12% vs 8% of prior R pts and 16% vs 12% of R-naïve pts. The most frequent AEs with N were diarrhoea, nausea and vomiting in both subgroups. Conclusions: N demonstrated clinical activity in CRC regardless of prior R treatment; significant improvement in PFS compared to P was observed in both R-pretreated and R-naïve pts, supporting the concept of continuous antiangiogenic therapy. A slight improvement in OS was observed in R-pretreated compared to R-naïve pts. Clinical trial information: NCT02149108.
Phase I study of vorinostat combined with isotretinoin and temozolomide in adults with recurrent malignant gliomas.
Authors: Marta Penas-Prado, Kenneth R. Hess, Victor A. Levin, John Frederick De Groot, Howard Colman, Morris D. Groves, Charles A. Conrad, Monica Elena Loghin, Kathy Hunter, Mark R. Gilbert, W. K. Alfred Yung, Vinay K. Puduvalli
Journal: Journal of Clinical Oncology (2015)

2039 Background: Vorinostat (Vor), a histone deacetylase inhibitor, has shown preliminary activity in recurrent GBM. Preclinical studies demonstrated that Vor can overcome resistance to isotretinoin (cRA) and temozolomide (TMZ). We hypothesized that Vor could overcome resistance to cRA and cytotoxic chemotherapy in the treatment of recurrent gliomas. Carboplatin (CBP) was originally selected as the cytotoxic drug since eligible patients would have failed prior standard TMZ therapy. Methods: We conducted a Phase I study of combinations of these agents preceding a proposed adaptive randomized 3-arm Phase II study. Adults with recurrent malignant glioma were enrolled into one of 3 arms. Arm 1: Vor + cRA, Arm 2: CBP + cRA, or Arm 3: Vor + cRA + CBP. Dose escalation was by a 3 + 3 design to define the maximum tolerated dose (MTD). Due to excessive toxicity in arms containing CBP, this drug was replaced by dose-dense TMZ due to preliminary evidence of activity in recurrent gliomas. Results: A total of 55 patients (8 anaplastic gliomas, 47 GBM) were enrolled from 11/2007 to 03/2012. Among 52 evaluable patients, a total of 11 DLTs were seen, but none after introduction of TMZ to Arm 3. MTDs are summarized in Table. Toxicities included: Arm 1 – neutropenia, thrombocytopenia, pulmonary embolism, elevated AST (DLT), and hypertriglyceridemia (DLT); Arm 2/CBP – neutropenia, thrombocytopenia (DLT), and hypertriglyceridemia; Arm 3A/CBP - thrombocytopenia (DLT) and hypokalemia (DLT); Arm 3B/TMZ – thrombocytopenia, hypertriglyceridemia, fatigue. Best response was stable disease in 26 patients, for ≥ 4 months in 15 patients; 10 patients achieved 6-month progression-free survival; 7 of whom had GBM. Conclusions: Two and 3 drug combinations of Vor, cRA, and dose-dense TMZ were well tolerated with MTD that will be used in a multicenter adaptive randomized Phase II study in the near future. Clinical trial information: NCT00555399. MTD Arm 1 (n=14) Vor 400 mg/day, D 1-14 cRA 100 mg/m2/day, D 1-21 Arm 2/CBP (n=12)* CBP AUC 5, D 1 cRA 100 mg/m2/day, D 1-21 Arm 3A/CBP (n=19)* De-escalation to dose level -3 (Vor 300 mg/day x 14 days; cRA 100 mg/m2/day x 21 days; CBP AUC 4) Arm 3B/TMZ (n =10) Vor 500 mg/day, D 1-7 & 15-21 cRA 100 mg/m2/day, D 1-21 TMZ 150 mg/m2/day, D 1-7 &15-21 *Not going to Phase II
Neoadjuvant chemoradiotherapy for locally advanced low-lying rectal cancer
Authors: B. Yu, M. Zhang, W. Wu, L. Chen, L. Peng, G. Bian, J. Fu, C. Fei
Journal: Journal of Clinical Oncology (2009)

e15095 Objective: The aim of this trial was to explore the possibility of further improvement of efficacy in neoadjuvant chemoradiation for the treatment of locally advanced low-lying rectal cancer and the management of patients with clinical complete regression. Methods: 192 cases with locally advanced low-lying rectal cancer (T3/T4 or N+) received preoperative radiotherapy comprising 40–46 Gy/20–23 fractions and concomitant oral capecitabine 625 mg/m 2 bid for 10 weeks prior to surgery. Curative resection with TME was carried out 6 weeks after the end of radiation. Results: Patients (pts) were recruited from May 2001 through August 2007. Overall, 117 pts (60.9%) experienced adverse events but only 2 suffered from grade 3 hand-foot syndrome. 17 pts (8.9%) had clinical complete tumor regression without surgery, 175 pts underwent curative resection including of 134 pts with low anterior resection (LAR), 32 pts with ultra-low anterior resection with Parks’ coloanal anastomosis and among them 6 pts with diverting temporary colostomy and 9 pts with APR. Sphincter preservation was achieved in 95.3%. Pathologically, 24 pts (12.5%) showed CR together with 17 pts with clinical CR; the overall CR rate was 21.4%. According to the pathological staging: T 0 N 0 41 cases, T 2 N 0 43 cases, T 3 N 0 77 cases, T 4 N 0 5 cases, T 2 N 1 11 cases, T 3 N 1 13 cases, T 4 N 0 5 cases, and T 4 N 1 2 cases; in semiquantitative Dworak's tumor regression grade, TRG0 8 pts,TRG1 32, TRG2 28,TRG3 83 and TRG4 41 with an overall tumor downstaging of 79.2%. There were no operative deaths, 5 pts suffered from rectovaginal fistulas and 4 anastomotic leakages with an overall anastomotic leakage rate of 5.1% (9/175) and all recovered without further events. All patients have been followed up for a median of 46 months (range 12–87). During the time, 11 pts had lung metastases, 6 liver metastases and 7 had local recurrences. The 3-year disease-free survival was 86.6% and overall survival was 92.6%. Conclusions: Neoadjuvant chemoradiotherapy has high efficacy resulting in tumor down-staging, increased resectability and sphincter preservation, and a reduction in local recurrences. Meanwhile those patients with clinical complete response can be followed up closely and safely without surgery. No significant financial relationships to disclose.
Association of eNOS polymorphisms with clinical outcome in bevacizumab-treated breast cancer patients.
Authors: Marzia Del Re, Andrea Fontana, Daniele Giulio Generali, Barbara Pistilli, Valentina Citi, Paola Ulivi, Wainer Zoli, Eleonora Bona, Barbara Salvadori, Ilaria Ferrarini, Elisabetta Landucci, Sara Fancelli, Ilaria Bertolini, Andrea Michelotti, Luciano Latini, Alberto Bottini, Alfredo Falcone, Romano Danesi
Journal: Journal of Clinical Oncology (2014)

e22075 Background: VEGF overproduction induces angiogenesis and up-regulates endothelial nitric oxide synthase (eNOS) resulting in endothelial barrier disruption, edema and impaired tumor drug delivery (Goel S et al. Physiol Rev 2011;91:1071). The eNOS gene variants c.-786C>T and c.894G>T are associated with reduced NO production and higher incidence of hypertension (HT) (Niu W, Qi Y. PLoS One 2011;6:e24266). Since suppression of VEGF-eNOS axis may normalize interstitial pressure and enhance tumor drug delivery, but may induce HT, this study examined the association between major eNOS variants c.-786C>T and c.894G>T with treatment outcome and risk of HT in metastatic breast cancer (MBC) patients receiving bevacizumab. Methods: MBC subjects (n=75) were enrolled; main characteristics were: mean age 49.5 yrs (range 29-73) at first diagnosis, 53 yrs (range 34-74) at metastatic progression and PS 0-1. Four subjects with HT and 1 patient with compensated cardiovascular disease were also included; 24 subjects had received anthracycline and/or taxane as neo- or adjuvant chemotherapy. All patients were given 1st-line paclitaxel plus bevacizumab for metastatic disease; 24 subjects received also hormone-therapy. Germline DNA was extracted from blood and used to screen patients for eNOS c.-786C>T and c.894G>T variants by Real Time PCR and automatic sequencing. The study was approved by the local Ethics Committee. Results: Genotype frequencies are shown in the Table; c.-786TT was associated with longer PFS compared with other genotypes (median PFS 95%CI, TT=12 vs CC/CT=8 months, p=0.0344, Gehan-Breslow-Wilcoxon test), but not with HT. None of the other variants were significantly associated with PFS or HT. Conclusions: Bevacizumab-induced vascular normalization may be facilitated by a reduced production of NO. Patients bearing deficient eNOS variant enjoied a longer PFS but were not at risk of developing HT with respect to the wild-type allele. eNOS -786TT may be a novel biomarker of bevacizumab efficacy. SNP Frequency (%) c.-786C>T CC (45) CT (29.3) TT (25.7) c.894G>T GG (40) GT (54.6) TT (5.3)
Overall survival in patients with Hodgkin lymphoma: Disparities by insurance status.
Authors: Rahul Parikh, Michael L. Grossbard, Louis B Harrison, Joachim Yahalom
Journal: Journal of Clinical Oncology (2015)

8569 Background: The association between insurance status and outcome has not been well established for patients with Hodgkin Lymphoma (HL). The purpose of this study was to examine the disparities in overall survival (OS) by insurance status in a large cohort of patients with HL. Methods: We used a prospectively collected nationwide database-the National Cancer DataBase (NCDB) to evaluate clinical features and survival outcomes among patients diagnosed with stage I-IV HL from 1998 to 2011. The association between insurance status, co-variables, and outcome was assessed in a multivariate Cox proportional hazards model. Survival was estimated using the Kaplan-Meier method. Results: Among the 76,672 patients with HD within the NCDB, a total of 45,777 patients with stage I-IV disease were eligible for this study, with a median follow-up of 6.0 years. The median age was 39 years (range: 18-90). The insurance status was as follows: 3,247(7.1%) uninsured; 7,962 (17.4%) Medicaid; 30,334 (66.3%) private insurance; 3,746 (8.2%) managed care; 488 (1.0%) Medicare. Patients with unfavorable insurance status (uninsured or Medicaid-insured) were found to be older ( > 50), more advanced stage at diagnosis, with higher co-morbidity score, more commonly with “B” symptoms, and lower income and education quartiles (all p < 0.01). These patients were also less likely to receive radiotherapy, start chemotherapy promptly ( < 30 days from diagnosis), and less commonly treated at academic/research centers (all p < 0.01). Patients with unfavorable insurance had a 10-year OS of 37% vs. 80% for those with favorable insurance (p < 0.01). When adjusting for all co-variates, unfavorable insurance status was associated with a significantly decreased OS (HR = 3.32; 95% CI, 3.02-3.64, p < 0.01). Unfavorable insurance status steadily increased from 22.8% to 28.8% between 1998 and 2011. Conclusions: Our study reveals that HL patients with Medicaid or uninsured status have inferior outcomes than patients with more favorable insurance. To our knowledge, this study represents the largest dataset examining the role of insurance status on survival for patients with HL. Targeting this subset of patients with limited access to care may help improve outcomes.
Effects of pazopanib therapy on mean corpuscular volume in patients enrolled in MC1112: Analysis of correlation with time to disease progression in solid tumors.
Authors: Aditi Kumar, Jill K. Burton, Vera J. Suman, Rui Qin, Charles Erlichman, Paul Haluska, Pamela Jo Harris, Keith Christopher Bible
Journal: Journal of Clinical Oncology (2015)

e13596 Background: Pazopanib is a multi-targeted kinase inhibitor approved for use in renal cell carcinoma and soft tissue sarcoma and has also shown benefit in other cancers. Macrocytosis has been reported consequent to therapy with some kinase inhibitors (e.g. sunitinib, imatinib) but not previously with pazopanib. Interestingly, macrocytosis has been correlated with tumor response in some reports. We assessed both changes in Mean Corpuscular Volume (MCV) and its potential association with time to disease progression (TTP) observed in conjunction with a phase I pharmacokinetic (PK)-guided dose-individualized pazopanib clinical trial in solid tumors (MC1112, clinicaltrials.gov identifier: NCT01552356). Methods: We collected and analyzed MCV data on patients who received pazopanib as part of MC1112 from April 2012 to December 2014 (N = 35). Patients who discontinued therapy (N = 4) due to toxicity were censored for analysis of TTP. Logrank test was used to assess whether TTP differed with respect to MCV changes. Results: Changes in MCV associated with pazopanib therapy varied temporally: an initial drop in MCV was observed in 27/35 (77%) patients after 4 weeks of therapy [median: -1.41% (range: -4.77 to +4.83%)]; MCV increased progressively thereafter, and subsequently plateaued around cycle 6. Median change in MCV after 2, 3, 6 and 12 cycles were +1.8% (N = 32), +5.9% (N = 18), +13.3% (N = 12) and +11 % (N = 6) respectively. There was a trend towards increased TTP in patients with > 2% increase in MCV from baseline after 8 weeks of pazopanib therapy (p = 0.021). Conclusions: Pazopanib therapy is associated with initial drop in MCV after 4 weeks of therapy, followed by a progressive rise in MCV, reaching a plateau around cycle 6. MCV changes may be a biomarker of pazopanib antitumor effects; however, these findings need further validation in larger studies and across distinct tumor types. Supported by: UL1 TR000135 and CA186686 (NIH/NCI). Clinical trial information: NCT01552356.
Implications of high tumor infiltrating lymphocytes (TIL) in HER2-positive and triple-negative breast cancer (TNBC).
Authors: Vassiliki Kotoula, Kyriakos Chatzopoulos, Sotiris Lakis, Zoi Alexopoulou, Eleni Timotheadou, Flora Zagouri, George E. Pentheroudakis, Helen Gogas, Eleni P. Galani, Eleftheria Tsolaki, Sofia Chrisafi, Angelos Koutras, Gerasimos Aravantinos, Pavlos Papakostas, Paris A. Kosmidis, Dimitrios G. Pectasides, George Fountzilas
Journal: Journal of Clinical Oncology (2015)

592 Background: High TIL may confer better prognosis to TNBC patients and may interfere with trastuzumab (T) benefit in HER2-positive breast cancer (BC) patients. Here, we investigated the effect of TIL on BC patient outcome with respect to immunohistochemical subtypes and treatment. Methods: Intratumoral mononuclear infiltrates were assessed as % of stromal area under low magnification on whole routine sections of 2613 breast carcinomas. Three different cut-offs (c/o) for high/low TIL were used (50%, 35% and 25%). Subtyping revealed 948 Luminal A, 615 Luminal B, 477 Luminal-HER2, 246 HER2-enriched, and 327 TNBC tumors. Patients had been treated in the frame of 4 prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-T era. T was administered sequentially for 1 year. Results: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively, and were subtype specific. Using the 35% c/o, high TIL were significantly more frequent in TNBC (13.8%), HER2-enriched (11.8%) and Luminal-HER2 (9.2%) than in Luminal B (5.7%) and Luminal A (1.8%) tumors (p < 0.0001). No significant TIL effect was observed on the outcome of patients with Luminal A and B tumors. High TIL, at all c/o, conferred decreased risk for relapse in patients with TNBC (e.g. 35% c/o, HR = 0.37, 95% CI 0.15-0.90, Wald’s p = 0.030) and Luminal-HER2 (e.g. 25% c/o, HR = 0.41, 95% CI 0.21-0.82, p = 0.011), but not with HER2-enriched tumors. Among all HER2-positive patients, a significant T benefit was noticed for those with low TIL (35% c/o, HR = 0.61, 95% CI 0.44-0.85, p = 0.003), but not for those with high TIL tumors; non-T treated patients with high TIL performed better than those with low TIL (HR = 0.56, 95% CI 0.36-0.87, p = 0.009), but this effect was insignificant among T treated patients. No interaction between T and TIL was found. Similar results were obtained for all TIL c/o, in distinct test and validation sets within the entire cohort. Conclusions: In the context of operable BC, high TIL is a favorable prognosticator in patients with TNBC and HER2-positive tumors. In the latter, high TIL does not seem to specifically predict for T benefit upon sequential T administration.
Preliminary circulating tumour cell (CTC) analysis in phase II study of weekly cabazitaxel for "unfit" metastatic castration resistant prostate cancer patients (mCRPC) progressing after docetaxel treatment (SOGUG-CABASEM trial).
Authors: Luis Leon Mateos, Laura Muinelo, Begoña Perez-Valderrama, Begoña Mellado, María José Juan Fita, Ovidio Fernandez Calvo, Eva Fernandez Parra, Daniel E. Castellano, Urbano Anido, Montserrat Domenech, Susana Hernando Polo, Jose Angel Arranz Arija, Cristina Caballero, Maria Ochoa de Olza, Ignacio Duran, Miguel Angel Climent Duran
Journal: Journal of Clinical Oncology (2014)

e16034 Background: Docetaxel (D) is standard first-line chemotherapy in patients (pts) with mCRPC. Cabazitaxel (C), a novel taxane developed to overcome D resistance, showed an overall survival improvement in second line CRPC in a three-weekly dose schedule. We aimed to evaluate efficacy and safety of weekly C/prednisone in