tbuckley/cabot-search huggingface dataset:
A phase I dose-escalation study of two cycles carboplatin-olaparib followed by olaparib monotherapy in patients with advanced cancer.
Authors: Jill J.J. Geenen, Gwen Dackus, Philip C. Schouten, Dick Pluim, Serena Marchetti, Gabe S. Sonke, Alwin Huitema, Jos H. Beijnen, Jan H. M. Schellens, Sabine C. Linn
Journal: Journal of Clinical Oncology (2019)

3118 Background: The PARP-inhibitor olaparib has single-agent activity in BRCA mutated breast and ovarian cancer. Preclinical studies show synergistic effects when combining PARP-inhibitors and platinum drugs in BRCA1/2 mutated cancer cell models. A formulation change from olaparib capsules to tablets initiated a new dose finding study of olaparib tablets BID continuously with carboplatin. Methods: Patients were included in a 3+3 dose-escalation schedule in the following dose-levels: olaparib 25mg BID and carboplatin AUC 3 d1/d22, olaparib 25mg BID and carboplatin AUC 4 d1/d22, olaparib 50mg BID and carboplatin AUC4 d1/d22, olaparib 75mg and carboplatin AUC 4 d1/d22 and olaparib 100mg BID and carboplatin AUC 4 d1/d22. After two cycles patients continued olaparib 300mg BID as monotherapy. Primary objective was to assess the Maximum Tolerable Dose (MTD). Secondary objectives were to investigate the preliminary response rate, pharmacodynamics and systemic exposure. Results: In total 24 patients were included with breast cancer (n = 18), ovarian cancer (n = 3), melanoma (n = 1), colorectal cancer (n = 1) and esophageal cancer (n = 1). Nineteen out of 24 patients had a germline BRCA mutation (79%). Most common AEs were nausea (46%), fatigue (33%) and platelet count decrease (33%). The majority of AEs (83%) were grade 1/2 in severity. Because two dose-limiting toxicities (consisting of ≥ 7 days dose delay of cycle 2 or missing ≥ 5 doses of olaparib due to hematologic toxicity) occurred in dose-level 4, dose-level 3 (olaparib 75mg and carboplatin AUC 4; n = 6 patients) was determined to be the MTD. Fourteen out of 24 patients (56%) had a partial response as best response, according to RECIST 1.1. Systemic exposure of the olaparib tablet formulation appeared comparable to the previous capsule formulation with an olaparib tablet AUC 0-14 of 16.3 μg/ml*h at MTD. PARP activity in PBMCs was decreased by 98.7% ± 0.14% at day eight compared to day one for dose-level 3. Conclusions: Olaparib tablets 75mg BID and carboplatin AUC 4 for two cycles preceding olaparib monotherapy is a feasible and tolerable treatment schedule with encouraging clinical antitumor activity. Clinical trial information: NCT02418624.
Antitumor activity and safety of MK-1308 (anti-CTLA-4) plus pembrolizumab (pembro) in patients (pts) with non-small cell lung cancer (NSCLC): Updated interim results from a phase I study.
Authors: Ruth Perets, Kiyotaka Yoh, Dong-Wan Kim, Jair Bar, Myung-Ju Ahn, Adnan Nagrial, Miyako Satouchi, Drew W. Rasco, Dae Ho Lee, David R. Spigel, Dusan Kotasek, Martin Gutierrez, Jiaxin Niu, Shabana Siddiqi, Anne Chain, Brent D. Butts, Xiaoyun Nicole Li, Jobin Cyrus, Rachel Altura, Byoung Chul Cho
Journal: Journal of Clinical Oncology (2019)

2558 Background: An ongoing multicenter, open-label, phase 1 study of the anti–CTLA-4 antibody MK-1308 in combination with pembro in advanced solid tumors (NCT03179436) revealed a manageable safety profile and promising efficacy in pts with first-line (1L) advanced NSCLC. Data from a larger sample size and longer follow-up are presented. Methods: In dose escalation (DE), pts with advanced solid tumors received MK-1308 by IV administration at 25, 75, or 200 mg Q3W ×1 cycle then in combination with pembro 200 mg Q3W ×4 cycles followed by pembro monotherapy (up to 35 cycles). In dose confirmation (DC), pts with 1L advanced NSCLC received MK-1308 at 25 or 75 mg—Q3W or Q6W—plus pembro 200 mg Q3W (up to 35 cycles). Safety (all treated pts), efficacy (subset of 1L NSCLC pts), pharmacokinetics (PK, all treated pts), and PD-L1 tumor expression (subset of 1L NSCLC pts) were analyzed. Results: 213 pts were treated (DE, n=39; DC, n=174). All pts were included in the safety analyses (median follow-up, 8 months); 113 pts from DC were included in the efficacy analyses (median follow-up, 8 months). PK showed a dose-dependent increase in MK-1308 exposure. Neither target dose-limiting toxicity (≥10%) nor maximum tolerated dose were reached for MK-1308 plus pembro; however, toxicity increased with increasing MK-1308 dose and shorter dosing intervals. Treatment-related adverse events grade ≥3 occurred at the lowest rates at 25 mg Q3W in DE (0%) and 25 mg Q6W in DC (25%) and at the highest rates at 200 mg Q3W in DE (75%) and 75 mg Q3W in DC (50%). Efficacy was observed at all MK-1308 dose levels and intervals: confirmed ORR per RECIST 1.1 by central review in 1L advanced NSCLC was 39% at 25 mg Q3W, 33% at 25 mg Q6W, 22% at 75 mg Q6W, and 25% at 75 mg Q3W; 6-month PFS and OS rates are 67% and 89% for the 25 mg Q6W arm. There was a 25% ORR in PD-L1–negative 1L advanced NSCLC pts. Conclusions: MK-1308 plus pembro was generally well tolerated with no unexpected toxicity and conferred encouraging antitumor activity in 1L advanced NSCLC pts. Efficacy, safety, and PK data suggest that 25 mg given Q6W is the recommended phase 2 dose for MK-1308 in combination with pembro. Clinical trial information: NCT03179436.
Quality of life outcomes including neuropathy‐associated scale from a phase II, multicenter, randomized trial of eribulin plus gemcitabine versus paclitaxel plus gemcitabine as first‐line chemotherapy for HER2‐negative metastatic breast cancer: Korean Cancer Study Group Trial (KCSG BR13‐11)
Authors: Ji‐Yeon Kim, Seri Park, Seock‐Ah Im, Sung‐Bae Kim, Joohyuk Sohn, Keun Seok Lee, Yee Soo Chae, Ki Hyeong Lee, Jee Hyun Kim, Young‐Hyuck Im, Tae‐Yong Kim, Kyung‐Hun Lee, Jin‐Hee Ahn, Gun Min Kim, In Hae Park, Soo Jung Lee, Hye Sook Han, Se Hyun Kim, Kyung Hae Jung, Yeon Hee Park
Journal: Cancer Communications (2019)

Abstract Background A phase II clinical trial of the comparison between eribulin plus gemcitabine (EG) and paclitaxel plus gemcitabine (PG) as first‐line chemotherapy for patients with metastatic breast cancer (MBC) found that the EG regimen was less neurotoxic, but was similar in efficacy to the PG regimen. In the present study, we analyzed functional assessment of cancer therapy‐taxane (FACT‐Taxane) questionnaires from patients in this clinical trial to determine their quality of life (QoL). Methods QoL was assessed using the Korean version of the FACT‐Taxane questionnaires. After baseline assessment, QoL was assessed every 2 cycles for 12 cycles and every 3 cycles thereafter. The linear mixed model was used to evaluate the difference in QoL between the EG and PG arms. Results Of the 118 enrolled patients, 117 responded to the FACT‐Taxane questionnaires at baseline, 1 in the PG arm did not. Baseline QoL scores were not different between the EG and PG arms. During treatment, taxane subscale scores were significantly higher in the PG arm than in the EG arm after 2–13 cycles of chemotherapy (all P &lt; 0.05), except for the 11th cycle. Neuropathy‐specific analysis showed that patients in the PG arm had earlier and more severe neuropathic symptoms than those in the EG arm ( P &lt; 0.001). Conclusions In our QoL analysis, the EG regimen delayed and decreased neuropathy as compared with the PG regimen. Therefore, eribulin would be a reasonable substitute for paclitaxel as first‐line chemotherapy for MBC.
First real-world experience of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors (NET) since US FDA approval.
Authors: Bhavana Konda, Sherise C. Rogers, Cassandra Natalie Grenade, Claire F. Verschraegen, Ye Zhou, Ashima Goyal, Mona Natwa, Chadwick Wright, Akram Hussein, Hallie Barr, Dramane Konate, Andrew Brown, Rochelle Batdorf, Bonnie Williams, Songzhu Zhao, Lai Wei, Manisha H. Shah
Journal: Journal of Clinical Oncology (2019)

e15691 Background: PRRT using 177 Lu-DOTATATE was US FDA approved in Jan 2018, and real world data in the US is lacking. Methods: We retrospectively reviewed medical records of patients who began PRRT 03/14/18 - 10/01/18 at our institution. 177 Lu-DOTATATE was administered at a dose of 200mCi over 20-30 min every 8 weeks for 4 doses. Infusion of arginine-lysine 25gm/25gm in 1-liter normal saline was given over 4 hours starting 30 min prior to treatment, in addition to intravenous palonosetron 0.25mg. Results: 51 patients received at least 1 of 4 doses and 40/51 were no longer on active therapy. 28/40 received all 4 doses and 12/40 discontinued treatment after &lt; 4 doses. 25/40 were evaluable for response per RECIST v1.1. 16/25 (64%) had GI NET, 3/25 (12%) pancreatic NET, 4/25 (16%) atypical lung carcinoid, 1/25 (4%) multifocal NET, and 1/25 (4%) had paraganglioma. 28% had grade 1, 56% grade 2, and 8% (2/25) had grade 3 (Ki 67: 25% and 40%) NET. 12/25 (48%) had received ≥2 prior systemic therapies not including somatostatin analogs, and 10/25 (40%) had ≥1 prior liver-directed therapy. Median follow-up from date of last PRRT was 61.5 days. Objective response (partial response) rate was 16% (4/25; table). 18/25 (72%) had stable disease and 3/25 (12%) had progressive disease. Most adverse events (AEs) were grade 1-2 and included fatigue, nausea, abdominal pain, and cytopenias. ≥Grade 3 AEs requiring treatment discontinuation included symptomatic gastric outlet obstruction (2/51), small bowel obstruction (1/51), ischemic enteritis (1/51), confusion/bone pains (1/51), liver failure (1/51), and severe neutropenia (1/51). All patients with ≥grade 3 AEs had a high tumor burden at baseline. Conclusions: 177 Lu-DOTATATE is an effective and safe treatment in advanced NET, and our results are consistent with NETTER 1 data.[Table: see text]
Defining the heterogeneity landscape of pancreatic cancer copy number alterations.
Authors: Timour Baslan, Jie Wu, Yee Him Cheung, Jonathan Bermeo, Nevenka Dimitrova
Journal: Journal of Clinical Oncology (2019)

e15776 Background: Pancreatic cancer (PDAC) is projected to become the second leading cause of cancer related mortality by 2030. Bulk whole genome sequencing studies of PDAC have characterized the landscape of clonal mutations and highlighted the prominence of copy number alterations (CNAs) in PDAC genomes. However, little is known with regards to the extent of sub-clonal heterogeneity of somatic CNAs and it is hypothesized that this heterogeneity is a contributing factor to the limited effectiveness of existing therapies. Methods: We retrieved absolute copy number information using bulk sparse whole genome sequencing of multi-region sampled PDAC samples as well as matching primary-metastasis tumor samples from over 100 patients. In addition, we analyzed copy number variations in a subset of these samples (n = 15) at single-cell resolution (~1000 cells in total). Results: We describe a detailed picture of sub-clonal CNAs genetic heterogeneity. Our results illustrate, among other findings, (1) extensive sub-clonal diversity of CNAs giving rise to many genetically unique sub-clonal cancer populations, (2) somatic mosaicism of chromosomal amplicons in single-cancer cells, (3) variation in the dosage of cancer genes, including the KRAS oncogene, in different tumor sub-clones and (4) somatic alterations, such as amplification of 8q11 containing the metastasis promoting gene IKBKB, associated with primary PDAC progression to liver metastasis. Conclusions: Our results offer an in-depth view of the sub-clonal heterogeneity of somatic CNAs in pancreatic cancer and illustrate ways in which such heterogeneity could lead to therapeutic resistance.
The influence of obesity on tumor recurrence in vulvar cancer patients.
Authors: Rüdiger Klapdor, Peter Hillemanns, Linn Lena Woelber, Julia Kathrin Jueckstock, Felix Hilpert, Nikolaus de Gregorio, Annette Hasenburg, Jalid Sehouli, Atanas Ignatov, Sophie Fuerst, Hans-Georg Strauss, Klaus Baumann, Falk Thiel, Alexander Mustea, Werner Meier, Philipp Harter, Pauline Wimberger, Lars Christian Hanker, Barbara Schmalfeldt, Sven Mahner
Journal: Journal of Clinical Oncology (2019)

e17130 Background: Obesity is associated with worse patients’ survival in several cancer entities. Vulvar cancer as well as obesity show increasing incidence over the last years. The influence of obesity on prognosis of vulvar cancer patients is not clear. However, knowledge about this may have consequences on prevention, treatment, and follow-up. Methods: This is an analysis of the large AGO-CaRE-1 study. Patients suffering from squamous cell vulvar cancer (UICC stage IB and higher), treated in 29 cancer centers between 1998 and 2008, were categorized in a database, in order to analyze treatment patterns and prognostic factors in a retrospective setting. Results: In total, 849 patients with documented height and weight were divided into two groups depending on their body mass index (BMI, &lt; 30 vs. ≥30 kg/m²). There was no difference in the baseline variables (age, tumor diameter, depth of infiltration, tumor stage, nodal invasion, tumor grade) between both groups (p &gt; 0.05). However, we identified differences regarding ECOG status and preexistent comorbidities (cardiovascular, dementia) towards healthier patients with BMI &lt; 30 kg/m². Treatment variables (R0 resection, chemotherapy, radiotherapy, continuation of adjuvant therapy) did not differ (p &gt; 0.05). Patients with BMI ≥30 kg/m² underwent radical vulvectomy more often (61.1 % vs. 51.8%, p = 0.042). During follow-up, there was a higher recurrence rate in the group having a BMI ≥30 kg/m² (43.4%, vs. 28.3%, p &lt; 0.01) due to an increased rate of local recurrences (33.3% vs. 18.5%, p &lt; 0.01). The rate of groin and distant recurrences was similar between both groups (p &gt; 0.05). Noteworthy, we observed a significantly shorter disease free survival (DSF) of the obese patients in univariate analysis (HR 1.362, 95%CI 1.093-1.696, p = 0.006). Even in multivariate Cox-regression analysis including age, ECOG, tumor stage, type of surgery, nodal invasion, tumor grade, and comorbidities patients with BMI ≥30 kg/m² had a significantly shorter DFS (HR 1.811, 95%CI 1.005-3.262, p = 0.048). Conclusions: In this first large study about the association between obesity and prognosis of vulvar cancer patients, we observed that a BMI ≥30kg/m² was associated with shorter DFS, mainly attributed to a higher risk for local recurrence.
Benefit of early-phase targeted, basket, and immune-based trials for patients with chemorefractory gastrointestinal (GI) cancers.
Authors: Rajiv Agarwal, Nicholas Anthony Cangemi, Andrew S. Epstein, James J. Harding, Neil Howard Segal, Diane Lauren Reidy, David Michael Hyman, Leonard B. Saltz
Journal: Journal of Clinical Oncology (2019)

e15700 Background: Historically, phase I trials were designed to establish phase II tolerable doses of new drugs. Efficacy concerns were secondary. In the modern era of targeted and immune-based therapies, investigator and patient expectations of efficacy in such trials have increased. Patients (pts) who have exhausted standard treatment options often seek participation in phase I drug development or phase II basket studies, with hope for therapeutic benefit. We assessed the benefit to pts with chemorefractory GI cancers from investigational early drug development trials at our institution. Methods: We reviewed the referral records of our Early Drug Development and Immunotherapy Services to identify pts referred from our GI Oncology Service in 2018. As pts are typically not referred unless with performance status 0-1, and normal liver, renal, and marrow function, those requesting early phase studies but not meeting these criteria were excluded from this analysis. End points were enrollment on a trial, 3 and 6-month PFS, and tumor shrinkage. Results: Of 245 GI Oncology pts referred in 2018, 26 (11%) were accrued to a trial: 14 to immune-based (1 withdrew before treatment) and 12 to targeted (3 to phase II basket): median age 53 (range 23-76); 15 female. GI cancer types included: colon (7), pancreas (7), cholangiocarcinoma (4), rectal (3), and appendiceal, peritoneal mesothelioma, small bowel, unknown primary, and gastric (1). Most common reasons for non-accrual were lack of available treatment spots and failure to meet eligibility criteria for specific trials. Of 22 pts with adequate follow up at time of analysis, none achieved 6-month PFS; one (5%) met 3-month PFS with tumor growth below RECIST criteria at 3 months and came off study for progression at 4 months. No pts achieved any degree of tumor shrinkage while receiving trial drugs. Conclusions: Phase I and phase II basket options for chemorefractory GI cancers were limited relative to demand. Benefit from investigational treatment in this patient population was limited; expectations may be overstated. Further research is underway to evaluate pts’ expectations for therapeutic benefit from early phase targeted and immune-based trials.
National trend of gastric cancer mortality in China (2003–2015): a population‐based study
Authors: Kun Gao, Jun Wu
Journal: Cancer Communications (2019)

Gastric cancer mortality decreased substantially over the last decades in most countries worldwide. This study aimed to assess the most recent national trend of gastric cancer mortality and examine the disparity of gastric cancer mortality between rural and urban areas in China.The crude mortality data of gastric cancer by sex, age group, and area were obtained from China Health Statistical Yearbooks (2003-2015) covering 10% of Chinese population. The age-standardized rates of mortality (ASRM) of gastric cancer in rural and urban areas were estimated using the 2010 Chinese Census population stratified by age, sex, and area. The trend of mortality of gastric cancer was assessed by using Joinpoint analysis.During the 13-year period, the ASRM was reduced from 31.5/100,000 in 2003 to 20.9/100,000 in 2015 in rural areas and from 18.9/100,000 in 2003 to 14.5/100,000 in 2015 in urban areas. In the male population, the annual percent changes of mortality were - 2.2% in urban areas (95% confidence interval [CI] - 3.8% to - 0.6%; P < 0.001) and - 3.4% in rural areas (95% CI - 5.1% to - 1.8%; P < 0.001). In the female population, the annual percent changes of mortality were - 2.7% in urban areas (95% CI - 4.2% to - 1.2%; P < 0.001) and - 4.6% in rural areas (95% CI - 5.5% to - 3.7%; P < 0.001).The declining trend of mortality of gastric cancer was presented from 2003 to 2015 in both rural and urban areas in China. The decrease in gastric cancer mortality is greater in rural areas than in urban areas in China.
POF (paclitaxel plus FOLFOX) versus IP PAC (intraperitoneal paclitaxel plus FOLFOX) versus FOLFOX as a first-line treatment in advanced gastric cancer (AGC): Update from a multicenter, randomized phase II trial, FNF-004 trial.
Authors: Rongbo Lin, Yigui Chen, Jinfeng Zhu, Peicheng Lin, Wujin Chen, Wenzheng Fang, Hui Li, Jie Liu, Shen Zhao, Nan-Feng Fan
Journal: Journal of Clinical Oncology (2019)

4035 Background: The PFS with POF was statistically significantly improved and IP PAC was trending to improve compared to FOLFOX in first-line setting in AGC were reported in 2019 ASCO-GI (abstract 6). Update and subgroup analysis were released herein. Methods: The patients with AGC were randomized to three groups. The POF or IP PAC was paclitaxel 135 mg/m 2 intravenously (POF) or paclitaxel 80 mg/m 2 intraperitoneally (IP PAC) followed by mFOLFOX6 omitted 5-Fu bolus. Every 14 days repeated for all three regimens. Up to 9 cycles of treatment were administered, followed by S-1 until disease progression. The primary endpoint was PFS. Results: Between Nov 2015 and May 2018, 89 pts (30 POF, 29 IP PAC, 30 FOLFOX) were randomly allocated. PFS, OS and RR were seen in the table below. Either POF or IP PAC was statistically significantly better than FOLFOX in PFS. In subgroup with female, peritoneal metastasis, ascites, lymphadenopathy in peritoneal cavity, number of organs involved &gt; 2, POF was statistically significantly better than FOLFOX in PFS. In subgroup with female, gastrium of primary tumor site, peritoneal metastasis, ascites, no lymphadenopathy out of peritoneal cavity, IP PAC was statistically significantly better than FOLFOX in PFS. Intravenously docetaxel plus S-1 still saw response after IP PAC. Conclusions: either POF or IP PAC improved survival compared to FOLFOX, especially in patients with female or peritoneum metastasis. Only POF, not IP PAC, improved response rate compared to FOLFOX. Clinical trial information: NCT02845908. [Table: see text]
Age-related efficacy and safety of apalutamide (APA) plus ongoing androgen deprivation therapy (ADT) in subgroups of patients (pts) with nonmetastatic castration-resistant prostate cancer (nmCRPC): Post hoc analysis of SPARTAN.
Authors: Julie Nicole Graff, Matthew Raymond Smith, Fred Saad, Boris A. Hadaschik, Hiroji Uemura, Ji Youl Lee, Paul N. Mainwaring, David Olmos, Stephane Oudard, Anil Londhe, Amitabha Bhaumik, Oliver Brendan Rooney, Angela Lopez-Gitlitz, Eric Jay Small
Journal: Journal of Clinical Oncology (2019)

5024 Background: SPARTAN, a randomized phase 3 placebo (PBO)-controlled study in pts with high-risk nmCRPC and PSA doubling time ≤ 10 mo, showed that, compared with PBO, addition of APA to ongoing ADT treatment (tx) prolonged metastasis-free survival (MFS) by &gt; 2 y, reduced the risk of symptomatic progression by 55%, and increased second progression-free survival (PFS2), which is the time from randomization to disease progression on first subsequent anticancer tx, or death. The impact of APA in terms of benefit and safety profile was evaluated in pts aged &lt; 65, 65-74, and ≥ 75 y. Methods: Pts with nmCRPC were randomized 2:1 to APA (240 mg QD) or PBO; ADT was continuous. APA effect was analyzed by Cox models and Kaplan-Meier methods across age subgroups. Results: Baseline characteristics among age groups were similar, although ECOG PS 1 vs 0 increased with age. MFS benefit with APA was highly significant for all age subgroups (Table). In pts ≥ 75 y, MFS risk with APA vs PBO was reduced by 59%; MFS risk was reduced by 86% and 76% for pts &lt; 65 and 65-74 y, respectively. Risk of PFS2 with APA vs PBO was reduced across all age subgroups. PFS2 in pts &lt; 65, 65-74, and ≥ 75 y: HR, 0.09 (p &lt; 0.0001); HR, 0.56 (p = 0.0343); HR, 0.59 (p = 0.0092), respectively. Risk of symptomatic progression was lessened with APA vs PBO for all age subgroups (Table). There was a similar increase in incidence of tx-emergent adverse events (TEAE) with age in both tx arms that remained higher with APA. Incidence of grade 3/4 TEAE (≥ 75 vs &lt; 65 y): APA, 50% vs 37%; PBO, 37% vs 28%. Conclusions: Pts in all age subgroups with high-risk nmCRPC had significant improvement in MFS with APA + ongoing ADT. The safety profile of APA was similar across age subgroups. Clinical trial information: NCT01946204. [Table: see text]