tbuckley/cabot-search huggingface dataset:
A phase 3 randomized, placebo-controlled double-blind study of ARN-509 plus abiraterone acetate (AA) in chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC).
Authors: Dana E. Rathkopf, Gerhardt Attard, Eleni Efstathiou, Margaret K. Yu, Thomas W. Griffin, Mary Beth Todd, Daphne Wu, Thian Kheoh, Xin Zhao, Fred Saad
Journal: Journal of Clinical Oncology (2015)

TPS5071 Background: ARN-509, a potent and selective androgen receptor (AR) antagonist, inhibits AR nuclear translocation and DNA binding (Clegg, Cancer Res. 2012). AA directly inhibits androgen biosynthesis and has been approved for the treatment of mCRPC. Although ARN-509 and abiraterone both target the AR, each works through a different mechanism: the former blocks ligand binding, the latter inhibits ligand synthesis. Importantly, lack of sensitivity to one AR-targeted therapy does not necessarily imply resistance to another (Rathkopf, AACR 2014). Inhibiting the AR through multiple mechanisms simultaneously may be more effective than single pathway inhibition and has the potential to have a significant impact on the mCRPC field. This phase 3 trial will compare radiographic progression-free survival (rPFS) in pts with chemotherapy-naïve mCRPC treated with ARN-509 in combination with AA + prednisone/prednisolone (P) vs placebo + AA + P. Methods: This multicenter, double-blind, placebo-controlled trial is enrolling men with mCRPC with progressive disease and an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1. Pts will be stratified by presence or absence of visceral metastases, ECOG PS, and region (European Union, North America, and rest of world) and randomized (1:1) to ARN-509 (240 mg QD) + AA (1000 mg po QD) + P (5 mg po BID) or placebo + AA + P. The primary end point is rPFS using RECIST 1.1 or PCWG2 criteria. Secondary end points are overall survival, time to long-term opioid use, time to initiation of cytotoxic chemotherapy, and time to pain progression. Population pharmacokinetics of AA and biomarker analyses will be performed. The study uses a group sequential design, including 2 interim analyses. The stratified log rank test will be used for the time-to-event analysis. An independent data monitoring committee will review safety and efficacy data. Approximately 960 pts will be randomized over 2 years in 225 sites in 18 countries. (ClinicalTrials.gov Identifier: NCT02257736) Clinical trial information: NCT02257736.
Phase 1 trial of zoptarelin doxorubicin (Zop-Dox) in advanced unresectable or metastatic urothelial carcinoma (UC) patients who failed platinum-based chemotherapy.
Authors: Gustavo L. Fernandez, David J. Vaughn, Andrew V. Schally, Tulay Koru-Sengul, Jaime R. Merchan, Aurea M. Flores, Merce Jorda, Pasquale W. Benedetto, Rakesh Singal, Norman L. Block
Journal: Journal of Clinical Oncology (2014)

e15517 Background: No standard of care exists for locally advanced unresectable or metastatic UC patients (pts) who fail platinum-based chemotherapy. LHRH receptors may be expressed on UC and their high expression on tumor cells and minimal expression in normal cells make them an attractive therapeutic target. Zop-Dox is a hybrid anticancer agent in which doxorubicin is chemically linked to zoptarelin, an LHRH agonist. Clinical activity and favorable safety profile were previously demonstrated in pts with LHRH receptor positive ovarian, endometrial and prostate cancers. Methods: An open-label dose escalation study (3+3 design) was conducted to determine the maximum tolerated dose (MTD) of Zop-Dox. Dose escalation (160, 210 and 267 mg/m2 IV every 21 days) was based on dose-limiting toxicity (DLT) defined as grade 4 hematologic or grade ≥ 3 non-hematologic toxicity (per CTCAE) during cycle 1. Eligible pts had LHRH receptor positive locally advanced unresectable or metastatic UC that had progressed after platinum-based chemotherapy. Results: Phase 1 was completed with 13 pts (10 males/3 females, mean age [years] = 67, range = 55 to 87). Most pts had bladder primaries and had received 2-3 prior chemotherapy regimens. Mean Zop-Dox administered was 4 cycles. DLTs consisted of mucositis (1 pt) and febrile neutropenia/ thrombocytopenia (1 pt) observed among 4 pts treated with Zop-Dox 267 mg/m2. De-escalation to 210 mg/m2 with 1 DLT (dehydration) among 6 pts confirmed that dose as the MTD. One durable partial response and 3 stable disease (SD) were observed. One of the pts with SD received 267 mg/m2x 14 cycles then discontinued following ejection fraction < 45 %. Serious AEs (1 pt each) other than DLTs were febrile neutropenia, hematuria, herniated disc, pyrexia, thrombophlebitis, urosepsis and UTI. The most frequent grade 3 or 4 AEs were leucopenia (4 pts), neutropenia (3 pts) and lymphopenia (3 pts). Conclusions: The phase 1 portion of the study is closed to accrual. The MTD dose for phase 2 studies was determined to be 210 mg/m2. Preliminary evidence of activity is encouraging. Clinical trial information: NCT01234519.
Impact of body mass index and ethnicity on asparaginase toxicity in adult acute lymphoblastic leukemia patients.
Authors: Jennie York Law, Bao Duy Dao, Phat Le, Chul Ahn, Kirthi Kumar, Hong Zhu, Larry Don Anderson, Robert Collins, Hsiao Ching Li, Prapti Arvind Patel, Navid Sadeghi, Madhuri Vusirikala, Harris V. K. Naina, Pier P. Scaglioni
Journal: Journal of Clinical Oncology (2015)

e18051 Background: Adolescent young adults (age 15-39 years) with acute lymphoblastic leukemia (ALL) and relapsed adult ALL patients receiving asparaginase (ASP) containing regimens (ASP+) have favorable outcomes as compared to ALL patients treated without ASP (ASP-). Treatment associated toxicity limits use of ASP in adult ALL patients. However, risk factors for ASP associated toxicity are not clearly defined. Methods: 107 consecutive ALL patients were treated at our institution from 2004-2014. ASP+ (47) patients were grouped according to body mass index (BMI) and ethnicity. Incidence of ASP associated toxicities was determined. The common terminology criteria for adverse events was used to grade toxicity. Results: 30/47 (64%) ASP+ patients were overweight or obese (BMI ≥ 25) compared with 45/60 (75%) ASP- patients. 22/47 (47%) ASP+ patients and 30/60 (50%) ASP- patients died. Of patients with a BMI ≥ 25, 14/30 ASP+ (46.7%) and 22/45 (48.9%) ASP- patients died. The ASP+ group consisted of Hispanic (28), Caucasian (12), Asian (4), and African-American (3) patients. In the Hispanic group, 15/28 (53.6%) ASP+ died compared to 21/38 (55.3%) ASP- patients. ASP+ with BMI ≥ 25 included Hispanic (21), Caucasian (5), Asian (2) and African-American (2) individuals. Common ASP associated toxicities were hepatotoxicity (26), hypofibrinogenemia (9), and pancreatitis (3). For ASP+ patients with a BMI ≥ 25, the most frequent adverse event was hepatotoxicity (16) with the majority either grade 3 (6) or grade 4 (3). Hepatotoxicity occurred in Hispanic (16), Caucasian (7), African-American (2), and Asian (1) patients. Grade 3 or 4 hepatotoxicity occurred in Hispanic (7), Caucasian (1; grade 3 only), and an African-American patient (1; grade 4 only). Death from hepatotoxicity in ASP+ patients occurred only in the Hispanic group (2) both of whom had a BMI ≥ 25. Conclusions: At median follow up of 21 months, there was no difference in the relative risk of death between ASP+ and ASP- patients (p = 0.89) regardless of BMI (p = 0.97). Hispanic patients developed hepatotoxicity at an increased rate compared to other ethnicities (p = 0.02) with a trend towards increased severity of toxicity and death among Hispanic patients with a BMI ≥ 25.
Efficacy, safety, and pharmacokinetics (PK) of the BRAF inhibitor dabrafenib (D) hydroxypropyl methylcellulose (HPMC) capsule formulation in combination with the MEK1/2 inhibitor trametinib (T) in patients (pts) with BRAF mutation-positive metastatic melanoma (MM).
Authors: Lynn Mara Schuchter, Ragini Reiney Kudchadkar, Rene Gonzalez, Donald P. Lawrence, Jeffrey Alan Sosman, Jeffrey R. Infante, Adil Daud, Richard Kefford, Jonathan S. Cebon, William Howard Sharfman, Ravi K. Amaravadi, Peter D. Boasberg, Karl D. Lewis, Keith Flaherty, Danielle Ouellet, Shonda M Little, Jennifer Clark, Geoffrey Thomas Gibney, Kiran Patel, Omid Hamid
Journal: Journal of Clinical Oncology (2013)

9066 Background: Preclinical studies ofD + T show enhanced activity in BRAF mutant MM vs either drug alone. D + T safety and efficacy were evaluated in a 4-part (A–D) phase I/II study. Part D assessed the impact on efficacy, safety and PK of a more stable HPMC capsule formulation of D alone, and in combination with T, instead of the gelatin capsule used in Parts A–C. Methods: 110BRAF V600E/K MM pts with RECIST measurable disease were randomized to 4 cohorts. Dose-limiting toxicities (DLTs) were evaluated for the first 3 weeks of treatment. PK sampling was done on Days 1 and 21. Primary endpoints were PK and safety; secondary endpoints were response rate (RR) and overall survival (OS). Results: Median age was 54 years, 58% male, 65% ECOG PS 0, 88% V600E, 68% M1c stage, 97% no prior brain metastases, and 45% LDH &gt; ULN. Treatment (tx) with D HPMC + T had little impact on ratio of D C max (1.16) and D AUC (1.23) vs D tx alone; but led to higher ratio of D C max (1.51) but similar D AUC (1.10) vs D gelatin + T seen in Part B. Median progression-free survival (PFS) and RR are in Table. Median PFS not reached in D4. No DLTs occurred in the first 15 subjects enrolled in D4. Most common AEs (≥40%) for all cohorts were pyrexia, nausea, chills, vomiting, arthralgia, and fatigue. Most common grade &gt;3 AEs (all 5%) were hypertension, pyrexia, increased GGT, and hyponatremia. 11% of pts discontinued treatment due to an AE. There were no major differences in toxicities between cohorts and Parts A–C. Conclusions: The D + T combination had an acceptable safety profile with clinically manageable side effects. D HPMC + T had little impact on D C max and D AUC vs D alone. D HPMC led to higher D C max but similar D AUC vs gelatin + T. Meaningful clinical activity was seen in all dose combinations with D HPMC +T; PFS, RR, and duration of response were consistent with other study parts. Phase 3 studies with D HPMC + T are ongoing. Clinical trial information: NCT01072175. [Table: see text]
Prognostic relevance of circulating PIGF levels in patients with neuroendocrine tumors.
Authors: Christian Fischer, Ulrich-Frank Pape, Tabea Neumann, Katharina M Detjen, Georg Hilfenhaus, Georg Hess, Bertram Wiedenmann, Marianne E. Pavel
Journal: Journal of Clinical Oncology (2012)

4128 Background: Placental growth factor (PlGF), a VEGF homolog implicated in tumor angiogenesis and adaptation to antiangiogenic therapy, is emerging as candidate target in malignancies. As antiangiogenic treatments are introduced in the management of neuroendocrine tumors (NETs), we addressed the expression and function of PlGF in NETs. Methods: Serum levels of PlGF were determined in two independent cohorts of NET patients collected retrospectively and prospectively (n=87 and n=84) using Roche Elecsys and correlated with clinical data. Expression of PlGF in tumors was evaluated by immunohistochemistry. PlGF effects on proliferation and migration were examined in vitro using NET cell lines. Results: Circulating and tumoral PlGF were found elevated in NET patients as compared to control sera and pancreatic tissues in a retrospective analysis restricted to patients with pancreatic NETs (pNETs). De novo expression of PlGF occurred primarily in the tumor stroma, suggesting paracrine stimulatory circuits. Indeed, PlGF enhanced proliferation and migration of NET cells, and elevated circulating PlGF levels correlated with advanced tumor grading, suggesting that PlGF supported a more aggressive phenotype. In line with this notion, circulating PlGF levels above median predicted reduced tumor related survival in pNET patients (p=0.012). Furthermore, pathologic PlGF levels were associated with poor prognosis within the subgroup of grade 2 tumors. Subsequent prospective PlGF determinations confirmed and extended our observation of elevated PlGF levels for both, pNETs (n=32, p&lt;0.001) and midgut NETs (n=58, p&lt;0.001). Since median follow up was too short to determine survival, time to progression (TTP) was analyzed instead. Most pNETs were progressive at the time of sample collection, precluding an informative evaluation of TTP in this subgroup. However, PlGF levels above median were correlated with shorter TTP in midgut NETs (p=0.0091; TTP 27 months versus undefined, HR 3.802). Conclusions: These data assign to PlGF a novel function in the pathobiology of NETs and propose PlGF as a prognostic parameter in patients with NETs.
Immediate hormonal therapy versus observation after radical prostatectomy and pelvic lymphadenectomy for node positive prostate cancer: At 10 years results of EST3886
Authors: E. M. Messing, J. Manola, M. Sarosdy, G. Wilding, D. Crawford, M. Kiernan, D. Trump
Journal: Journal of Clinical Oncology (2004)

4570 Purpose: We previously reported 7 year follow-up of men with clinically localized prostate cancer, who underwent radical prostatectomy (RP) and pelvic lymphadenectomy (PLD) and were found to have nodal metastases (N+), had significantly improved survival and disease-specific survival with immediate (within 3 months of surgery) and continuous hormonal monotherapy (HT) compared with those who had androgen ablation withheld until distant metastases were identified (NEJM 341:1781,1999). To determine the durability of this effect, we update results at 10 years median follow-up. Methods: 98 men were randomized to receive Goserelin acetate or bilateral orchiectomy (N=47) vs. observation (N=51) until distant disease was documented. Patients were followed with semi-annual exams and laboratory tests, and annual bone scans. Results: Patients were well-matched for age (mean 65.9 yrs), prostate size, local extent, and Gleason score. Only 20% of men had detectable PSA's following their surgery at the time of randomization. At median follow-up of 10 years, 13 of 47 men who received immediate HT died (6 of prostate cancer, 7 of non-prostate cancer causes with undetectable PSA's at the time of death) vs 26 in the deferred arm (22 of prostate cancer, 4 of non-prostate cancer). The differences in both overall (immediate 72.4%; deferred 49.0%, p = .025), and cause specific (immediate: 87.2%; deferred: 56.9%, p = .001) survivals, between the two arms were significant. Toxicities of treatment were tolerable, and at last follow-up, no immediately treated man had experienced an osteoporotic fracture or had discontinued HT. Conclusion: 10 years, early HT in patients with N+ disease following RP+PLD continues to be associated with highly significant improvements in overall and disease-specific survival. The treatment has been generally well tolerated. Early HT's role in other disease scenarios warrants testing in prospective randomized studies. No significant financial relationships to disclose.
Targeted agents matched with tumor molecular aberrations: Review of 160 patients with advanced melanoma treated in a phase I clinic.
Authors: Haby Adel Henary, David S. Hong, Gerald Steven Falchook, Apostolia Maria Tsimberidou, Goldy George, Jennifer J. Wheler, Siqing Fu, Aung Naing, Sarina Anne Piha-Paul, Filip Janku, Kevin B. Kim, Patrick Hwu, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

8551 Background: Identification of activating mutations in melanoma has increased the number of novel targeted agents for this disease. Methods: Weretrospectively reviewed clinical outcomes of 160 consecutive metastatic melanoma patients (pts) treated in the Dept of Investigational Cancer Therapeutics (Phase I program) at M. D. Anderson since 2008, and compared their median progression free survival (PFS) to their first and last standard systemic therapy PFS. In addition, we compared those pts’ outcomes tested for tumor molecular aberrations on a phase I trial with a matched targeted agent with those of pts who were treated without regard for their molecular profiles. Results: Of 160 pts treated on 35 different phase 1 clinical trials, 110 pts (69%) had ≥ 1 molecular aberration. Of those pts who had adequate tissue for molecular analysis, 63% (85/134) pts had BRAF mutation, 20% (22/109) NRAS mutation, 20% (1/5) GNAQ mutation, 11% (1/9) P53 mutation, 2.5% (1/39) PIK3CA and 1.3% (1/76) had KIT mutation. 77 (48%) pts were treated on a phase I trial with a matched targeted agent and 83 (52%) pts were treated on a non-matched phase 1 trial. The overall response rate was 39% (complete response [CR], 9%; partial response [PR], 30%) in the 77 pts treated with matched therapy and 9% (all PRs) in the 83 pts treated without matched therapy (P = 0.0018). 139 (87%) pts received at least one systemic therapy before referral to phase I, median PFS was longer on phase 1 therapy than on last line standard therapy prior to referral to phase 1 (4.2 vs. 2.8 months, P = 0.002). Median PFS was greater for pts on matched vs. non-matched therapy (5.3 vs. 3.7 months, log rank P = 0.004). Also, median PFS was longer on phase 1 matched trial than on first standard treatment (5.3 vs. 3.9 months, log rank P = 0.045).PFS did not differ between first standard and non-matched phase 1 study. Univariate analyses with the log rank test revealed that matched therapy (P = 0.004) was positively associated with longer PFS on phase I clinical trials. Conclusions: Matching melanoma pts with targeted drugsbased on specific molecular aberrations in the phase I setting can be associated with superior outcomes compared to prior standard systemic therapies.
Pancreatic neuroendocrine tumors: A population-based analysis of epidemiology and outcomes.
Authors: Samer Alsidawi, Gustavo Figueiredo Marcondes Westin, Timothy J. Hobday, Thorvardur Ragnar Halfdanarson
Journal: Journal of Clinical Oncology (2017)

401 Background: Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms comprising less than 2% of pancreatic tumors. Outcomes of PNETs vary by stage, grade, and clinical presentation. New therapies may have improved outcomes. We present an analysis of the epidemiology and prognosis of patients (pts) with PNETs evaluating a more recent period than previously reported. Methods: Using data from the SEER registry, we identified adults with PNETs between 2000 and 2013. Cases were identified using a combination of ICD-O-3 site and histology codes. The JMP and SEER*STAT 8.3.2 were used for statistical analysis. Overall survival (OS) was analyzed using the Kaplan–Meier method. The prognostic effect of variables was studied using multivariate Cox proportional hazards models. Results: We identified 5993 pts with PNETs. Over the study duration, there was an increase in the annual incidence from 0.3 to 1.2 per 100.000. This was largely explained by the increase in number of pts with localized disease. The OS for the entire cohort was 54 months (95%; CI 50-58) and 5-year OS rates in localized, locally advanced and metastatic disease were 81.7%, 62% and 26% respectively. New therapies were increasingly implemented after 2008 such as sunitinib, everolimus and capecitabine/temozolomide. OS was better for pts diagnosed after 2008 (HR 0.73; 95% CI, 0.69-0.79; P &lt; 0.0001) and this remained significant after excluding pts with localized disease (HR 0.85; 95% CI, 0.78-0.92; P = 0.0002). Factors found to favorably affect OS included younger age, female sex, early stage, low grade, and surgery. In metastatic disease, pts who had surgery had better OS and this was significant after adjusting for possible confounders (HR 0.36; 95% CI, 0.3-0.45). Conclusions: In this large population-based study, we saw an increase in the annual incidence of PNETs mainly due to an increased number of pts with localized disease. The OS has improved over the study duration likely due to both stage migration and new therapies used in advanced disease. Younger age, female gender, low histologic grade, early stage and surgery were found to be factors that favorably affected survival. Surgery was found to be a predictor of better outcomes in metastatic disease.
Effect of zoledronic acid (Zol) compared with pamidronate (Pam) on disease progression in breast cancer (BC) patients with bone metastases stratified by baseline characteristics
Authors: Y. Hei, A. Lipton, N. Shirina, Y. M. Chen, T. Xie
Journal: Journal of Clinical Oncology (2006)

678 Background: Zol has been shown to significantly reduce the risk of skeletal complications compared with Pam in BC pts with bone metastases. Zol has also demonstrated antitumor effects in animal models of human BC and significantly delayed bone lesion progression in pts with renal cancer. To assess whether Zol may reduce the risk of overall disease progression compared with Pam, we conducted a retrospective analysis of BC pts enrolled in a large randomized, controlled trial. Methods: Patients treated with Zol or Pam were retrospectively stratified by baseline characteristics, including Brief Pain Inventory (BPI) composite pain score, time from initial cancer diagnosis to development of bone metastases, and duration of cancer. The relative risk of overall disease progression during 25 months on study was analyzed using the Cox proportional hazards model. Results: Median BPI pain score at baseline was 2.75, median time to development of bone metastases was 44 months, and median time with cancer was 58 months for all patients. In the subset of pts with a baseline BPI score ≥ 2.75 (n = 556), treatment with Zol significantly reduced the risk of disease progression by 21% compared with Pam (hazard ratio [HR] = 0.793; P = .018). Similarly, among pts who developed bone metastases &lt; 44 months from initial diagnosis of cancer (n = 564) and pts with cancer for &lt; 58 months (n = 563), treatment with Zol reduced the risk of disease progression by approximately 20% compared with Pam (HR = 0.805; P = .026 and HR = 0.800; P = .023, respectively). Conclusions: Zol significantly reduced the risk of overall disease progression compared to Pam in specific subsets of pts with higher pain scores and shorter time to development of bone metastases. This exploratory analysis suggests that Zol has potential antitumor effects that may reduce the risk of disease progression in this patient population. These results are consistent with published reports and provide the initiative for further investigations with additional clinical studies. [Table: see text]