tbuckley/cabot-search huggingface dataset:
A phase I study of paclitaxel poliglumex (PPX) in combination with cisplatin (CIS) for patients (pts) with advanced cancer
Authors: K. M. Skubitz, C. F. Verschraegen, A. Daud, A. Bernareggi, F. B. Oldham
Journal: Journal of Clinical Oncology (2005)

2089 Background: PPX (XYOTAX) is a macromolecular drug conjugate that links paclitaxel with a biodegradable polymer, poly-L-glutamic acid. PPX is water soluble and is administered as a 10 minute infusion. Eliminating the need for CremophorEL reduces the risk of hypersensitivity reactions, even without premedication. Macromolecules like PPX can take advantage of the greater permeability of tumor vasculature and lack of lymphatic drainage to accumulate in tumor tissues. Methods: Escalating doses of PPX in combination with CIS to evaluate safety, pharmacokinetics (PK), and efficacy. Pts entered were diagnosed with advanced tumors. PPX was administered q3w as a 10-minute IV infusion, followed by CIS (75 mg/m2). 44 pts were treated (30 evaluable for efficacy, 28 for safety). Pts were treated at 175 mg/m2 (3), 210 mg/m2 (17), 225 mg/m2 (7), 250 mg/m2 (6), 270 mg/m2 (3). Results: Pts had 0–10 prior chemotherapy regimens (median, 2). Pts received 1–12 cycles (median, 2) of PPX. 15/30 pts had disease control defined as partial response [PR] (5 pts; 3 ovarian, 1 thymoma, 1 malignant schwannoma) or stable disease [SD] for > 8 weeks (10 pts). Response duration ranged from 4–10 months in pts with PR and 3–6 mo in pts with SD. CA125 values in pts with ovarian cancer were normalized in the 3 pts with PR and reduced (>70%) in 3 pts with SD. 6/7 ovarian responders had relapsed from platinum/taxane. Neutropenia was responsive to growth factor therapy and did not cause withdrawal. Of the 28 pts with adverse event data available, grade 4 treatment-related toxicities were neutropenia (14 pts) and febrile neutropenia (2). Nonhematologic grade 3 toxicities in >1 pt were dehydration (4), nausea/vomiting (7), fatigue (5) and neuropathy (8). 7/8 pts with grade 3 neuropathy had received ≥5 cycles (up to 10) of PPX and/or prior platinum/taxane therapy. 7 pts withdrew for toxicity. 3 pts had dose reductions. PK of PPX and CIS will be presented. Conclusions: PPX in combination with CIS exhibits promising efficacy and manageable toxicity. Based on the responses seen in ovarian cancer in studies with PPX alone and in combination with platinum agents, studies in ovarian cancer are in development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Cell Therapeutics Cell Therapeutics Cell Therapeutics
Can response to treatment predict outcome in patients with metastatic pancreatic adenocarcinoma (MPAC)?
Authors: Shinoj Pattali Jayavalsan, Shannon Leah Schmidt, Vipal Durkal, Paul S. Ritch, James P. Thomas, Beth Erickson, Kathleen K. Christians, Susan Tsai, Douglas B. Evans, Ben George
Journal: Journal of Clinical Oncology (2016)

443 Background: Front-line (FL) chemotherapy regimens for MPAC include FOLFIRINOX (FFX)/FOLFOX (FX) and Nab-paclitaxel plus Gemcitabine (NabG). We examined our hypothesis that objective response (OR) to these regimens can influence clinical outcome when employed sequentially. Methods: All MPAC patients treated with FFX/FX or NabG from 1/1/2011 to 12/31/2014 at the Froedtert and Medical College of Wisconsin (MCW) Clinical Cancer Center were reviewed. This study was approved by the MCW Institutional Review Board. Results: 64 patients were evaluated and the baseline characteristics are summarized in the table below. OR to FL chemotherapy included partial response(PR) - 23/64 (35.9%), stable disease (SD) - 14/64 (21.9%) and disease control rate (DCR) of 57.8%; OR to second line (SL) therapy included PR - 7/37 (18.9%), SD - 14/37 (37.8%) and DCR of 56.7%. Only 57.8% patients received SL chemotherapy. Among patients who demonstrated PR to FL chemotherapy, 64% were refractory to SL chemotherapy, while 33% of patients who were refractory to FL chemotherapy demonstrated a PR to SL chemotherapy. 3/64 patients who demonstrated PR to both FL and SL chemotherapy had excellent outcomes with overall survival (OS) of 20.9 months, 37 months and not met (PFS of 11 months to FL chemo and ongoing response of &gt; 4 months to SL chemo). Median OS of patients who demonstrated a PR/SD to FL and SL chemotherapy (15/64; 23.4 %) was 20.9 months. The patients who demonstrated progressive disease(PD) to both FL and SL chemotherapy (5/64; 7.8%) had a median OS of 3.8 months. Conclusions: Patients with MPAC who are refractory to FL chemotherapy may demonstrate a response to SL chemotherapy. Patients who are able to undergo sequential therapy with FFX/FX and NabG (in either sequence) and demonstrate either a PR or SD with both treatment regimens have an excellent clinical outcome. The minority of patients who demonstrate PR to both sequential regimens have a distinctly different outcome compared to patients who demonstrate PD to both regimens; tumors from these two subsets of patients need to be better characterized to improve our understanding of pancreatic cancer biology. [Table: see text]
Novel PAK4 inhibitors for pancreatic cancer therapy.
Authors: Asfar S. Azmi, William Senapedis, Erkan Baloglu, Yosef Landesman, Ori Kalid, Amro Aboukameel, Bin Bao, Sharon Shacham, Fazlul H. Sarkar, Michael Kauffman, Ramzi M Mohammad
Journal: Journal of Clinical Oncology (2014)

233 Background: Pancreatic cancer (PC) is a deadly disease in urgent need of novel molecularly targeted drugs. Gene copy number amplification studies in PC patient cohorts has shown amplification of the p21-activated kinase (PAK) family member PAK4. PAK4 acts as a key effector of the Rho family GTPases downstream of Ras signaling. Moreover, PAK4 protein is over-expressed in PC cell lines but not in normal human pancreatic ductal epithelial (HPDE) cells. Most importantly, RNA interference of PAK4 has been shown to suppress PC cell proliferation. These studies clearly make PAK4 an attractive therapeutic target especially because direct targeting of Kras has been a failure. Methods: We have identified a new class of PAK4 allosteric modulators that show anti-proliferative activity against several PC cell lines (IC 50s &lt;250nM) while sparing normal HPDE (IC 50s 5 fold higher). Results: Cell growth inhibition is concurrent with apoptosis induction and suppression of colony formation in the PC cell lines (and not in HPDE cells). Our small molecule PAK4 allosteric modulator, KPT-7189, suppresses PAK4 protein expression and caused reversal of anti-apoptotic signaling. PAK4 RNA interference enhances KPT-7189 activity, and co-immunoprecipitation experiments showed disruption of PAK4 binding partners. KPT-7189 also inhibited spheroid forming ability of highly resistant PC cells carrying markers of cancer stem cells (CSCs;triple positive for CD33 + CD44 + EpCAM +) consistent with epithelial-to-mesenchymal (EMT) phenotype. Molecular analyses of KPT-7189 treated CD33 + CD44 + EpCAM + spheroids showed suppression of EMT and CSC markers with re-expression of epithelial phenotype markers. Another potent PAK allosteric modulator in the same series, KPT-7651 showing good oral bioavailability (%F = 95%) was well tolerated by mice with a maximum tolerated dose of 60 mg/kg following oral administration. Pre-clinical animal efficacy trial in sub-cutaneous, orthotopic and LSL-Kras G12D/+ ;LSL-Trp53 R172H/+ ;Pdx-1-Cre transgenic mice model is currently under investigation. Conclusions: This is the first proof of concept study demonstrating the development of a PAK4-targeted drug for the treatment of PC, and thus further pre-clinical and clinical investigations are warranted.
Phase III study of single-dose casopitant in combination with ondansetron and dexamethasone for the prevention of oxaliplatin-induced nausea and vomiting.
Authors: P. J. Hesketh, V. Moiseyenko, G. Rosati, A. Makhson, J. Levin, M. W. Russo
Journal: Journal of Clinical Oncology (2011)

9019 Background: Currently, the NK-1 receptor antagonist (NK-1 RA) aprepitant combined with a 5-HT3 receptor antagonist (5-HT3 RA) and dexamethasone (DEX) constitutes the antiemetic standard of care with highly emetogenic chemotherapy (HEC) and with the moderately emetogenic chemotherapy (MEC) agents cyclophosphamide and anthracyclines (AC) when used together. The role of the NK-1 RA’s with MEC other than AC is less clear. Casopitant (GW679769) is an NK-1 RA with demonstrated efficacy when added to ondansetron and DEX in both the HEC and AC-MEC settings. This study was conducted to determine if the addition of a single dose of casopitant to ondansetron and DEX would improve the control of CINV following oxaliplatin-based MEC compared to ondansetron and DEX alone. Methods: Patients (pts) with colorectal cancer undergoing their first cycle of oxaliplatin (85 mg/m2–130 mg/m2) in combination with 5-flourouracil/leucovorin or capecitabine were randomized to receive casopitant (C) 90 mg or placebo (PL) intravenously (IV) and DEX 8 mg IV both on day 1 prior to chemotherapy, added to ondansetron 8 mg bid orally (PO) on days 1-3. The primary endpoint was the percentage of pts achieving complete response (CR; no vomiting/retching or use of rescue medication in the 120 hours after the start of chemotherapy. Results: Subjects – 710, median age - 61.3, females 44%, performance status 0-1 – 99%. Overall CR: C – 86%, PL – 85% (p =0.7273); acute (< 24 hours) CR: C – 97%, PL 96%; delayed (24-120 hours) CR: C – 86%, PL 85%. No significant differences in secondary endpoints of no emesis or no nausea were noted. Conclusions: Addition of a single 90 mg IV dose of casopitant did not improve the control of CINV with oxaliplatin-based MEC. In this setting, excellent control of CINV was achieved with the combination of a 5-HT3 RA and DEX alone. Unlike with cisplatin and AC chemotherapy, the emetogenic challenge posed by oxaliplatin-based chemotherapy may not be sufficient to warrant the use of an NK-1 RA.
ERCC1, RRM1, and BRCA1 mRNA expression levels and clinical outcome of advanced non-small cell lung cancer.
Authors: C. Su, S. Zhou, L. Zhang, S. Ren, C. Zhou
Journal: Journal of Clinical Oncology (2010)

e18045 Background: Customizing chemotherapy on the basis of biomarkers may improve outcome in advanced non-small cell lung cancer (NSCLC) patients. The purpose of this study was to investigate whether the expressions of DNA repair genes ERCC1 (excision repair cross complementing 1), RRM1 (ribonucleotide reductase subunit M1) and BRCA1 (breast cancer 1) affected clinical outcome in NSCLC patients. Methods: Patients with stage IIIb/IV NSCLC were given platinum-based chemotherapy. Messenger RNA expression levels of ERCC1, BRCA1 and RRM1 were determined by real-time polymerase chain reaction (RT-PCR) with TaqMan probes in the tumor. The relationship between these three genes with chemoresponse and overall survival was analyzed in this study. Results: Eighty-five patients (median age 59 years, range 30..C78) were enrolled into the study. Median overall survival (OS) was 13 months (range 10.8..C15.2). Time to progression (TTP) was 6.1 months (range 5.5..C6.7). Patients with low ERCC1 expression benefited more from a platinum-containing regimen (p = 0.094). Patients with low RRM1 expression benefited more from a gemcitabine- containing regimen. Patients with high BRCA1 expression benefited more from an anti-tubulin containing regimen (p = 0.046). Partial response rate was 42.4%. A statistically significant difference in OS was seen in patients with low ERCC1 levels compared to patients with high ERCC1 ones. (16.5 months vs. 10.0 months, p = 0.045). A significant relationship was observed between expression of ERCC1 and BRCA1 and TTP (6.5 vs. 5.1 months, p = 0.001, 5.2 vs. 6.5 p = 0.019, respectively). High expression of BRCA1 was associated with better survival in the anti-tubulin containing regimen subgroup. (8.7 vs 13.0 p = 0.035) Conclusions: ERCC1, RRM1 and BRCA1 are promising predictive and prognostic biomarkers in advanced non-small cell lung cancer. No significant financial relationships to disclose.
First-line treatment with modified FOLFOX6 (mFOLFOX6) + panitumumab (pmab) or bevacizumab (bev) in wild-type (WT) <i>RAS</i> metastatic colorectal carcinoma (mCRC): Tumor response outcomes beyond RECIST.
Authors: Fernando Rivera, Meinolf Karthaus, J. Randolph Hecht, Gianpiero Fasola, Jean-Luc Re Canon, Reija Koukakis, Jan-Henrik Terwey, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2015)

660 Background: In the PEAK study, pmab + FOLFOX6 was associated with longer OS than bev + FOLFOX6 in first-line RAS WT mCRC. RECIST overall response rates (ORR) were similar between treatment arms. Here, we report exploratory analyses of tumour assessments beyond RECIST. Methods: PEAK was a randomised phase II study of first-line pmab + mFOLFOX6 vs bev + mFOLFOX6 in previously untreated mCRC. ORRs (investigator assessed), median duration of response (DoR; from first confirmed response to disease progression or death [secondary endpoint]) and depth of response (DpR; defined as the percentage of tumour shrinkage at nadir or progression) in RAS WT pts were calculated by treatment. Early tumour shrinkage (ETS) was defined as the proportion of patients with ≥30% tumour shrinkage at week 8 (exploratory analysis). Results: Overall, 169 pts withRAS WT mCRC were included in the ORR analysis and 154 had tumour-shrinkage data available at baseline and week 8. Significantly more pts in the pmab + mFOLFOX6 arm had ETS at week 8 vs. the bev + mFOLFOX6 arm (Table). ORRs were similar in the two arms, while DoR was significantly longer and DpR significantly greater with pmab + mFOLFOX6 (Table). ≥30% vs. &lt;30% tumour shrinkage at week 8 was associated with longer median PFS (HR: 0.52 [95% CI: 0.29–0.92] and HR: 0.65 [95% CI: 0.38–1.13]) and OS (HR: 0.44 [95% CI: 0.15–1.32] and HR: 0.23 [95% CI: 0.08–0.66]) for pmab + mFOLFOX6 and bev + mFOLFOX6, respectively. Conclusions: Although ORR appeared to be similar or only numerically improved in the pmab arm of PEAK, the responses observed appeared to occur earlier, last longer and be deeper in our exploratory analyses. This is consistent with the observed OS and PFS benefit, and with data reported earlier from the FIRE3 study. Clinical trial information: NCT00819780. [Table: see text]
Interleukin-2 (IL-2) and 13-cis retinoic acid (RA) decrease vascular endothelial growth factor (VEGF) and prolong disease-free and overall survival in patients with non-small cell lung cancer (NSCLC) responsive to chemotherapy
Authors: F. Recchia, G. Saggio, A. Cesta, G. Candeloro, A. Nuzzo, M. Lombardo, S. Rea
Journal: Journal of Clinical Oncology (2005)

3171 Background: Patients with advanced NSCLC, responsive to chemotherapy, with high levels of VEGF have a poor prognosis. In 2 studies (Clin Cancer Res 2001;7:1251, Proc Am Ass Cancer Res 2004; 45:1082) we showed that low dose IL-2 and RA, decreased VEGF and improved the immune function in patients with advanced tumors treated with chemotherapy. The primary endpoint was to verify if IL-2 and RA decreased serum VEGF of NSCLC patients showing a partial (PR) or complete (CR) response or disease stability (SD) to chemotherapy. The secondary endpoints were the evaluation of the clinical outcome, compared with a group of historical controls and the cost of the therapy. Methods: 36 NSCLC patients (22% stage IIIB, 78% stage IV, mean age 66 years) were treated from June 2000 to December 2003 with subcutaneous IL-2, 1.8 x 106 IU and oral RA, 0.5 mg/Kg for 5 days/week for 2 cycles of 3 weeks, with a 1 week rest, for 1 year and with intermittent schedules until progression. Response to vinorelbine-platinum based regimens was as follows: CR 3 (8.4%), PR 15 (41.6%), SD 18 (50%). Controls belonged to a group of 72 patients, well matched for all characteristics, treated with the same chemotherapy by members of the IORAM. VEGF and response were monitored every 8 weeks. Results: After a median follow-up of 19 months and 277 courses of therapy, the 36 patients had a statistically significant decrease of VEGF with respect to baseline values. Compared with historical controls, there was a statistically significant difference both in disease-free survival (11.4 vs. 8.4 months) and overall survival (16.5 vs. 12.5 months). Six patients (16.6%) with SD were converted to CR after IL-2+RA therapy. No grade 3 or 4 toxicities were observed. Conclusions: These preliminary data show that the administration of low-dose IL-2 and RA to patients with NSCLC treated with chemotherapy is feasible, has low toxicity and is cost-effective in decreasing VEGF. Compared with one of the commercially available inhibitors of VEGF, our antiangiogenic therapy is 6.7 times less expensive (Wall Street J. 09/07/2004). A phase III randomized trial has been started. No significant financial relationships to disclose.
Understanding variation in the timeliness of diagnosis of cancer in symptomatic patients.
Authors: Georgios Lyratzopoulos
Journal: Journal of Clinical Oncology (2014)

301 Background: Diagnosing cancer promptly in symptomatic patients is a priority for healthcare systems worldwide, but little is known about how initiatives can be targeted to patients at greater risk. Methods: UK data on the number of consultations with a family doctor before specialist referral (‘pre-referral consultations’); the time interval from presentation to referral (‘primary care interval’); and stage at diagnosis, were analysed using multivariable regression models. Results: Both patient experience (41,299 patients, 24 cancers) and clinical audit (13,031 patients, 18 cancers) data indicated wide variation in two correlated measures* of the difficulty of suspecting the diagnosis of cancer once the patient had presented to their family doctor. For example, &gt;30% of patients with multiple myeloma, pancreatic and lung cancer experienced three or more pre-referral consultations; in contrast, this was true for &lt;10% of patients with breast cancer and melanoma (p&lt;0.001). Adjusting for diagnostic case-mix, younger and ethnic minority patients, and women, were more likely to experience three or more pre-referral consultations. Data from 88,657 patients (10 cancers) suggested socio-demographic disparities in stage at diagnosis for some only cancers: For patients with melanoma, breast and endometrial cancer, lower socioeconomic status was associated with higher risk of advanced stage at diagnosis and for, these three cancers, the same was true for older age. Conclusions: Different diagnostic intervals vary widely by cancer diagnosis and patient characteristics. Notable disparities in stage at diagnosis are apparent for ‘easy-to-suspect’ cancers (which are associated with minimal delay post-presentation), strongly implicating psychosocial patient factors as the source of these disparities. These findings can help to appropriately target early diagnosis policy initiatives and future research to patients at greater risk of prolonged diagnostic intervals. *Number of pre-referral consultations with a primary care physician and length of primary care interval (Spearman’s r=0.70).
A phase I study of <i>nab</i>-paclitaxel in patients (pts) with advanced solid tumors and hepatic dysfunction
Authors: M. Y. Biakhov, D. Kirsanov, G. Kononova, S. Loibl
Journal: Journal of Clinical Oncology (2008)

13503 Background: 130-Nanometer albumin-bound paclitaxel (nab-pac, nab-paclitaxel) 260 mg/m2 produced an increased objective response rate (ORR) in comparison with solvent-based paclitaxel (sb-pac) 175 mg/m2 (33% vs. 19%, p = .001) and a favorable safety profile in pts with metastatic breast cancer. [Gradishar et al, JCO, 2005] To address concerns about potential life-threatening toxicities in pts with hepatic impairment, we studied nab-paclitaxel in pts with incurable solid tumors using the same percentage dose reductions recommended for sb-pac according to degree of hepatic dysfunction (Taxol Package Insert). The safety profile was the primary objective secondary objective is assess antitumor activity in those pts with measurable disease. Methods: In this open-label, parallel design study, nab-pac was administered IV over 30 minutes every 3 weeks to pts with advanced solid tumors. Pts with AST > upper limit of normal (ULN) and < 10×ULN and bilirubin ≤ 5.0×ULN were included. nab-pac dosing was determined according to baseline bilirubin: > ULN - ≤ 1.25 ULN, 260 mg/m2; 1.26 - 2.0 ULN, 200 mg/m2; 2.01 - 5.0 ULN, 130 mg/m2. Results: 34 pts were enrolled, median age, 55.5 years; ECOG PS = 1, 2 were 77%, 23% respectively; 43% of pts had colorectal cancer, 37% other gastrointestinal cancer; 17% breast cancer, 3% head/neck cancer. 30 pts received nab-pac, 83% received ≥90% of the planned dose. 5 pts (17%) are ongoing. Median number of cycles received by the 260 mg/m2, 200 mg/m2 and 130 mg/m2 cohorts were 5.5, 3.0 and 3.0 respectively. The most commonly- occurring adverse events and hepatic enzyme elevations are summarized in the Table. Grade 1, 2 sensory neuropathy was observed (17%, 7%). ORR was 10%, 10% and 0 respectively. Disease control (ORR+SD>16 wks) was achieved in 40%, 30%, 10% respectively. Conclusions: Preliminary data suggest that with appropriate dose modification, nab-pac has an acceptable tolerability profile and shows antitumor activity in pts with solid tumors and hepatic dysfunction. Mature data will be presented. 260 mg/m2 (n = 10) 200 mg/m2 (n = 10) 130 mg/m2 (n = 10) Most Common Grade 3/4 Adverse Events (reported at ≥20% in all 30 patients [%/%]) Neutropenia 10/20 22/11 0/10 Fatigue 0/0 30/0 50/0 Grade 3/4 Bilirubin [%/%] 20/0 0/0 20/0 Grade 3/4 Liver Enzymes [%/%] AST 10/0 0/0 10/0 Alkaline phosphatase 10/0 0/0 0/0 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Abraxis