tbuckley/cabot-search huggingface dataset:
First-in-human phase I trial of NHS-IL12 in advanced solid tumors.
Authors: Joseph W. Kim, Christopher Ryan Heery, Marijo Bilusic, Nishith K. Singh, Ravi A. Madan, Helen Sabzevari, Jeffrey Schlom, James L. Gulley
Journal: Journal of Clinical Oncology (2012)

TPS2617 Background: NHS-IL12 is an antibody-cytokine conjugate consisting of two heterodimers of interleukin (IL)-12, fused to a human monoclonal antibody specific for DNA-histone H1 complex exposed in tumor necrosis. IL12 is a proinflammatory cytokine, produced by activated phagocytes and dendritic cells, that plays a critical role in regulating the transition from innate to adaptive immunity. Early clinical trials of IL12 reported clinical responses in metastatic renal cell carcinoma, Kaposi sarcoma (50–71% response rate), T-cell lymphoma (56%), and non-Hodgkin’s lymphoma (21%). However, systemic toxicity limited further clinical development. NHS-IL12 is designed to reduce toxicity associated with systemic administration of IL12 by selectively targeting delivery to necrotic areas of tumors. A fluorescence imaging study of NHS-murine (mu)-IL12 in mice with syngeneic lung carcinoma demonstrated effective targeting by NHS-muIL12. Immunohistochemistry studies further confirmed effective targeting of tumors by NHS-muIL12. In another study in canines with spontaneously occurring solid tumors, 2 of 11 subjects achieved a partial response with a single dose. Methods: This is a phase I dose-escalation study designed to determine the maximum tolerated dose of NHS-IL12 and to define the biologically optimal dose and schedule based on immunologic (pharmacodynamic) analysis of cytokines such as interferon-g, and IL-10, at multiple times points from 4 hours up to 2 weeks following the administration of NHS-IL12. Eligible patients (pts) include those with evaluable or measurable solid tumors who have progressive disease on at least one prior line of therapy. Pts with a condition associated with significant necrosis of non-tumor bearing tissue, (e.g., ulcerative colitis), are excluded. Modified immune-related response criteria are used to assess response, the major features of these criteria being (a) imaging confirmation of both progression and response at least 4 weeks after initial imaging, and (b) no consideration of new lesions unless the total measurable tumor burden meets the criteria for progressive disease. This trial opened to accrual in Nov. 2011 and may enroll up to 78 pts.
A randomized phase III study of adjuvant capecitabine vs observation in curatively resected stage IB (by AJCC 6<sup>th</sup> edition) gastric cancer (CATALYSIS; KCSG ST14-05).
Authors: Min-Hee Ryu, Jae Yong Cho, Dae Young Zang, Woon Kee Lee, Keun-Wook Lee, Dong Bok Shin, Byung-Ho Nam, Sung Sook Lee, Hyun Woo Lee, Jong Gwang Kim, Jin-Soo Kim, In Gyu Hwang, Jin Ho Baek, Chang Hak Yoo, Yoon-Koo Kang
Journal: Journal of Clinical Oncology (2015)

TPS4137 Background: In stage I (by AJCC 6thedition) gastric cancer (GC), recurrence rate is generally low, and long-term outcomes are considered very good after curative resection. For this reason, only limited number of stage I GC patients (pts) were included in most previous studies of adjuvant treatment, and no stage I GC pts were included in ACTS-GC and CLASSIC trials which compared adjuvant chemotherapy vs observation after D2 dissection. However, a large scale retrospective study (Park et al, Gastric Cancer. 2015 Jan 23 [Epub ahead]) demonstrated that pts with stage IB GC with other risk factors showed high recurrence rate more than 20%. Considering more than 30% risk reduction of recurrence by adjuvant chemotherapy in stage II GC, stage I GC pts at high risk of recurrence may also get benefit from adjuvant chemotherapy. Moreover, in Korea, more than 50% of GC pts have stage I disease, which is increasing due to nationwide screening program. Based on this background, a phase III randomized study has been initiated and here we present the progress. Methods: Since November 2013, pts with curatively resected gastric or gastroesophageal junction adenocarcinoma at stage IB have been recruited from 12 sites in Korean Cancer Study Group (KCSG). Other key eligibility criteria include ECOG performance status 0-2, age of 18-74 years, at least one more other risk factors for recurrence-free survival (RFS) (i.e., age ≥ 65 years, male gender, lymphovascular invasion, and/or perineural invasion). Three to 6 weeks after curative surgery (D1 beta or D2 dissection), pts are randomized 1:1 in open label to adjuvant capecitabine arm vs observation arm. In adjuvant chemotherapy arm, pts receive capecitabine 1,250 mg/m2 p.o. twice daily on days1-14 every 3 weeks for 8 cycles. Primary endpoint is 5-year RFS rate. Secondary endpoints include overall survival, safety, compliance, and pharmacokinetic study of capecitabine. With power of 80% and two-sided α level of 5%, 174 events are required to detect 7% difference in 5-year RFS rate, i.e., 85% in adjuvant capecitabine arm vs. 78% in observation arm (HR = 0.654). Considering 10% of drop-out rate, target enrollment is 870 subjects. NCT01917552 Clinical trial information: NCT01917552.
Tumour volume analysis (TVA) as applied to a pilot randomized study of neoadjuvant endocrine versus neoadjuvant chemotherapy (NEOCENT).
Authors: Angus Gordon, Carlo Palmieri, Susan Jane Cleator, James P Morden, Roaul Charles Coombes
Journal: Journal of Clinical Oncology (2015)

e12003 Background: RECIST is a standard method of radiological assessment of tumour response based on longest diameter(s). Tumour Volume Analysis (TVA), assessment of response using a three diameter measurement of tumour volume, has been proposed as an alternative. A comparison was made between RECIST and corresponding TVA measurements as assessed by ultrasound in patients receiving either primary cytotoxic or endocrine therapy for ER positive breast cancer as part of a randomized study (NEOCENT). Methods: The NEOCENT protocol mandated recording of longest tumour diameters on ultrasound at defined time points, but also requested where possible measurements in 3 dimensions. Baseline and end of treatment tumour US-dimensions were used to derive TVA measurements. Any degree of increase or decrease in longest diameter or TVA measurements was considered ‘enlargement’ or ‘regression’ respectively and corresponding measurements were compared using a Wilcoxon signed-rank test. Results: Of 44 patients randomized, baseline and post treatment volume estimates could be calculated for 28 patients. One tumour showed no changes in diameter or TVA, 3 tumours enlarged by TVA alone, 1 tumour enlarged by diameter and TVA, 23 tumours regressed by both diameter TVA and 1 tumour regressed 29% by TVA but enlarged 5.5% by diameter. In the 24 tumours that regressed according to diameter and/ or TVA (10 chemotherapy and 14 endocrine treated patients), median percentage regression was -34 (-44 - -25.5) by diameter and -73.5 (-85.5 - -42.5) by TVA (p < 0.0001). Of 24 patients showing regression, degree of regression was greater by TVA than diameter in 21 patients. No difference was seen in response to endocrine versus chemotherapy by either RECIST or TVA. Conclusions: Most but not all responses were classified consistently by diameter and TVA. Range and degree of proportional response measured by TVA was greater than by diameter indicating that TVA is more discriminatory for measuring radiological regression to neoadjuvant therapy. We propose that the threshold change required to qualify as response or progression for TVA-based response assessments should differ from that which has been adopted for RECIST.
Phase I dose-escalation, open-label study of HSP990 administered orally in adult patients with advanced solid malignancies.
Authors: Leticia De Mattos-Arruda, Lillian L. Siu, Javier Cortes, Yann Berge, Albiruni R A Razak, Jordi Rodon Ahnert, Ewa Cottura, Philippe Bedard, Mikhail Akimov, Hong Lu, Scott Pain, Audrey Kaag, Jean-Pierre Delord
Journal: Journal of Clinical Oncology (2013)

2561^ Background: NVP-HSP990 is a synthetic small molecule that potently and selectively inhibits heat-shock protein 90. HSP990 leads to degradation of client proteins, offering potential simultaneous blockade of multiple oncogenic signaling pathways. The primary objective of this Phase l first-in-man study (NCT00879905) was to determine the single-agent MTD of HSP990 administered once (qw) or twice (biw) weekly to patients (pts) with advanced solid malignancies (preselected CYP2C9 genotypes only). Secondary objectives included safety, efficacy, PK, and biomarkers. Methods: HSP990 was administered orally qw or biw in 28-day cycles. Dose escalation was guided by a Bayesian logistic regression model. The MTD was determined by assessing DLTs in Cycle 1. Eligible pts included those with histologically confirmed advanced solid tumors that had progressed on standard therapy or for whom no standard therapy exists. Results: 64 pts (median age 57 yr: 44% male; 37.5% Stage IV; WHO PS 0/1) received HSP990. 53 pts received HSP990 qw at 2.5, 5, 10, 20, 30, 50 or 60 mg; and 11 pts received HSP990 biw at 25 mg. Median duration of exposure was 8 wks; 12 pts remained on treatment for &gt;16 wks. DLTs occurred in 7 pts: 4/22 at 50 mg qw (including G3 diarrhea, G3 QTc prolongation, G4 ALT/AST elevations); 2/5 at 60 mg qw (including G3 tremors); and 1/11 at 25 mg biw (including G2 ataxia, G2 confusion, G2 visual hallucination). The 50-mg qw dose was declared as the MTD. Further dose escalation was not possible due to neurologic toxicity. Most common reported CTCAE G3/4 AEs were diarrhea (12.5%), increased ALT/AST (11% each), anemia, or cholestasis (6% each). HSP990 had Tmax of 3 h and T½ of ~20 h. Large inter-patient variability in PK exposures was observed. For qw dosing, approximate dose-dependent HSP70 induction was observed from 5−30 mg qw, which plateaued after 20 mg qw. There were no objective responses; however, 25 pts (39%) had SD. (RECIST v1.0). No pt showed a complete metabolic response (MR; by FDG-PET) and 11 pts (17%) showed a partial MR. All pts discontinued treatment, primarily due to disease progression (84%). Conclusions: The single-agent MTD of HSP990 in pts with advanced solid tumors was 50 mg qw. SD was observed in 39% of pts. Clinical trial information: NCT00879905.
Role of radiation (RT) in primary mediastinal large B-cell lymphoma (PMBCL): An analysis of the Surveillance, Epidemiology, and End Results (SEER) database.
Authors: Smith Giri, Vijaya Raj Bhatt, Ranjan Pathak, Gregory Bociek, Julie Vose, James O. Armitage
Journal: Journal of Clinical Oncology (2015)

8562 Background: In the rituximab era, patients with PMBCL demonstrate high complete remission rate and a plateau in survival curve beyond 2-3 years. The use of RT in these young patients may predispose to the risk of cardiopulmonary toxicities and secondary malignancies. Methods: We used SEER 18 database and histology code 9679/3 to identify adult patients with PMBCL between 1973 and 2011. FDA approved rituximab for diffuse large B cell lymphoma in 2006. Hence, using the year 2006 as a cutoff, we compared the survival differences among patients treated with and without radiotherapy. Kaplan Meier survival curves with log rank test were plotted to compare survival statistics. Chemotherapy regimen could not be ascertained. Cox proportional hazard regression model was done to adjust for other covariates including age, year of diagnosis, race, Ann Arbor stage and gender. All p-values were two-sided and level of significance was chosen at 0.05. Results: Of 358 PMBCL patients, 50.5% patients (n = 181) received RT. Those who received radiation were more likely to be younger than 50 years (90% vs. 81%, p = 0.01) but were similar in terms of gender, race and stage at diagnosis. The unadjusted five-year overall survival (OS) was higher for RT vs. non-RT group (84% vs. 74%, p = 0.02). When stratified by year of diagnosis, OS was higher for RT vs. non-RT group in pre-rituximab era (before 2006) but not in post-rituximab era (after 2006). In multivariate analysis, RT remained an independent predictor of improved OS in pre-rituximab era (HR 0.36; 95% CI 0.17-0.79; p = 0.01) but not in post-rituximab era (HR 0.96; 95% CI 0.45-2.05; p = 0.93) after adjusting for age, year of diagnosis, gender, race and stage at diagnosis. Conclusions: Our study suggests that the effect of rituximab may reduce the benefit of RT in select patients such as patients treated with R-EPOCH or those with important risk factors for breast cancer/coronary artery disease. However, select patients such as those with large masses, positive PET scan after chemotherapy or those treated with R-CHOP may still benefit from RT. Resolving these questions is an important topic for future research.
Short-term clinical outcomes from a randomized controlled trial to evaluate laparoscopic versus open complete mesocolic excision for stage II,III colorectal cancer (CRC): Japan Clinical Oncology Group study JCOG0404 (NCT00147134).
Authors: Yusuke Nishizawa, Norio Saito, Masafumi Inomata, Tsuyoshi Etoh, Seigo Kitano, Hiroshi Katayama, Junki Mizusawa, Seiichiro Yamamoto, Yusuke Kinugasa, Shoichi Fujii, Fumio Konishi, Yoshihisa Saida, Yasuhiro Shimada, Yoshihiro Moriya
Journal: Journal of Clinical Oncology (2012)

3569 Background: The benefits of laparoscopic surgery (LAP) in comparison with open surgery (OP) have been suggested; however, the long-term survival of LAP for advanced CRC requiring complete mesocolic excision is still unclear. We conducted a study to confirm the non-inferiority of LAP to OP in terms of overall survival (OS)with less frequent post-operative morbidity. Short-term outcomes including post-operative complications are presented here. Methods: Only accredited surgeons from 30 Japanese institutions participated. Eligibility criteria included histologically proven CRC; tumor located in the cecum, ascending, sigmoid or rectosigmoid colon; T3 or deeper lesion without involvement of other organs; N0–2 and M0; tumor size =&lt;8 cm; patient age 20-75 years. Patients were randomized preoperatively.Patients with pathological stage III received adjuvant chemotherapy with fluorouracil plus leucovorin. The primary endpoint is OS. and the planned sample size was 1050. Results: A total of 1057 patients were randomized (OP: 528, LAP: 529) between October 2004 and March 2009. Conversion to OP was needed for 29 (5.4%) patients in LAP arm (technical conversion; 2.3%, indicated conversion; 2.8%, complicated conversion; 0.4%). Patients assigned to LAP had less blood loss compared with those assigned to OP (median 30 ml vs 85 ml, p&lt;0.001), although LAP lasted 52 minutes longer than did OP (p&lt;0.001). Radicality of resection as assessed by number of resected lymph nodes did not differ between two groups. LAP was associated with earlier recovery of bowel function (p&lt;0.001), and with a shorter hospital stay (p&lt;0.001) compared with OP. Morbidity and mortality untill discharge did not differ between two groups, except for less wound-related complications in LAP (p=0.007). Conclusions: Laparoscopic complete mesocolic excision for stage II,III colorectal cancer can be performed safely and short-term clinical benefits was demonstrated. If the non-inferiority of LAP in OS is demonstrated in the primary analysis planned in 2014 , LAP will be the new standard procedure for CRC.
Disparities in age-related incidence of colon and rectal cancer in the United States, 1975-2010.
Authors: Christina Edwards Bailey, Chung-Yuan Hu, Y. Nancy You, Brian Bednarski, Miguel A. Rodriguez-Bigas, John Michael Skibber, Scott B. Cantor, George J. Chang
Journal: Journal of Clinical Oncology (2014)

6579 Background: The overall incidence of colorectal cancer (CRC) has been decreasing since 1998, but there has been an apparent rise in the incidence of CRC in young adults. The primary aim of this study was to evaluate age-related disparities in secular trends in CRC incidence in the United States. Methods: A retrospective cohort study was performed using the Surveillance, Epidemiology, and End Results (SEER) registry. All patients diagnosed with colon or rectal cancer from 1975 to 2010 was queried. SEER*Stat (version 8.04, National Cancer Institute) was used to obtain the annual cancer incidence rates, annual percent change (APC), and corresponding p-values for the secular trends. Results: Overall age-adjusted CRC incidence decreased by 0.92% between 1975 and 2010. There has been a steady decline in the incidence of CRC in patients age 50 years or older, but the opposite trend has been observed in patients 20 to 34 years of age. The APC for patients with localized, regional, and distant colon cancer at diagnosis in the 20 to 34 year age group was 1.10 (95% CI 0.28 to 1.93; P=0.01), 0.91 (95% CI 0.23 to 1.61; P=0.01) and 1.81 (95% CI 0.88 to 2.75; P<0.001). The APC for patients with localized, regional and distant rectal cancer in the 20 to 34 year age group was 4.03 (95% CI 3.02 to 5.05; P<0.001), 3.05 (95% CI 1.95 to 4.17; P<0.001) and 2.66 (95% CI 1.33 to 3.99; P<0.001). Based on current trends, in 2030 the incidence rate for colon and rectal cancer will increase by 90% and 124.2% respectively for patients 20 to 34 years of age while decreasing by 37.8% and 34.3% for patients 50 to 75 years of age. Conclusions: There has been a significant increase in the incidence of CRC diagnosed in patients aged 20 to 34, with a decline in older patients. Further studies are needed to determine the cause for these trends and identify potential preventive and early detection strategies. Percent change of APC-based predicted incidence rate of colon and rectal cancer by age compared to incidence rate in 2010. Age group Colon Rectal 2020 2030 2020 2030 20-34 37.8% 90.0% 49.7% 124.2% 35-49 13.0% 27.7% 20.8% 46.0% 50-75 -21.2% -37.8% -19.0% -34.3% >75 -25.5% -44.5% -30.3% -51.5%
Colorectal cancer in patients 50 years and younger: The Beaumont Health System experience.
Authors: Adewale Alade Fawole, Foluso Nelson Ogunleye, Jatin Rana, Daniel Isaac, Mohammed Ibrahim, Marianne T. Huben, Harry Wasvary, Joseph M Anderson, Susanna S. Gaikazian, Dana Zakalik, John M. Robertson, Ishmael A. Jaiyesimi
Journal: Journal of Clinical Oncology (2015)

e14583 Background: Colorectal cancer (CRC) is a common and lethal disease. Age is a major risk factor for developing sporadic CRC. CRC is uncommon before 50 years of age, and it is often discovered at later stages. These factors may explain why there are limited studies in this age group. Although the incidence of CRC has been decreasing over the past three decades, the incidence in people younger than 50 years has been on the rise. The declining incidence of CRC in individuals older than 50 years has been attributed to early detection and intervention through screening studies. Methods: After obtaining IRB approval, the Beaumont Hospital’s oncologic database was used to identify patients 18 to 50 years of age with histologically confirmed adenocarcinoma of the colon and/or rectum between 2008 and 2010. Results: Charts of 159 patients were included for the final analysis. Their ages ranged from 21-50 years, with a median age of 46 years. Only 3.7% of all patients had preexisting colonic polyps or inflammatory bowel disease. Twenty-eight (17.6%) of 159 patients had a family history of predisposing conditions such as colonic polyps, CRC, and/or endometrial carcinoma prior to CRC diagnosis. Among patients with a family history of predisposing conditions, only four (14.3%) had screening colonoscopy. Stage IV CRC was diagnosed at presentation in 36 (22.6%) patients. CRC was located in the sigmoid colon and the rectum in 103 (64.8%) patients in this cohort. Conclusions: One in five young adults with CRC already had advanced stage cancer at presentation. The majority of young patients with CRC had no family history of predisposing conditions. Most young adults considered at increased risk of CRC were not being screened by colonoscopy. In this cohort, CRC was most commonly located in sigmoid colon and rectum.
The role of highly selective androgen receptor (AR) targeted therapy in men with biochemically relapsed hormone sensitive prostate cancer.
Authors: Rahul Raj Aggarwal, Joshi J. Alumkal, Russell Zelig Szmulewitz, Celestia S. Higano, Alan Haruo Bryce, Margaret K. Yu, Carla De Boer, Gonzalo Choque-Gonzales, Eric Jay Small
Journal: Journal of Clinical Oncology (2015)

TPS5084 Background: Androgen deprivation therapy (ADT) is frequently applied in men with a rising PSA after surgery and/or radiation, often on an intermittent basis (Crook et al. NEJM 2012). Yet, progression to castration-resistant prostate cancer (CRPC) is a near universal event and many ultimately succumb from their disease, especially those with a short PSA doubling time (PSADT) (Freedland et al. JAMA 2005). Furthermore, ADT is associated with an adverse impact on quality of life (QOL), decreased bone density (BMD), and insulin resistance (Keating et al. JCO 2006). Potent AR antagonists have proven beneficial in metastatic CRPC but their role in castration-sensitive disease is unknown. We hypothesize that compared to standard ADT with luteinizing hormone releasing hormone (LHRH) agonist monotherapy: (1) potent AR antagonist monotherapy may have less detrimental impact on QOL and metabolic effects yet preserved efficacy, and (2) LHRH agonist + potent AR blockade may lead to more durable PSA suppression thereby allowing longer treatment-free intervals and hence improved QOL within an intermittent treatment framework. Methods: In the ongoing, open-label, phase 2 study (NCT01790126), patients are randomized 1:1:1 to receive ARN-509 monotherapy (240 mg/day), ARN-509 + LHRH agonist, or LHRH agonist monotherapy. Patients are treated for 12 months, then observed until the time of PSA progression. Eligibility criteria include prior definitive local therapy, rising PSA with PSADT ≤ 12 months, minimum PSA > 1 if prior surgery (nadir + 2 if radiation alone), serum testosterone (T) > 150 ng/dL, no prior ADT for biochemical relapse, and no metastases. The primary study endpoint is the percent change from baseline to 12 months in QOL as measured by FACT-P. Secondary endpoints include PSA nadir on treatment and PSA progression-free survival, median time to T recovery, and percent change from baseline in bone density, fasting insulin/glucose/lipids, and serum T and estradiol levels. Correlative studies include analysis of AR mutations in circulating tumor DNA and association with clinical outcomes. Thus far, 34 out of 90 planned patients have been accrued across five investigational sites. Clinical trial information: NCT01790126.
Use of Statins in Adults Older Than 75 Years
Authors: Neil J. Stone, Conrad B. Blum
Journal: JAMA (2017)

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