tbuckley/cabot-search huggingface dataset:
Phase I/II dose-finding study of crizotinib (CRIZ) in combination with erlotinib (E) in patients (pts) with advanced non-small cell lung cancer (NSCLC).
Authors: Sai-Hong Ignatius Ou, Ramaswamy Govindan, Keith D. Eaton, Gregory Alan Otterson, Martin Gutierrez, Alain C. Mita, Athanassios Argiris, Nicoletta Brega, Tiziana Usari, Weiwei Tan, Steffan Nicholas Ho, Francisco Robert
Journal: Journal of Clinical Oncology (2012)

2610 Background: c Met expression is common in NSCLC tumors and has been implicated in the development of resistance to EGFR inhibitors. CRIZ is an ALK and MET/HGF receptor tyrosine kinase inhibitor (TKI). In pre-clinical studies, combining CRIZ with an EGFR inhibitor enhanced anti-tumor activity in NSCLC cell lines that were either sensitive or resistant to EGFR inhibition. The phase I portion of a phase I/II study (A8081002; NCT00965731) investigated the combination of E (EGFR TKI) and CRIZ in pts with advanced NSCLC. Methods: Pts had advanced NSCLC, 1 or 2 prior chemotherapy regimens, and no previous MET-directed therapy. Endpoints included maximum tolerated dose (MTD) determination, safety, and pharmacokinetics (PK). Pts received CRIZ 150 or 200 mg BID combined with E 100 mg QD (150/100 and 200/100, respectively). Results: Twenty-five pts have been treated to date. Median duration of combination therapy in 150/100 (n=18) was 6.6 weeks (0.1–25.3); for 200/100 (n=7) was 6.9 weeks (3.0–64.7). Five pts had dose-limiting toxicities (grade [G] 2 and unable to receive at least 80% of the planned dose or ≥G3), all of which resolved: 3 pts at 150/100, G2 vomiting, G2 esophagitis and dysphagia, G3 diarrhea and dehydration; and at 200/100, G3 dry eye (1 pt) and G3 esophagitis (1 pt). Most pts (92%) experienced treatment-related adverse events (TRAEs), mainly of G1 or 2 severity. Common TRAEs were diarrhea (72%), rash (56%) and fatigue (44%). Six pts discontinued therapy due to TRAEs (150/100: G3 diarrhea, G3 dehydration, and G2 rash in 1 pt, G2 asthenia, G2 vomiting, G2 esophagitis, n=1 each; 200/100: G3 dry eyes, G1 esophagitis, n=1 each). One partial response (200/100; duration 61 weeks) and 9 stable diseases (n=7 150/100, n=2 200/100; duration 7–54 weeks) were observed overall. Co-administration of both doses of CRIZ with E increased E AUC by 1.8 fold, while CRIZ PK parameters appeared to be unaffected. Plasma exposure to E 100 mg QD with CRIZ was comparable to that of 150 mg QD from historical data. Conclusions: E plus CRIZ at the MTD was well tolerated, with no unexpected AEs, and showed signs of activity in a pre-treated population. E 100 mg QD plus CRIZ 150 mg BID was defined as MTD.
Phase II study of concurrent cetuximab (C225) plus definitive thoracic radiotherapy (XRT) followed by adjuvant docetaxel in poor prognosis patients with locally advanced non-small cell lung cancer (LA-NSCLC).
Authors: Thomas J. Dilling, Martine Extermann, Jongphil Kim, Lora Thompson, Binglin Yue, Craig William Stevens, Scott Antonia, Jhanelle Elaine Gray, Charles C. Williams, Eric B. Haura, Mary Colleen Pinder, Tawee Tanvetyanon, Alberto Chiappori
Journal: Journal of Clinical Oncology (2012)

7065 Background: Recursive partitioning analysis has shown that ECOG PS ≥ 2, male gender, or age &gt; 70 are prognostic of poor outcome in LA-NSCLC pts. Concurrent chemoradiotherapy improves survival, but toxicity is concerning in this frail pt cohort. We therefore opened this trial of concurrent definitive-dose XRT (70 Gy in 35 fractions) and C225 (250 mg/m 2 /dose), followed by adjuvant C225 and docetaxel (60 mg/m2 q3weeks x 3 cycles). Methods: Eligible patients had pathologically-proven LA-NSCLC (stage IIA – “dry” IIIB), not surgically resectable. They had ECOG PS 2 OR weight loss ≥5% in 3 months OR age &gt;70. The primary objective was progression-free survival (PFS). Secondary objectives included overall survival (OS) and overall response rate (ORR). Results: From 5/2008 to 11/2010, 32 pts were evaluated for our single-institution, IRB-approved prospective clinical trial. 3 pts were screen-failures and 2 more withdrew consent prior to treatment, leaving 27 evaluable patients. 1 was removed due to poor therapy compliance and 2 were taken off trial due to grade 3 toxicity from the C225 loading dose, but were followed under intent-to-treat analysis. Median follow-up and OS was 10.5 months. Median PFS was 7.8 months. ORR = 59.3%. 8 early/sudden deaths were reported, so the trial closed early: radiation pneumonitis (RP) was the apparent cause in 1 and probably/possibly in 4 others, with insufficient information in 2 additional pts; 1 pt died of failure to thrive. Of the remaining pts, 3 developed grade 3+ RP and 2 had grade 2 RP. Conclusions: Pts enrolled on this trial had improved OS compared with poor-PS historical controls (10.5 vs 6.3 months) and comparable OS compared with good-PS historical controls (10.5 vs 11.9 months) treated with RT (Werner-Wasik M et al. Int J Radiat Oncol Biol Phys. 2000;48:1475-82). However, pulmonary toxicity is a concern. Analysis of RP events is ongoing. Updated results will be presented at the meeting.
A decision-analytic model of idelalisib in relapsed or refractory patients with indolent non-Hodgkin lymphoma.
Authors: Nathaniel Smith, Alexander Xenakis, Rachel Beckerman, Jagpreet Chhatwal, Stephanie A. Gregory, Andrew Briggs
Journal: Journal of Clinical Oncology (2014)

e17655 Background: There are currently few treatment options for relapsed / refractory (RR) indolent non-Hodgkin’s lymphoma (iNHL) patients. Idelalisib (IDELA) is a first-in class PI3Kδ inhibitor with substantial clinical efficacy in iNHL patients refractory to rituximab and an alkylating agent. A single-arm clinical trial (Study 101-09) showed IDELA treatment results in a median of 11 and 20.3 months of progression-free and overall survival (PFS and OS), respectively, in these RR iNHL patients. Methods: A decision-analytic model simulated a cohort of RR iNHL patients over a 1 to 5 year time horizon. Patients first received IDELA or an aggregate comparator of current RR iNHL chemotherapy regimens in a progression-free state before transitioning to a progressive-disease state where they received palliative care until death. Survival data was fit and extrapolated from Study 101-09 (IDELA). A database claims analysis provided survival, disease- and treatment-related adverse events (AEs) profiles, and medical resource utilization data for RR iNHL patients in the comparator arm. Utility was based on literature review. All outcomes were discounted at 3%. Results: IDELA treatment resulted in better health outcomes versus the comparator, increasing life-years (LYs) by 2.4 to 7.8 mos, increasing progression-free life-years (PFLYs) by 2.5 to 4.6 mos, and improving quality-adjusted life-years (QALYs) by 0.2 to 0.5 over 1 to 5 years, respectively, while reducing AEs and hospitalizations by 17% to 59%, respectively, over 1 year. Conclusions: IDELA was projected to improve health outcomes in RR iNHL patients compared to current treatments, largely driven by improved PFS and OS; short-term reductions in AEs were specifically related to a delayed progression to the PD state. Health outcomes (per patient) Time horizon (years) Idela Comp Δ (IDELA-comp) LYs (months) 1 10.7 8.4 +2.4 3 21.1 14.0 +7.1 5 23.1 15.3 +7.8 PFLYs (months) 1 8.4 5.9 +2.5 3 12.5 8.0 +4.5 5 12.7 8.1 +4.6 QALYs 1 0.7 0.5 +0.2 3 1.3 0.9 +0.4 5 1.4 0.9 +0.5 Health outcomes (1,000 patient cohort) Time horizon (years) IDELA Comp Δ (idela-comp) No. AEs incurred 1 282 340 -58 3 627 566 +61 5 704 614 +89 No. hospitalizations incurred 1 256 595 -339 3 900 1,017 -117 5 1,085 1,108 -23
The efficacy and safety of CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy in patients with metastatic colorectal cancer: A multi-center, single-arm, phase II study (CCOG-0902 study).
Authors: Yuuki Sunakawa, Goro Nakayama, Kiyoshi Ishigure, Hiroyuki Yokoyama, Keisuke Uehara, Mitsuro Kanda, Kenta Murotani, Tsutomu Fujii, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2017)

795 Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC). Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety. Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0–14.8) and 30.6 months (95% CI, 27.6–33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy. Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC. Clinical trial information: UMIN000006478.
The SUNPAZ study: Results of an open label, single arm trial to evaluate patients with mRCC treated with everolimus after failure of first line therapy with sunitinib or pazopanib.
Authors: Martin Schostak, Arnd Nusch, Patrick de Geeter, Thomas Decker, Anna Resch, Claudia Weiss, Stephan H. Schmitz
Journal: Journal of Clinical Oncology (2017)

473 Background: The VEGFR-TKIs Sunitinib and Pazopanib are the currently recommended 1 st line agents for the treatment of renal cell carcinoma (RCC). Everolimus is a well-established treatment option after failure of a prior VEGFR-TKI. However, few prospective clinical data exist on the efficacy and safety of Everolimus after failure of a single line of VEGFR-TKI therapy and no clinical data exists on the efficacy and safety of Everolimus following Pazopanib treatment. Methods: This phase IV clinical trial investigated Everolimus 10 mg daily in patients who have progressed on or after 1 st line treatment with Sunitinib or Pazopanib. Adult patients with advanced clear cell RCC and an ECOG 0-1 were included. The primary endpoint was the rate of patients progression-free after 6 months of treatment. Results: 16 and 13 patients who received prior Sunitinib and Pazopanib, respectively, have been enrolled at 13 German sites. The median age was 65 years in the Sunitinib (SUN) group and 74 years in the Pazopanib (PAZ) group. After 6 months of Everolimus treatment, 11/12 (92%) patients in the SUN group showed disease progression, whereas 6/13 (46%) patients in the PAZ group remained progression-free (FAS population). The median OS was 14.8 months in the SUN group (95% CI 9.4 – not reached (NR)) and 20.4 months in the PAZ group (95% CI 11.7 – NR). The most common adverse events (AE) regardless of any relation to study drug included anemia (31.1% (SUN group) vs. 53.8% (PAZ group)), nausea (25.0 vs. 46.2%), stomatitis (12.5 vs. 61.5%), peripheral edema (12.5 vs. 53.8%), and dyspnea (12.5 vs. 46.2%). Conclusions: Patients in the PAZ group showed a lower rate of tumor progression within 6 months and a longer PFS as compared to the SUN group. The results confirm Everolimus as an effective 2nd line treatment option with a favorable safety profile, especially following Pazopanib, and the sequence Pazopanib - Everolimus as effective treatment option for mRCC patients. However, due to the small number of patients enrolled in the study, results have to be interpreted with caution. The types of observed AE are consistent with the well-known toxicity profile of Everolimus. Clinical trial information: NCT01514448.
Progesterone receptor isoform ratio to define the molecular signature of luminal breast cancers and their antiprogestin responsiveness.
Authors: Maria May, Paola Rojas, Gonzalo Sequeira, Andres Elia, Paula Martinez Vazquez, Pedro Gonzalez, Martin C Abba, Alfredo Molinolo, Stephen M. Hewitt, Charles M. Perou, Hugo Gass, Claudia Lanari
Journal: Journal of Clinical Oncology (2015)

11016 Background: Current therapies for hormone receptor (+) breast carcinomas target the estrogen receptor. Evidence indicates that the progesterone receptor (PR) also participates in cancer growth. In experimental models, we showed that mifepristone (MFP) inhibits the growth of mammary carcinomas when the predominant isoform is PR-A. The aim of our study was to confirm these observations and explore the molecular signatures of breast cancers overexpressing isoforms PR-B or PR-A. Methods: Tissue sections from 100 surgical samples were cultured with MFP (10 nM) or vehicle for 48 hs, and embedded in paraffin for Ki-67 staining. Frozen samples were processed for Western blotting (n = 360) or RNAseq (n = 16). Patients were considered PR-A(+) if PR-A/PR-B ≥ 1.2, or PR-B(+) if PR-A/PR-B ≤ 0.83. The sample size required to detect a 50% difference in MFP response between PR-A+ vs. non PR-A+ samples (type I error: 5%; type II error: 10%) was 19 patients/group. Results: MFP only inhibited Ki-67 expression in PR-A+ samples (p < 0.001). The 9 ductal HER2 (-) cancer samples analyzed by RNA-Seq with the EBseq algorithm showed 140 transcripts (FC > ±2; FDR < 0.05); 55 up-regulated in PR-A, and 85 in PR-B. Gene ontology showed functional modules associated with cancer cell proliferation such as 'Aurora B signaling' and the 'FOXM1 transcription factor network' (p < 0.01) linked with PR-B up-modulated genes. Intrinsic subtypes and risk score (ROR-S) predicted by the 50-gene PAM50 model were associated with each PR isoform group; 4/4 PR-B cases were Luminal B and 4/5 PR-A were Luminal A (p < 0.01). Studies of 140 deregulated transcripts discriminating PR-A from PR-B (TCGA RNASeq breast cancer dataset) demonstrated that a large number of genes up-regulated in PR-B group, remained up-regulated in luminal B and basal-like cancers, compared with PR-A associated genes that are expressed in normal-like and luminal A subtypes. The gene expression signatures associated to each PR isoform are now under validation using an independent cohort of breast cancer samples. Conclusions: The PR isoform ratio may define subgroups within the luminal breast cancers: those with PR-A/PR-B ≥ 1.2 are candidates for MFP treatment.
Phase I trial of panobinostat (P) and imatinib (IM) in patients with treatment-refractory gastrointestinal stromal tumors (GIST).
Authors: Sebastian Bauer, Ralf A. Hilger, Florian Grabellus, James Nagarajah, Mathias Hoiczyk, Annette Reichardt, Marit Ahrens, Daniel Pink, Thomas Mühlenberg, Max E. Scheulen, Martin H. Schuler, Peter Reichardt
Journal: Journal of Clinical Oncology (2012)

10032^ Background: Panobinostat (LBH589; P) is a pan-deacetylase-inhibitor that has preclinical activity in combination with IM in GIST models in vitro and in vivo. Aim of this study was to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of escalating doses of P in combination with IM in patients with GIST who have failed IM and sunitinib treatment. Methods: This was a two-center phase I study using a 3+3 design with a prespecified expansion of the MTD cohort. IM was administered at a dose of 400mg qd. Following a 7 day run-in phase, escalating doses of P were added. The starting dose for P was 20 mg given as a three-times-per-week (MWF schedule) oral dose for 3 out of 4 weeks. Doses were increased by 10 mg if no dose limiting toxicities emerged. Blood samples were drawn for PK and biomarker assessments of IM, its main metabolite N-desmethyl-IM, and P using a validated RP-HPLC method. Acetylation of histone A3 was evaluated in peripheral blood mononuclear cells (PBMNC) as pharmacodynamic marker for P activity. Metabolic response using PET (EORTC-PET study criteria) was assessed on day 7 of IM run-in and after 3 weeks of combined treatment with IM and P. Results: In total 12 extensively pretreated (median 5 pretreatments) pts (4 f, 8 m; median age 56 y, 34-75 y) received study treatment at 2 dose levels (DL). 2 dose-limiting toxicities (grade 4 thrombocytopenia) occurred at DL 2 (30 mg). Most common AEs were thrombocytopenia, anemia, fatigue, nausea, emesis, diarrhea, creatinine elevation, abdominal cramping, and weight loss. DL 1 (20mg) was declared MTD, and 5 additional pts were enrolled at DL1. Analysis of P and IM PK revealed mean peak concentration of 14.8 +/- 9.5 ng/ml for P (20 mg). IM plasma concentrations with 400 mg once-daily administration were 2.8 ± 1.1 μg/mL at peak and 1.2 ± 0.4 μg/mL at trough. Histone A3 acetylation was demonstrated in PBMNC from pts treated at DL 1. 11 pts were evaluable for PET response: 1 had mPR, 7 had mSD and 3 had mPD. Longest treatment duration was 17 weeks (median: 6wks). Conclusions: P in combination with IM is moderately tolerated. Evidence of target inhibition at the MTD was associated with limited clinical activity in heavily pretreated pts with GIST.
A phase II, open-label, multicenter study of IMC-1121B (ramucirumab; RAM) monotherapy in the treatment of persistent or recurrent epithelial ovarian (EOC), fallopian tube (FTC), or primary peritoneal (PPC) carcinoma (CP12-0711/NCT00721162).
Authors: Richard T. Penson, Kathleen N. Moore, Gini F. Fleming, Patricia S. Braly, Veronica L. Schimp, Hoa Nguyen, Ursula Matulonis, Susana N. Banerjee, Paul Haluska, Martin Eric Gore, Diane C. Bodurka, Alexei Morozov, Yihuan Xu, Mark D. Rutstein, Jonathan D. Schwartz, William P. McGuire
Journal: Journal of Clinical Oncology (2012)

5012 Background: VEGF receptor-mediated-signaling contributes to ovarian cancer pathogenesis. Elevated VEGF expression and serum levels are associated with poor clinical outcomes. We investigated RAM, a fully human VEGFR-2 antagonist antibody, in patients (pts) with persistent or recurrent EOC/FTC/PPC. Methods: Adult women with EOC/FTC/PPC who had completed ≥1 platinum (P)-based chemotherapeutic (ct) regimen and had a P-free interval (PFI) of &lt;12 months (m), progression on, or persistent disease after P-based therapy were eligible. Any number of prior ct regimens was allowed. ECOG PS 0-1 and adequate organ function were required. Pts received 8 mg/kg RAM IV every 2 weeks. Primary endpoints were progression-free survival at 6m (PFS-6) and confirmed objective response rate (ORR) by RECIST 1.0. Results: 60 pts were treated; 1 remains on study as of Dec 2011. Median age was 62 years (range 27-80). Median number of prior regimens was 3 (range 1– 14). 51 pts (85%) received ≥ 2 prior regimens; 25 pts (42%) received &gt;3 prior regimens. 45 pts (75%) were P resistant or refractory, with 65% (39 pts) serous tumors. PFS-6: 34.2% (95% CI: 21.7% – 47%). Best overall response: 3 PR (5%), 34 SD (57%), 20 PD (33%) and 3 not evaluable (5%). Median duration of PR: 5.6m (3.7, 5.6, 17.5); median PFS: 3.5m (95% CI: 2.3 – 5.3). Median OS: 11.1m (95% CI: 8.3 – 17.0). No unexpected toxicities were observed. Grade (G) 3 adverse events (AEs) observed in &gt;5% of pts were: headache (10%) and fatigue (8%). No G4 AEs were observed in &gt;5% of pts. 5 deaths occurred on RAM or within 30 days of discontinuation; 4 due to PD, and 1 due to intestinal perforation. 1 G4 bowel perforation and one G4 colo-vaginal fistula were noted. All 3 cases of perforation/fistula occurred in the setting of progressive, large-volume disease. Correlative biomarker studies are ongoing to identify patients most likely to benefit. Conclusions: Ramucirumab was reasonably tolerated and demonstrated single-agent activity in persistent or recurrent ovarian carcinoma, with approximately one-third of patients progression free at 6 months.
Abstract 339: Oxygen Blunts A2aR to Augment Lung Injury
Authors: Neil Aggarwal, Landon King, Vsevelod Polotsky
Journal: Circulation Research (2012)

Introduction: Mechanisms leading to acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) remain incompletely understood, yet the severity of illness and societal disease burden necessitate continued investigation. On-going lung inflammation and injury may occur due to inhibition of anti-inflammatory pathways in alveolar macrophages. With tissue injury, released adenosine preferentially activates the adenosine 2A receptor (A2aR), a pathway which has been implicated in mediating anti-inflammatory effects and tissue protection; however, modifiers of this pathway in macrophages are not well-described. In a murine model, we have observed that moderate levels of oxygen after intratracheal LPS increase and sustain macrophage inflammation. We hypothesize that moderate oxygen inhibits the A2aR pathway in macrophages to augment inflammation and lung injury. Methods: Murine model consists of intratracheal (IT) delivery of LPS, followed 12 hours later by 60% oxygen or 21% oxygen (RA) via sealed chamber. Results: Wild-type mice exposed to IT LPS (0.375 [[Unsupported Character - Symbol Font &amp;#61549;]]g/g mouse) followed by 60% oxygen had significantly more lung injury at days 2-4 in comparison to mice exposed to LPS or 60% oxygen alone, with increased alveolar cell influx, histologic injury, and epithelial barrier permeability. 60% oxygen after LPS significantly reduced lung A2aR mRNA and alveolar cell intracellular cyclic AMP (IC cAMP), located directly downstream of A2aR. Reduction in IC cAMP also occurred in isolated macrophages exposed to both LPS and oxygen when compared to LPS alone; this reduction was reversed using a specific A2aR agonist, CGS 21680. Adding oxygen or ZM241385 (A2aR antagonist) to LPS-exposed macrophages increased secretion of pro-inflammatory cytokines TNF-[[Unsupported Character - Symbol Font &amp;#61537;]] and MIP-2, and expression of co-stimulatory molecules CD86 and CD40. Murine delivery of CGS 21680 (125ug/dose/mouse) every 24 hours starting concurrently with oxygen exposure reduced lung injury in LPS and oxygen-exposed mice. Conclusion: After LPS exposure, 60% oxygen acts to decrease activation of the A2aR pathway in macrophages which may directly exacerbate lung injury.