tbuckley/cabot-search huggingface dataset:
A first-in-class, first-in-human phase I trial of p28, a non-HDM2-mediated peptide inhibitor of p53 ubiquitination in patients with metastatic refractory solid tumors.
Authors: J. M. Richards, M. A. Warso, D. Mehta, K. Christov, C. M. Schaeffer, T. Yamada, C. W. Beattie, L. R. Bressler, T. K. Das Gupta
Journal: Journal of Clinical Oncology (2011)

2511 Background: A 28 aa peptide (p28) derived from azurin, a redox protein secreted from the opportunistic pathogen Pseudomonas aeruginosa, preferentially enters a wide variety of cancer cells and inhibits their proliferation at G2/M through a non HDM2 mediated post translational increase in the level of wild type and mutated p53. Methods: Refractory (Stage IV) solid tumor patients (15) with p53+ lesions (>10% cells; IHC) were enrolled in an escalating, 5 dose level (.83, 1.66, 2.5, 3.33 and 4.16 mg/kg) Phase I trial to evaluate safety, tolerability, immunogenicity, pharmacokinetics and pharmacodynamics (PK/PD) of p28 as a single agent. p28 was administered 3 X per week for 4 weeks as an iv bolus with a two week PK break before the next, higher dose. Serum and tumor specimens were assessed for levels of p28. Results: To date, none of the 14 patients evaluated exhibited an immune (IgG) response or toxicity grade > 1. This group consisted of 7 melanoma, 4 colon, 1 pancreatic, 1 prostate and 1 sarcoma patient(s), with a median age of 61, age range of 51-71, and ECOG performance status of 0-2 including those receiving the highest dose level. Consequently, the NAOEL and MTD were above the highest dose studied. p28 distributes rapidly (t½ α, 0.1 hr), has a prolonged terminal half-life (t½ γ > 1.7 hr above 2.5 mg/kg) where distribution (Vdss) is maximal. Tumor levels mirrored serum concentrations. Objective responses were observed in target lesions of 8 of 14 patients evaluated to date (1 CR, 7 PR). Patient survival paralleled objective response. The current range in overall survival for patients initially receiving dose levels 1-5 was 2-4, 5-13.5, 3.5-11, 1.5-6 and 2.5-4.5 months, respectively. Currently, 6 of 11 patients receiving dose levels 2-5 remain alive; one with a CR. Conclusions: p28 may provide a new opportunity to improve overall survival in patients with metastatic, p53+ solid tumors as a single agent without significant toxicity.
The nationwide genomic screening project for gastrointestinal cancer in Japan (GI-SCREEN): Simultaneous identification of <i>KRAS, NRAS, BRAF, </i>and<i> PIK3CA </i>mutation in advanced colorectal cancer (aCRC) (GI-SCREEN 2013-01).
Authors: Kohei Shitara, Satoshi Fujii, Tadamichi Denda, Takeshi Kajiwara, Satoshi Yuki, Takako Eguchi Nakajima, Atsuo Takashima, Kenta Kawasaki, Takao Tamura, Taito Esaki, Daisuke Naruge, Hiromichi Ebi, Toshihiro Kudo, Hiroya Taniguchi, Kiwamu Akagi, Takeharu Yamanaka, Atsushi Ochiai, Toshihiko Doi, Atsushi Ohtsu, Takayuki Yoshino
Journal: Journal of Clinical Oncology (2015)

578 Background: Recent studies confirmed that minor KRAS or NRAS mutations are associated with the resistance to anti-EGFR therapy for advanced colorectal cancer (aCRC). Although the impact of BRAF or PIK3CA mutation on efficacy of anti-EGFR therapy is still controversial, targeting agents for these mutations are under developing. Efficient screening systems for these relatively minor mutations with short turnaround time are necessary for the successful development of targeted therapies. Methods: This study was initiated in February 2014 as one of new nationwide genomic screening projects for advanced gastrointestinal cancer patients in Japan. Patients with aCRC who are planned to receive systemic chemotherapy were eligible. A total of 36 mutations of KRAS codon 61, 146, NRAS codon 12, 13, 61, BRAF codon 600, PIK3CA codon 542, 545, 546 and 1047 in genomic DNA of cancer cells were simultaneously analyzed at a quality-controlled central laboratory using Luminex (xMAP) technology in a single reaction using 50 ng of DNA. Results: As of August 31, 2014, this study is ongoing with the participation of 16 major cancer centers in Japan. A total of 437 aCRC patients were enrolled to this study and 361 tumor samples has been analyzed with success rate for genomic analysis of 100%. Among the 237 patients with KRAS exon 2 wild type, 28 patients (11.8%) had other RAS mutations and 15 patients (6.3%) had BRAF mutation. Twenty-seven of 437 patients had PIK3CA mutations (6.2%). One patient with BRAF mutation was enrolled in early clinical trials of BRAF inhibitors in combination with anti-EGFR antibody and most of other patients are still treated with standard chemotherapies, which may become future candidates for early clinical trials. Conclusions: From our preliminary results, this nationwide screening system enabled to detect rare mutations using limited amounts of samples from aCRC, which may facilitate the enrollment of patients in IND registration trials for targeted therapies as well as optimal individualized treatment.
Biweekly gemcitabine, doxorubicin and paclitaxel (GAT) regimen as neoadjuvant chemotherapy (NC) in locally advanced breast cancer (LABC) patients: Final results from 2002–01 GEICAM study
Authors: P. Sánchez-Rovira, A. Antón, M. Margelí, A. Velasco, M. Lomas, C. Crespo, J. M. López-Vega, J. Casado, E. Carrasco
Journal: Journal of Clinical Oncology (2005)

842 Background: GAT regimen has being tested as NC in LABC patients (pts), based on its efficacy in metastatic disease (Sanchez-Rovira et al. Oncology 2001; 15(2): 44–47). Methods: Newly diagnosed stage IIB-III non-inflammatory BC pts were enrolled in this phase II trial. 2 pathological complete responses (pCR) were needed among the first 29 pts to continue accrual (Simon’s test, 95% probability of 10% pCR). Doxorubicin (A) 40 mg/m2 was given on day 1 as a 15 minutes IV infusion; gemcitabine (G) 2000 mg/m2 and paclitaxel (T) 150 mg/m2 were given as a 60 minutes and 3 hours IV infusion respectively on day 2. Cycles (Cy) were administered biweekly for a total of 6 courses. The study was approved by appropriate ethics committees; informed consent was obtained for all pts. Results: 46 pts have been enrolled, median age was 49.6 years (range 30.1–72.5) and median tumour size 6 cm (range 3.0–14.0). 4 (8.7%) and 42 (91.3%) pts presented with stage IIB and III disease, respectively. 56.5% of pts were premenopausal and 43.5% postmenopausal. 23 pts (50%) had histological grade 2–3 tumours and 12 (26.1%) were ER-negative. Median number of Cy administered was 6.0. Median Dose Relative Intensity (DRI) was 88.6%, 88.2% and 87.5%, for G, A and T respectively. Objective clinical response rate was 93.5% (95% CI: 86.4–100.6) with 7 (15.2%) complete responses and 36 (78.3%) partial responses. After surgery, 8 pts (17.4%) achieved a pCR in the breast, 3 of them were also free of malignant cells in the nodes. Toxicity: leucopenia G3/4 was present in 14 (30.4%) pts and 19 (7%) Cy; neutropenia G3/4 in 38 (82.6%) pts and 50 (18.3%) Cy; anemia G3/4 in 9 (19.6%) pts and 10 (3.6%) Cy. 67.4% of pts received G-CSF. Asthenia grade 3 /4 was present in 7 (15.2%) pts and 9 (3.3%) Cy; mucositis G3/4 in 6 pts (13%) and 7 (2.5%) Cy.Conclusions: GAT is an effective regimen in LABC pts. No significant financial relationships to disclose.
A phase I/II (P1/P2) study of AT-101 in combination with topotecan (T) in patients with relapsed or refractory small cell lung cancer (SCLC) after prior platinum-containing first-line chemotherapy
Authors: R. S. Heist, J. Fain, B. Chinnasami, W. Khan, J. Molina, V. Brainerd, L. Leopold, T. Lynch
Journal: Journal of Clinical Oncology (2009)

8106 Background: Bcl-2 family proteins are expressed in SCLC and are associated with chemotherapy resistance. AT-101 is an oral, pan Bcl-2 family protein inhibitor (Bcl-2, Bcl-X L , Mcl-1, and Bcl-w) and potent inducer of proapoptotic proteins. AT-101 has demonstrated activity in SCLC models, including those that express Mcl-1 and are resistant to other Bcl-2 inhibitors. The P1 portion of the study was previously reported. Methods: Pts ≥18 years of age, PS 0–1, with relapsed or refractory SCLC after first line chemotherapy with measurable disease per RECIST were eligible. Pts were stratified into 2 cohorts; cohort A ≥ 60 days and cohort B &lt; 60 days relapse from prior chemotherapy and treated with T 1.25 mg/m 2 daily and AT-101 40 mgs daily on days 1–5, q21 along with the use of myeloid growth factors. Adverse Events (AEs) were graded by the NCI CTCAE v. 3.0. Efficacy assessments (RECIST) were performed every 6-weeks. A 2-stage design was used with power/alpha of 80%/0.05 to detect a RR of &gt; 25% and &gt; 5%, in cohort A and B respectively. Results: 36 pts enrolled: ages 41–76; cohort A/B 23/13. The PR/SD/PD/NE rates were 17%/70%/9%/4% and 8%/54%/23%/15%, in cohorts A/B respectively. The median times to progression (TTP) were 18 and 13 weeks, respectively. The most common (&gt;20 %) AEs (all grades): anemia (64%); neutropenia (53%); nausea (47%); fatigue (44%); thrombocytopenia (42%); dyspnoea (25%); and vomiting (22%). Most common Grade 3/4 related events (&gt;5%): neutropenia (31%); thrombocytopenia (25%); anemia (14%); and asthenia (6%). No ileus was reported. Conclusions: AT-101 can be safely combined with T. The observed toxicities were consistent with the known rates of G4 cytopenias of T alone. The response rates observed did not meet the criteria for additional enrolment; however, many patients had a best response of SD and the median TTP in both cohorts was favorable compared to historical controls. Additional trials of AT-101 in SCLC are ongoing. [Table: see text]
Phase I, pharmacokinetic (PK), pharmacodynamic (PD) study of lapatinib (L) in combination with sorafenib (S) in patients with advanced refractory solid tumors.
Authors: M. Simonelli, P. A. Zucali, R. De Sanctis, E. Lorenzi, F. De Vincenzo, L. Rimassa, M. C. Tronconi, N. Personeni, G. Masci, M. Zuradelli, M. Perrino, M. Bertossi, L. Giordano, A. Santoro
Journal: Journal of Clinical Oncology (2011)

2521 Background: Combined targeting of ERBB receptors and VEGF-dependent signaling pathways has proven to be a successful strategy in preclinical studies. L is a dual HER2/EGFR tyrosine kinase inhibitor, S is an oral multikinase inhibitor (VEGFR-2,3, PDGFR-b, Flt-3, Raf-1 and c-KIT). We conducted a phase I dose-escalation study to assess the maximum tolerated dose (MTD), safety/tolerability, PK, PD and preliminary antitumor activity of the combination of these two agents. Methods: Patients (pts) with advanced malignancies refractory to standard therapy were eligible. A traditional 3+3 dose escalation schema was employed. Dose levels (DL) were 1) L 750 mg + S 200 mg BID; 2) L 1000 mg + S 200 mg BID; 3) L 1000 mg + S 400 mg BID; 4) L 1250 mg+ S 400 mg BID. L and S were given together on a continuous schedule with a 28-day cycle. Once the MTD has been determined, additional 9 patients were enrolled in the PK part of the study and received L alone during a “running-in” period for two weeks before starting with the combined schedule. Results: 30 pretreated pts (median 3 previous lines, range 1-6) were enrolled, M/F: 19/11, median age: 65 yrs (25-76), PS: 0/1=15/15. DLTs were observed in 2 pts, one at DL 2 [grade (G) 3 fatigue] and one at DL 3 (G3 rash). The MTD was reached at DL4. The most common toxicities were fatigue (64%), diarrhea (61%), anemia (61%), rash (43%), and hand-foot syndrome (29%). G3 treatment-related AEs were reported in 9 pts (32%) (anemia, fatigue, diarrhea, hyponatremia, hypokalemia, rash, LDH and phosphatase alkaline increase) and G4 AST/ALT increase in one pt. Pts received a median of 2 cycles (1-14). Among 28 evaluable pts (5 ongoing), 5 had PR (prostate, colorectal, breast, and 2 thymic cancers), 12 SD (4 colorectal, 3 gastric, 2 pancreatic, 1 prostate, 1 breast, 1 bladder cancers) with a DCR of 61%. Median clinical benefit duration was 8 wks (2-43). Preliminary PK data suggest that S may alter L concentrations. Conclusions: The combination of L + S is safe and well tolerated. L 1250 mg + S 400 mg BID is the recommended dose for phase II trials. Preliminary evidence of anticancer activity has been observed. Updated clinical and biological data will be presented at the meeting.
Clinical significance of tumor budding in colorectal cancer.
Authors: Jae-Im Lee, Chang Hyeok An, Hyung Jin Kim, Sang Chul Lee, Seong-Taek Oh
Journal: Journal of Clinical Oncology (2013)

422 Background: Tumor budding was defined as an isolated single cancer cell or a small cluster of cancer cells at the invasive margins. We assessed the clinical significance of tumor budding, as a predictor of outcomes in patients with non-metastatic colorectal cancer. Methods: We studied a total of 148 patients with colorectal cancer who underwent curative resection. Tumor budding was assessed on slides stained with hematoxylin and eosin (H&amp;E). Tissue specimens including the entire invasive margin from largest cut sections of the whole tumor were examined. Tumor budding was not classified according to previously described classification. The actual number of tumor budding along the entire invasive margin was counted at a magnification of x200 with the use of light microscopy. We determined cut-off point of tumor budding, lymph node ratio and carcinoembryonic antigen (CEA) with receiver operating characteristic (ROC) curve. Results: Univariate analysis revealed that poorly differentiation (p=0.009), lymphatic invasion (p=0.035) venous invasion (p=0.007), CEA &gt;6.3 (p=0.0007) and tumor budding &gt;13 (p=0.0006) were significantly related to poor survival. Cumulative five survival rates differed significantly between patients with tumor budding ≤13 (92.3%) and those with tumor budding &gt;13 (73.1 %). Multivariate analysis with Cox’s regression analysis demonstrated that tumor budding &gt;13 (hazard ratio=4.925, p=0.003), poorly differentiation (hazard ratio=3.696, p=0.01) and CEA &gt;6.3 (hazard ratio=3.085, p=0.024) were independent prognostic factors for overall survival. CEA &gt;6.3 (hazard ratio=2.361, p=0.034) and tumor budding &gt;20 (hazard ratio=3.293, p=0.008) were significant prognostic predictors for disease free survival Conclusions: Tumor budding is useful for prognosis and identifying patients with colorectal cancer who have a high-risk of disease recurrence after curative surgery. The proper cut-off level of tumor budding is 13.
Dysregulation of the beta-catenin complex as an independent predictor of oncological outcomes in patients with ccRCC.
Authors: Laura-Maria Krabbe, Mary Elizabeth Westerman, Aditya Bagrodia, Bishoy A. Gayed, Oussama M. Darwish, Ahmed Q Haddad, Dina Khalil, Payal Kapur, Arthur I. Sagalowsky, Yair Lotan, Vitaly Margulis
Journal: Journal of Clinical Oncology (2014)

493 Background: Epithelial to mesenchymal transition (EMT) is thought to play a crucial role in cancer progression and development of metastasis. Thus, we evaluated dysregulation of beta-catenin as a part of EMT and its clinical implications in patients with clear cell renal cell carcinoma (ccRCC). Methods: Immunohistochemical staining was performed for beta-catenin on tissue microarrays of patients with ccRCC. Membranous and cytoplasmatic beta-catenin expression patterns were assessed separately. Beta-catenin was considered normal if none or only one component was abnormal and was considered dysregulated if both components were abnormal. Differences in pathological characteristics between both groups were investigated. Differences in recurrence-free survival (RFS) and cancer-specific survival (CSS) were assessed with the Kaplan-Meier method. Uni- and multivariate Cox proportional hazard models were used to assess independent predictors of oncological outcomes. Results: 406 patients with a median follow-up of 58 months were included. Overall, 52 (12.8%) and 25 (6.2%) patients recurred and died of ccRCC. Beta-catenin was dysregulated in 70 (17.2%) patients. Dysregulation of beta-catenin was significantly associated with adverse pathologic features, such as higher T-stage, nodal positivity, higher grade, presence of tumor thrombus, sarcomatoid features, necrosis and LVI (all p&lt;0.001). Patients with dysregulated beta-catenin had inferior RFS and CSS (both p&lt;0.001). In multivariate analysis adjusting for tumor stage, nodal status and grade, dysregulation of beta-catenin was an independent predictor of RFS (HR 2.2, 95%CI 1.2-3.9, p=0.008) and CSS (HR 2.4, 95%CI 1.1-5.6, p=0.044). Conclusions: Our results indicate that dysregulation of beta-catenin may be an important phenomenon in ccRCC carcinogenesis. These findings support further study of beta-catenin and systematic assessment of EMT in ccRCC.
Partners assessment of sexual function on androgen suppression (AS) for treatment of biochemical relapse of prostate cancer
Authors: S. Aubin, C. S. Higano
Journal: Journal of Clinical Oncology (2005)

8261 Background: AS leads to significant loss in quality of life domains of sexual and intimate relationships for the partner as well as for the patient. Men with biochemical relapse of prostate cancer live for years and therefore, defining the impact of AS on sexuality and intimacy issues of a couple is important for designing future intervention trials aimed at addressing these problems. Methods: Men with biochemical relapse of prostate cancer were entered on a clinical trial of IAS. The patient and his partner each answered questionnaires at baseline and after 9 months of AS. The partner was asked to answer the same questionnaire according to her own perceptions of the answers as they pertained to the patient. Results: 14 men were married, eugonadal, and Caucasian with a median age of 64.5 years (range 51.8 to 77.2). At baseline, 9 men and 11 women reported erectile dysfunction (ED); 9 couples had no sexual activity during the past month. After 9 months of AS, 13 men and 14 women reported ED; 13 couples had no sexual activity in the past month. Conclusions: Not surprisingly, AS adversely impacted sexual desire, overall sexual function and frequency of sexual activity in most patients. One couple maintained sexual activity throughout. However, baseline sexual function was already poor in the majority of patients. This emphasizes the need to assess baseline function and include the couple rather than just the patient in therapeutic strategies aimed at enhancing sexuality and intimacy. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Sanofi, TAP
Calcium and magnesium infusions for prevention of oxaliplatin-induced peripheral neuropathy.
Authors: M. Bupathi, G. Mahmud, J. Kovar, E. Wang, T. E. O'Brien
Journal: Journal of Clinical Oncology (2011)

387 Background: Oxaliplatin plays an important role in chemotherapy regimens for colorectal and other GI malignancies. Debilitating peripheral neuropathy (PN) often develops with use of this drug. One study (Grothey A et al, ASCO 2009, abst #4025) has shown that pre- and post-oxaliplatin infusions with calcium (Ca) and magnesium (Mg) may reduce this toxicity. To confirm this in an unselected indigent minority population, a retrospective review was performed comparing development of PN in oxaliplatin exposed patients treated with or without Ca/Mg. Methods: Records of patients who received oxaliplatin from 1/2008 to 12/2009 at MetroHealth Medical Center, a large safety net hospital in Cleveland, OH, were reviewed. 47 patients received Ca/Mg + oxaliplatin and 46 oxaliplatin alone. Data collected included age, race, gender, insurance status, performance status, tumor type, stage, concomitant diseases (DM and EtOH), number of cycles and cumulative dose of oxaliplatin. PN was determined using the Common Terminology Criteria of Adverse Events (CTCAE) version 3.0. Patients were followed 6 months after completion of oxaliplatin. Results: Demographic data was similar between the two groups. Colorectal cancer compromised 77% of the treatment group and 85% of control group. Patients who received Ca/Mg had significantly less PN in all three grades (1-3) compared with the control group (grade 1 89.4% vs. 71.7%, grade II 10.6% vs. 19.6%, grade 3 0% vs. 8.7%, respectively). The cumulative dose of oxaliplatin did not differ between the two groups (Ca/Mg median 1,143 range 260-2,169; control median 1,425 range 137-2,635). The combined total grades 2 and 3 in both the treatment and control (10.6% vs. 28.3%, p = 0.038) favored use of Ca/Mg. Conclusions: This small, retrospective study confirms that Ca/Mg infusions reduce the incidence of clinically significant (grade 2/3) PN in pts receiving oxaliplatin. No significant financial relationships to disclose.
Clinical trial enrollment (CTE) and related activities in a community-based cancer center (CBCC) in rural Nebraska before and after National Community Cancer Centers Program (NCCCP).
Authors: R. C. Ramaekers, H. Benzel, F. R. Loberiza, A. M. Obermiller, C. Fuller, M. Gulzow, R. Hadenfeldt, N. Nielsen, M. Norvell, M. Mickey, J. Goering, M. S. Copur
Journal: Journal of Clinical Oncology (2011)

e16509 Background: Majority of cancer patients (pts) are diagnosed and treated in the community. Community oncologists lack adequate time, resource, incentive, infrastructure, and reimbursement to conduct clinical trials, resulting in 3-5% national enrollment rate. NCCCP is designed to create a CBCC network to support basic, clinical and population-based research. Methods: CTE data before (July 2004-July2007) and after (July 2007-July 2010) NCCCP, at Saint Francis Cancer Treatment Center (SFCTC), an NCCCP site, were gathered and compared. This included number/percentage of pts, and percentage of underserved population on clinical trials, information regarding number/type of available trials, staffing, collection/storage of tissue samples, organizational infrastructure and linkage to NCI designated cancer centers. Results: Before NCCCP, there were 454, 542, and 515 new cancer cases/yr seen with 23 (5%), 22 (4%), and 47 (9%) pts/yr enrolled in clinical trials compared to 541, 540, and 528 cases/yr and 56 (10%), 103 (19%), and 143 (27%) pts/yr enrolled after NCCCP, representing an overall cumulative increase of 13% (Chi-square test, P<0.0001). All pts enrolled were from rural Nebraska, with 70% being 60 years or older. Number of available clinical trials before NCCCP was 8, 13, 15/yr, compared to 19, 37, 50/yr after NCCCP, reflecting 66% increase (Chi-square test, P<0.001). There were more treatment, tissue, and correlative trials after NCCCP. Clinical trial staffing increased from 1, 1, 2 FTEs (non-RN) to 2, 3 (2 RNs), 5 (3RNs)/yr before and after NCCCP. A nurse navigator and genetic counselor became available after NCCCP. Collection and storage of tissue samples increased from 27 before NCCCP to 100 after NCCCP. Affiliation with NCI designated Eppley Cancer Institute enhanced linkage to NCI programs improving existing infrastructure for clinical trials. Conclusions: During a 3-year period before and after NCCCP, significant increases in clinical trial enrollment and research related activities were observed at SFCTC. NCCCP may greatly improve access to cancer clinical trials, research and related activities in CBCCs like ours.
Ventricular arrhythmias and sudden death in patients taking ibrutinib
Authors: Benjamin L. Lampson, Lijian Yu, Robert J. Glynn, Jacqueline C. Barrientos, Eric D. Jacobsen, Versha Banerji, Jeffrey A. Jones, Renata Walewska, Kerry J. Savage, Gregory F. Michaud, Javid J. Moslehi, Jennifer R. Brown
Journal: Blood (2017)