tbuckley/cabot-search huggingface dataset:
Interim results from a phase 2 study of olaparib (without ADT) in men with biochemically-recurrent prostate cancer after prostatectomy, with integrated biomarker analysis.
Authors: Emmanuel S. Antonarakis, Hao Wang, Benjamin A. Teply, William Kevin Kelly, Jamie Willms, Rana Sullivan, Serina King, Catherine Handy Marshall, Tamara L. Lotan
Journal: Journal of Clinical Oncology (2019)

5045 Background: Pts with biochemically-recurrent (BCR) prostate cancer after local therapy with a PSA doubling time (PSADT) of ≤6 mo are likely to develop metastases and death from their disease. We hypothesized that the PARP inhibitor olaparib would be effective as a non-hormonal therapy for biomarker-unselected pts with BCR after prostatectomy, the first study of PARP inhibition in the hormone-sensitive setting. We report pre-specified interim results from the first stage of the trial. Methods: This investigator-initiated multicenter study (NCT03047135) enrolled pts with non-metastatic BCR after prostatectomy, with a PSADT of ≤6 mo. PSA had to be ≥1.0 ng/mL, with T ≥150 ng/dL. Pts received olaparib 300 mg twice daily (without ADT), until a doubling of their PSA or metastatic progression. The primary endpoint was confirmed ≥50% PSA decline (PSA50 response). Secondary endpoints included safety, minor PSA response (1-50% reduction), and PSA progression-free survival. Integrated biomarker analyses included somatic DNA sequencing, RNA expression analysis and IHC for DNA damage markers, using prostatectomy specimens. The study was designed to enroll a biomarker-unselected population using a staged-adaptive design, with up to 50 pts. In the first stage, ≥3 PSA50 responses out of 20 pts were required to proceed to the second stage; otherwise enrichment with biomarker-selected pts would occur. Results: Between 5/2017 and 11/2018, 20 men (median age, 65) enrolled in the first stage, with a median follow-up of 6 (range, 3-16) mo. Median PSADT was 3.1 mo, and 55% had Gleason ≥8 cancers. Seven men (35%) had BRCA2/ATM mutations. Three men (15%) had PSA50 responses (all had BRCA2 muts – 2 had complete PSA responses), and 4 other men (20%) had minor PSA responses. Median PSA progression-free survival was greater in men with vs. without BRCA2/ATM muts (9 vs. 4 mo; P= 0.02). Common toxicities of olaparib included fatigue, nausea, anemia and leukopenia; 2 men required a dose reduction. Conclusions: Olaparib (without ADT) was tolerable and showed activity in hormone-sensitive BCR prostate cancer, especially in men with BRCA2 muts. Second-stage enrolment is ongoing. Clinical trial information: NCT03047135.
Phase 1/2a study of once daily oral BAL101553, a novel tumor checkpoint controller (TCC), in adult patients with progressive or recurrent glioblastoma (GBM) or high-grade glioma.
Authors: Juanita Suzanne Lopez, Rebecca Sophie Kristeleit, Robert Rulach, Noor Md Haris, Mariana Scaranti, Paul James Mulholland, Donna Crawford, Saira Bashir, Caterina Aversa, Alison L. Hannah, Stephanie Anderson, Marc Engelhardt, Thomas Kaindl, Patrice Larger, Phil McKernan, TR Jeffry Evans, Elizabeth Plummer
Journal: Journal of Clinical Oncology (2019)

2025 Background: BAL101553 (prodrug of BAL27862) is a novel TCC that promotes tumor cell death by modulating the spindle assembly checkpoint. BAL27862 is a lipophilic, small molecule shown in rodents to penetrate the brain (brain/plasma ratio around unity), with promising antitumor activity in orthotopic preclinical GBM models as monotherapy or in combination with radiotherapy (RT) with or without temozolomide. In this ongoing study (NCT02490800, CDI-CS-002), daily oral BAL101553 was initially examined in solid-tumor patients, with an MTD of 16 mg/d and DLTs of G4 hyponatremia and G2 hallucinations (Lopez 2018, JCO 36, 2018, suppl. A2530). Subsequently the study was expanded by including a separate cohort of patients with progressive or recurrent GBM or high-grade glioma (Ingles Garces 2017, JCO 35, 2018, suppl. TPS2601). Methods: Patients with histologically-confirmed GBM or high-grade glioma, with progressive or recurrent disease after prior RT with/without chemotherapy, received once-daily oral BAL101553 (28-day cycles) in a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD). Adverse events were assessed by CTCAE v4.03 grade (G), and tumor response by RANO every two cycles. Pharmacokinetics (PK) were evaluated on Day 1 of Cycles 1 and 2. Results: In the ongoing study, 23 pts (13M/10F; median age 50 y), median (min–max) number of prior regimens = 2 (1–5), received doses of 8, 15, 20, 25 or 30 mg oral BAL101553 once daily. One DLT of reversible G2 depression and fatigue occurred at 20 mg. Both mean Cmax and AUC increased with dose between 8 and 30 mg. The PK exposure in GBM patients was lower than for solid tumor patients, in particular at 20 and 25 mg. At 25 mg/d (n = 3), one patient with IDH-mutated GBM had a partial response (63% area reduction per RANO) and continues on study &gt; 8 months, and another patient had stable disease for 5 months. At 15–20 mg/d, stable disease was observed in 3/10 patients. Conclusions: The current data in patients with GBM or high-grade glioma suggest that BAL101553 is well tolerated at dose levels above the MTD established in patients with advanced solid tumors, and shows indications of clinical activity. Clinical trial information: 02490800.
Anticoagulants for the treatment of venous thromboembolism in patients with cancer: An updated pairwise and network meta-analysis of randomized trials.
Authors: Shima Sidahmed, Ahmed Abdalla, Babikir Kheiri, Areeg Bala, Mohammed Salih, Zyad Kafri, Ghassan Bachuwa
Journal: Journal of Clinical Oncology (2019)

e14692 Background: Cancer-associated venous thromboembolism (VTE) is common. Although low molecular weight heparin (LMWH) is the standard therapy in this setting, little is known with regard to non-vitamin K antagonist oral anticoagulants (NOACs). Therefore, we thought about evaluating the safety and efficacy of various anticoagulants in this vulnerable population. Methods: Electronic database search was conducted to identify randomized clinical trials (RCTs) that compared LMWH, NOACs, and/or vitamin-K-antagonists (VKA) in cancer patients. We performed frequentist direct and Bayesian network meta-analysis using random-effects model to calculate odds ratios (ORs), 95% confidence intervals (CIs), and 95% credible intervals (CrIs). The primary outcome was VTE (pulmonary embolism and deep-vein thrombosis) recurrence. Secondary outcomes were major bleeding and all-cause mortality. Results: We identified 13 RCTs with 6,595 total patients (mean age 62.4 ± 12.2; 50.4% female; 17.7% hematological malignancies; and 6 months median follow-up). The most common cancer type was colorectal and 48% of the population had metastatic cancer at baseline. NOACs were associated with significantly reduced VTE recurrence compared with VKA (OR = 0.58; 95% CI = 0.40-0.83; P &lt; 0.01; number needed to treat [NNT] = 40) and LMWH (OR = 0.46; 95% CI = 0.25-0.85; P = 0.01; NNT = 20). LMHW was associated with significantly reduced VTE recurrence compared with VKA (OR = 0.52; 95% CI = 0.39-0.71; P &lt; 0.01; NNT = 18). NOACs were associated with significantly reduced major bleeding compared with VKA (OR = 0.56; 95% CI = 0.35-0.91; P = 0.02; NNT = 64). There was no significant difference identified between the anticoagulant groups in regard to all-cause mortality. Conclusions: Among cancer patients with VTE, NOACs were associated with significantly reduced VTE recurrence compared to LMWH and VKA, and significantly reduced major bleeding compared with VKA. LMWH was associated with significantly reduced VTE recurrence compared with VKA.
An open label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced solid/metastatic tumors.
Authors: Johann S. De Bono, Elena Cojocaru, Elizabeth Ruth Plummer, Tomasz Knurowski, Karen Clegg, Fay Ashby, Neil Pegg, William West, Anthony Nigel Brooks
Journal: Journal of Clinical Oncology (2019)

TPS5089 Background: CCS1477 is a potent, selective and orally bioavailable inhibitor of the bromodomain of p300 and CBP, two homologous and critical co-activators of the androgen receptor (AR) and its variant forms, including mutated, amplified and spliced AR, as well as c-Myc. CCS1477 represents a new therapeutic option for prostate cancer patients who have progressed after failure of anti-androgen therapy and in combination with anti-androgens such as enzalutamide or abiraterone. Methods: This is a Ph I/IIa study to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose and schedule(s) of CCS1477 and investigate clinical activity of CCS1477 monotherapy and CCS1477 in combination with abiraterone or enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). The trial aims to enrol approximately 150 patients and is currently recruiting in the UK with plans to open additional sites in the USA (NCT03568656). Key inclusion criteria (for the mCRPC) require previous treatment with abiraterone and/or enzalutamide, taxane as well as evidence of disease progression (PCWG-3 guidelines). Single dose and steady state pharmacokinetics will be determined along with changes in plasma PSA, LDH and ALKP and in circulating tumour cell number. Anti-tumour activity will be determined by standard imaging according to PCWG-3 guidelines. Paired tumour biopsies for biomarker assessment are being collected. Cohort 1 of the monotherapy dose-escalation (rolling 6 design; 3-6 patients/cohort) has completed. Enrolment to cohort 2 began in January 2019. Dose finding in combination (CCS1477 + abiraterone; CCS1477 + enzalutamide) will be open once monotherapy dose escalation completes. Following definition of a recommended phase 2 dose and schedule for monotherapy and in combination, three expansion arms in patients with mCRPC will be opened in parallel (25 patients/arm); CCS1477 monotherapy; CCS1477 + abiraterone; CCS1477 + enzalutamide. A further expansion in patients with advanced solid tumours with a mutation in p300 or CBP will also be opened. Clinical trial information: NCT03568656.
Addressing Clinical Challenges of Antidepressant Discontinuation
Authors: Giovanni A. Fava, Fiammetta Cosci
Journal: American Journal of Psychiatry (2019)

In the December 2018 issue of the Journal, Jha and colleagues (1) claim that antidepressant withdrawal typically resolves spontaneously over 2-3 weeks.They offer only three references in support.Two of these were case reports that included one and three patients (2, 3).In Pyke (3), the withdrawal reaction resolved in 3 weeks, whereas in the case report by Frost and Lal, withdrawal symptoms lasted between 3 and 23 weeks (2).The third reference, a small cohort study of 20 patients by Fava et al. ( 4), reported that a withdrawal reaction was observed in nine patients (45% of all patients examined), even though the drugs were tapered at the slowest possible pace.The withdrawal syndrome subsided within 4 weeks in six patients (67% of all patients experiencing withdrawal), whereas in three patients (33% of all patients with withdrawal), serious withdrawal symptoms persisted for several months after discontinuation.Not only did Jha and colleagues select only three studies, representing a total of just 24 patients, but the three studies they present to readers as evidence for their 2-3 weeks claim do not actually support their claim at all.In Frost and Lal (2), the three individual withdrawal reactions described lasted between 3 and 23 weeks, and in Fava et al. ( 4), withdrawal effects lasted considerably longer than 4 weeks in one-third of patients.Based on this evidence, the conclusion that withdrawal reactions "typically resolve spontaneously over 2-3 weeks" is fallacious and arbitrary.Moreover, two references were merely case reports, which have very little external validity.In our view, it is problematic to quote (or, rather, misquote) such anecdotal evidence to corroborate a controversial claim that should represent the broader antidepressant user population.Although there undoubtedly is a need for more research on this important issue, systematic reviews of the existing literature conclude that withdrawal is common, is often severe, and frequently lasts much longer than merely 2-3 weeks, with and without tapering (5, 6).
Adjuvant chemotherapy versus perioperative chemotherapy (CTx) for resectable gastric signet ring cell (SRC) gastric cancer: A multicenter, randomized phase II study (PRODIGE 19).
Authors: Clarisse Eveno, Antoine Adenis, Olivier Bouche, Karine Le Malicot, Vincent Hautefeuille, Roger Faroux, Anne Thirot Bidault, Joëlle Egreteau, Bernard Meunier, May Mabro, Nicolas Carrere, Nicolas Barriere, Meher Ben Abdelghani, François Mauvais, Frédéric Di Fiore, David Malka, Sylvain Manfredi, Guillaume Piessen
Journal: Journal of Clinical Oncology (2019)

4019 Background: The incidence of SRC gastric cancers is markedly increasing in Western countries. SRC cancers may harbor intrinsic resistance to chemotherapy (CTx) leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach. The primary objective of this study was to assess whether upfront surgery plus adjuvant CTx would provide enough survival benefit for study in a phase III trial when compared to perioperative CTx. Methods: Patients with stage IB-III SRC gastric cancer were randomly assigned to receive upfront surgery plus adjuvant CTx (epirubicin, cisplatin and 5-fluorouracil [ECF regimen], 6 cycles; experimental arm [SurgFirst]) or perioperative CTx (ECF, 3 cycles before and 3 cycles after surgery; control arm [CTxFirst]). Randomization (1:1) was stratified by tumor stage, tumor location, performance status and center. The primary endpoint was overall survival (OS) at 2 years (OS2; target (H 1 ): OS2 &gt; 26%). Results: 83 eligible patients were included in 27 centers from 11/12 to 09/16 (median age, 61 years (range: 32-80 years); male, 59%; ECOG PS 0-1, 99%). Results were (CTxFirst/SurgFirst): full completion of CTx, 87%/77%; surgical resection, 82.5%/90%; major postoperative complications (Clavien Dindo III-IV), 24%/23%; R0 resection rate, 88%/78%; OS2, 60%/53.5%; and median OS, 39/28 months (exploratory hazard ratio, 0.71 [95%CI: 0.40-2.64]). Conclusions: This trial met its primary endpoint (OS2 &gt; 26% in the experimental arm). With OS2 rates &gt; 50%, both CTx modalities deserve further evaluation in Phase III studies in stage IB-III SRC gastric cancer. Clinical trial information: NCT01717924.
Prognostic factors of overall survival for patients with FIGO stage IIIc or IVa ovarian cancer treated with neo-adjuvant chemotherapy followed by interval debulking surgery.
Authors: Laura Vincent, Clémentine Jankowski, Lobna Ouldamer, Marcos Ballester, Sofiane Bendifallah, Pierre-Adrien Bolze, Cherif Akladios, Hélène Costaz, Vincent Lavoué, Catherine Uzan, Pierre Collinet, Cyril Touboul, Cyrille Huchon, Alexandre Bricou, Sabrina Dridi, Marie-Martine Padeano, Jean Fraisse, Leila Bengrine, Laurent Arnould, Charles Coutant
Journal: Journal of Clinical Oncology (2019)

e17060 Background: The aim of this study was to identify prognostic factors of overall survival in patients with FIGO stage IIIc or IVa ovarian cancer treated by neo-adjuvant chemotherapy(NAC) followed by interval debulking surgery. Methods: Data of 483 patients from FRANCOGYN database, were retrospectively included in 11 French expert centers between January 2000 and December 2016. Interval cytoreductive surgery was realized in all patients after 2 or 3 or 4 or more than 4 courses of NAC. Completeness of Cancer Resection score led to define residual disease after surgery. Median overall survival was determined using the Kaplan-Meier method. Univariate and multivariate analysis were performed to define prognostic factors of overall survival. Results: The median overall survival was 52 months, after a median follow up of 30 months. 73.5% patients had no residual disease after surgery. After univariate analysis, factors significantly associated with decreased overall survival were; no pelvic and/or lombo-aortic lymphadenectomy (p= 0.002), residual disease after surgery ( p&lt; 0.001), positive cytology after NAC ( p&lt; 0.001), omental disease after NAC ( p= 0.002), no pathologic complete response (pCR) ( p= 0.002). In multivariate analysis, factors significantly associated with decreased overall survival were; residual disease after surgery (HR = 1.93; CI95% (1.16-3.21), p= 0.01) and positive cytology after NAC (HR = 1.59; CI95% (1.01-2.55), p= 0.05). Patients with no residual disease after surgery had a median overall survival of 64 months versus 35 months for patients with residual disease. Patients with negative cytology after NAC had a median overall survival of 71 months versus 43 months for patients with positive cytology after NAC. Conclusions: Residual disease after surgery and positive cytology after NAC are significantly associated with decreased overall survival of FIGO stage IIIc or IVa ovarian cancer. Therefore, complete cytoreductive surgery is ovarian cancer main prognostic factor.
Impact of prior chemotherapy or radiation therapy on tumor mutation burden in NSCLC.
Authors: Sushma Jonna, Ari M. Vanderwalde, Jorge J. Nieva, Kelsey Anne Poorman, Michelle Saul, Xinyu von Buttlar, John Y. Hu, Stephen V. Liu
Journal: Journal of Clinical Oncology (2019)

2627 Background: Higher non-synonymous tumor mutation burden (TMB) in non-small cell lung cancer (NSCLC) is associated with a higher likelihood of response to checkpoint inhibitors. Tissue samples subject to TMB analysis may be obtained after exposure to cytotoxic chemotherapy or radiation therapy – both of which introduce somatic mutations in DNA and can influence the number of identified mutations. The role of TMB as a potential predictive marker for immunotherapy is evolving, and the impact of prior therapy on TMB could influence interpretation. Methods: Eligible cases were from patients with confirmed NSCLC, available clinical annotation and tumor molecular profiling including TMB analysis at a CLIA-certified genomics laboratory (Caris Life Sciences, Phoenix, AZ) using the Illumina NextSeq platform. TMB was calculated using only missense mutations that had not been previously reported as germline alterations. Treatment history was obtained for each patient under an IRB approved protocol to determine whether patients had had received chemotherapy or radiation therapy in the year prior to collection of the tissue subject to TMB analysis. Data analysis was performed using the chi-square test of deviance to evaluate whether TMB was statistically significantly different between groups, correcting for smoking status. Results: Out of 1,118 patients identified, 459 cases met all eligibility criteria and were evaluated. 76 patients (17%) received either chemotherapy or radiation prior to tissue collection. Samples acquired prior to any therapy had a median TMB of 10 mut/Mb vs. 11 mut/Mb in samples acquired after any therapy. After adjusting for smoking, there was no significant difference in TMB between these cohorts (p = 0.41). Secondary pair wise analysis showed no statistically significant difference in TMB from chemotherapy-naïve and chemotherapy-treated samples (p = 0.28). The same was true for radiation (p = 0.75). Collection of clinical data is ongoing and further analysis, including additional cases will be presented. Conclusions: Though cytotoxic chemotherapy and radiation therapy can introduce somatic mutations, prior exposure to either was not associated with a significant difference in TMB.
A novel mutant-allele capture method for enrichment of low abundant cancer mutants.
Authors: Rui Lin, Yue Pu, Li Mao
Journal: Journal of Clinical Oncology (2019)

e14632 Background: High sensitivity detection of cancer mutants can facilitate cancer diagnosis, treatment selection, and disease monitoring. Improved methods to detect low abundance of cancer driver mutants are needed. Methods: We developed a novel method, termed PEAC, with a super high sensitivity to detect low abundant mutant from cancer driver genes through mutant capturing followed by Sanger sequencing. Circulating free DNA (cfDNA) standards containing 20 ng of 5%, 1%, 0% (wild-type), or 40 ng of 0.1% cancer driver mutants were used to establish the method. After pre-amplification of both wild-type and mutant alleles, mutant fragments were specifically bound by biotin-labelled, locked–nucleic acid modified probes, enriched by streptavidin beads, amplified through PCR and sequenced using Sanger for detection. Results: The wild-type standard did not show any mutation signal either with or without PEAC, nor did the standards with 5%, 1%, or 0.1% mutants prior to PEAC enrichment. However, after PEAC enrichment, 5%, 1%, and 0.1% of cancer driver mutants ( EGFR L858R, EGFR T790M, and BRAF V600E) predicting sensitivities to target therapies were enriched to ~90%, ~80% and 30-40% abundance, respectively. In addition to the application for point mutations, PEAC methodology was also used to enrich deletion mutant; 5%, 1%, and 0.1% of EGFR exon 19 deletion, E746_A750del, were all enriched to 90-100% frequency after PEAC. To address the limit of detection of PEAC technology, 100 ng of cfDNA standard containing 0.01% EGFR L858R and EGFR exon 19 deletion mutant were enriched to 15% and 50%, respectively, after PEAC, which indicates up to 5000-fold enrichment for EGFR exon 19 deletion by PEAC technology. Conclusions: PEAC technology can enrich very low abundance of key cancer driver mutants predicting sensitivities to tyrosine kinase inhibitors. PEAC enrichment in combination with Sanger sequencing may guide the application of cancer target therapy and represent a useful technology in the era of precision medicine.