tbuckley/cabot-search huggingface dataset:
An international phase 3 randomized, placebo-controlled study of CC-486 (oral azacitidine) maintenance therapy in patients with acute myeloid leukemia (AML) in complete remission (CR): The Quazar AML maintenance trial.
Authors: Gail J. Roboz, Farhad Ravandi, Dominik Selleslag, Pau Montesinos, Andrew Wei, Kimmo Porkka, Antonio Almeida, Michael R. Savona, Sanjay Ram Mohan, Jose F Falantes, Maria Teresa Voso, Keshava Kumar, Frederic Camus, Ignazia La Torre, Hagop Kantarjian, Barry Skikne
Journal: Journal of Clinical Oncology (2015)

TPS7097 Background: Few inroads have been made in the past 30 years to improve overall survival (OS) in older patients (pts) with AML. While induction chemotherapy (IC) can induce CR in 40-50% of older pts, most relapse within 3-18 months. Post-remission therapy (Tx) is required to prevent relapse. Parenteral azacitidine (AZA) prolonged OS in older pts with AML vs conventional care regimens (10.4 vs 6.5 months, P= 0.1009) (Dombret, Haematologica, 2014:LB2433). CC-486 is an oral formulation of AZA in development for use in hematologic malignancies. An oral formulation allows delivery of AZA at lower systemic doses over a more prolonged schedule than is practical with SC AZA. CC-486 taken at home is convenient for pts, eliminates injection- and catheter-site reactions, and avoids resource utilization costs of hospital/clinic visits. Thus, CC-486 may offer a relapse-free survival (RFS) advantage and improve quality of life. The Quazar phase 3 AML Maintenance trial (clinicaltrials.gov NCT01757535) is designed to assess whether CC-486 is an effective low-intensity maintenance Tx that can extend OS in older pts with AML. Methods: Pts aged ≥ 55 yrs with de novo AML or AML secondary to MDS in first CR or CRi (IWG 2003) after IC, with or without consolidation, are randomized 1:1 to 300 mg QD CC-486 or placebo for 14 days of 28-day treatment cycles. Randomization is stratified by age (55-64 / ≥ 65 yrs) and cytogenetic risk (Intermediate / Poor) at induction, prior MDS, and post-remission consolidation Tx. All pts can receive supportive care. The primary endpoint is OS. Secondary endpoints include RFS, time to relapse, time to discontinuation, and safety. Exploratory analyses assess molecular and cellular markers of minimal residual disease during maintenance Tx that may be predictive of clinical outcomes. Enrollment began in May 2013, with a target of 460 pts from 150 global sites. Accrual is designed to allow enough events for ≥ 90% power to detect a statistically significant treatment effect on OS (n = 330 deaths; expected duration 60 months). By Jan 2015, 168 pts had been randomized. Study enrollment continues through 2016. Clinical trial information: NCT01757535.
Phase IB trial of carboxyamidotriazole orotate (CTO) and temozolomide for recurrent malignant glioma (MG): A novel mechanism for modulation of multiple oncogenic pathways.
Authors: Antonio Marcilio Padula Omuro, Thomas Joseph Kaley, Elena Pentsova, Lisa Marie DeAngelis, Walter John Urba, Matthew Hiram Taylor, Barry Douglas Anderson, Greg Gorman, Sean McLean, Rashida A. Karmali
Journal: Journal of Clinical Oncology (2014)

2071 Background: A possible mechanism of resistance to targeted therapeutics is the existence of redundant signaling pathways. CTO is an oral inhibitor of non-voltage-dependent calcium signaling resulting in simultaneous modulation of several receptor-mediated, calcium-dependent signal transduction pathways, including EGFR, MEK, RAS, HDAC, HSP90, WNT/β-catenin and VEGF. A phase I single-agent study in solid tumors found a safe toxicity profile and predictable pharmacokinetics at doses of 75-427 mg/m2/day, with responses seen in refractory tumors with different mutations. CTO crosses the blood-brain barrier, and pre-clinical studies have shown single-agent activity in glioblastoma xenografts and robust synergism with temozolomide (TMZ), prompting this phase IB study. Methods: Patients with recurrent glioblastoma or MG were eligible regardless of number of recurrences and previous bevacizumab exposure. The primary objective was to establish the maximum tolerated dose (MTD) of daily oral CTO combined with TMZ 150 mg/m2x5 every 28 days, using a standard 3+3 design. Results: The combination was well tolerated, with no dose-limiting toxicities observed at the 4 dose levels examined (N=15), ranging from 219mg to 481mg/m2/day. The most frequent adverse events were fatigue, nausea, vomiting, and dizziness, all of which grades 1 or 2; no QTc prolongation was seen. PK data demonstrated therapeutically relevant metabolite (CAI) levels starting at 219mg/m2doses, with no significant interactions with TMZ. Preliminary evidence of activity was observed: three radiographic responses among 11 evaluable patients; 7 patients continuing treatment beyond 2 cycles; stable disease as durable as 9+ cycles. Tissue correlates and analysis of DCE-perfusion MRI are ongoing. Conclusions: CTO at doses as high as 481mg/m2/day is safe and well tolerated in combination with TMZ, with no MTD defined after examination of all pre-established dose-escalation levels; further escalation to increase CNS exposure may be warranted. The early signals of activity in this heavily pre-treated population are encouraging and deserve further investigation. Clinical trial information: NCT01107522.
Five years' results of the German ARO 04-01 trial of concurrent 72 Gy hyperfractionated accelerated radiation therapy (HART) plus once weekly cisplatinum/5-FU versus mitomycin C/5-FU in stage IV head and neck cancer.
Authors: Volker Budach, Chie-Hee Cho, Benedikt Sedlmaier, Michael Wittlinger, Heinrich Iro, Rita Engenhart-Cabillic, Matthias Hautmann, Juergen Strutz, Michael Flentje, Beatrix Hueltenschmidt, Lutz Moser, Martin Bleif, Wilfried Budach, Susanne Staar, Gerd Becker, Silke Tribius, Petra C. Feyer, Klaus Dieter Wernecke, Jochen Werner
Journal: Journal of Clinical Oncology (2012)

5512 Background: Are 6 cycles of once weekly DDP plus one cycle of 5-FU with concurrent HART superior to 2 cycles of MMC plus one cycle of 5-FU in terms of overall survival (OS) and metastases-free survival (MFS)? Methods: Eligibility: Stage IV SCC of oro(OP)- and hypopharynx(HP), KFS of ≥80% stratified for sites, N-status, grading, hemoglobin and center. The HART schedule was reported elsewhere (V.Budach, JCO 23;2005). HART was applied concurrently with DDP/5-FU at 30mg/m² days 1,8,15,22,29,36 or MMC/5-FU at 10mg/m 2 day 1+36 and for both arms with 600mg/m² 5-FU days 1-5 as 120 hrs. c.i. TVD dose prescription was 72 Gy using 3D-conformal or IMRT-TP. 364 patients were analysed using an ITT principle for OS, MFS, progression-free survival (PFS) and loco-regional control (LRC). Hazard ratio (HR) calculations were adjusted for competing risk factors. Results: Median follow-up was 48 mos. for both arms. Mean age was 55.4 years, 83/17% were male/female and 100% stage IV patients (UICC 2002). 58.5%/41.5% of all patients suffered from OP- or HP cancer, respectively. The OS and MFS at 4 years for the DDP- versus MMC-arm was 42.1% vs. 38.8% (n.s.) and 67.3% vs. 56.6% (p=.05), respectively. The LRC and PFS for the DDP versus MMC-arm was 58.6% vs. 57.2% (n.s.) and 46.4% vs. 38.7% (n.s.). Seven items recorded for acute toxicity and 9 for late morbidity showed no significant differences between the treatment arms except for creatinine for the DDP-arm (p &lt; 0.001) using nonparametric analyses of variances for repeated measurements. The overall compliance rates for RTX were 96%, DDP: 72%, 5-FU: 97%, MMC: 86%, respectively. Conclusions: This phase III trial first establishes level IB-evidence for a once weekly DDP chemoradiation regimen. For MFS at 4 yrs., DDP/5 FU-HART is superior to MMC/5 FU HART at equal levels of acute and late radiation sequelae for both treatment arms. No significant differences were seen yet for OS, PFS or LRC. Chemoradiation with weekly DDP/5-FU or MMC/5-FU shows excellent compliance rates and can easily compete with other concurrent chemo- or bio-radiation schedules including induction TPF followed by radiation.
Real world impact of treatment-induced peripheral neuropathy (TIPN) on patient reported outcomes (PROs) in patients with multiple myeloma (MM) in the United States.
Authors: Mark S. Walker, Ze Cong, Kevin B. Knopf, Sanjay Kumar Aggarwal, Jiandong Kerr, Arthur C. Houts
Journal: Journal of Clinical Oncology (2015)

e19531 Background: Some MM treatments can cause TIPN, which is associated with pain, burning, tingling and can impact multiple aspects of patients’ lives. This study examined the PRO impact of TIPN in MM patients using real world data in the US. Methods: Adults with ≥1 disease progression of MM and ≥1 Patient Care Monitor (PCM) records from the Vector Oncology Data Warehouse were included. Index scores (General Physical Symptoms, Treatment Side Effects, Acute Distress, Despair, Impaired Ambulation, and Impaired Performance) and 4 individual items (numbness/tingling; burning sensation in hands or feet; physical pain; and weakness of body parts) (0 not a problem –10 as bad as possible) were compared before and after the 1st TIPN occurrence using fixed effect models accounting for nesting within subjects. Results: 304 patients were included (mean age: 63.5; 50.3% male; ≥1 comorbidity conditions: 50.0%; renal disease: 24.3%; diabetes: 21.1%; cerebrovascular accident: 9.2%; congestive heart failure: 7.2%), 39.1% of whom had ≥1 TIPN during follow up. After the 1st TIPN occurrence, 2 index scores (General Physical Symptoms and Impaired Performance) and all 4 individual items investigated worsened statistically significantly in unadjusted analysis. Increased problems in Impaired Performance, numbness/tingling, and burning in hands or feet were clinically relevant (Table). Conclusions: Following TIPN events, MM patients experienced significant and clinically meaningful worsening of symptoms and performance in daily activities. Novel MM agents with lower TIPN rates might provide better patient quality of life and persistence. Unadjusted change in PCM results after 1st TIPN. Mean Standard Error Index Score General Physical Symptoms 0.91Ɨ 0.27 Treatment Side Effects -0.12 0.25 Acute Distress -0.57 0.37 Despair 0.16 0.31 Impaired Ambulation -1.29Ɨ 0.52 Impaired Performance 1.69*Ɨ 0.47 Individual Item Numbness/tingling 1.03*Ɨ 0.10 Burning in hands or feet 1.60*Ɨ 0.10 Physical pain 0.29 0.12 Weakness of body parts 0.64Ɨ 0.13 *A ≥1.5-3 change in index score or ≥1.0 change in items are considered clinically relevant. Ɨp<0.05
Phase II study of the PARP inhibitor talazoparib (BMN-673) in advanced cancer patients with somatic alterations in BRCA1/2, mutations/deletions in PTEN or PTEN loss, a homologous recombination defect, mutations/deletions in other BRCA pathway genes and germline mutation S in BRCA1/2 (not breast or ovarian cancer).
Authors: Sarina Anne Piha-Paul, Jennifer Brooke Goldstein, Kenneth R. Hess, Siqing Fu, David S. Hong, Filip Janku, Daniel D. Karp, Aung Naing, Vivek Subbiah, Apostolia Maria Tsimberidou, Jennifer J. Wheler, Ralph Zinner, Gordon B. Mills, Funda Meric-Bernstam
Journal: Journal of Clinical Oncology (2015)

TPS2617 Background: Cancer cells deficient in BRCA1/2 and other components of the homologous recombination repair pathway are selectively sensitive to the double stranded DNA breaks whose repairs are inhibited by poly (ADP-ribose) polymerase (PARP) inhibitors, and in particular PARP inhibitors with “trapping” properties. Talazoparib tosylate, a potent oral “trapping” PARP1/2 inhibitor, exhibits selective anti-tumor cytotoxicity at far lower concentrations than other PARP inhibitors. Multiple ongoing trials are evaluating PARP inhibitor efficacy in patients with germline BRCA mutations. There is, however, a great need to define the spectrum of patients who may benefit. Methods: This is an investigator-initiated, single-center, non-randomized, multi-cohort trial of subjects >18 years old with measurable advanced solid tumors with no curative therapeutic options. Up to 180 patients will be treated with talazoparib at 1 mg PO daily following a two stage design with futility assessment at ten patients in each cohort with a maximum enrollment of thirty patients in each cohort. Patients will be enrolled in one of 6 cohorts: 1) Somatic mutations of BRCA1/ 2, 2) Somatic deletions of BRCA1/2, 3) Mutations or homozygous deletions in other BRCA pathway genes (e.g. ATM, PALB2, NBS1, Fanconi Anemia genes), 4) Mutations or homozygous deletions in PTEN and/or PTEN loss by IHC, 5) HR defects (Myriad HRD assay LOH >40), 6) Germline BRCA1/2 mutations (not breast or ovarian cancer). Primary endpoint is clinical benefit rate (CR, PR or SD>24 weeks). Secondary endpoints include baseline molecular and pharmacodynamics markers, concordance of BRCA1/2 alterations and HRD status, concordance of genomic alterations in tumor and circulating free DNA, progression free survival, duration of response, and overall survival. Statistical plan includes descriptive statistics, Kaplan Meier techniques and Cox proportional hazard modeling. Enrollment has already commenced. Clinical trial information: NCT 02286687.
Phase I study results of nanomolecular liposomal annamycin in refractory ALL
Authors: R. C. Shepard, C. C. Talluto, G. Jacob
Journal: Journal of Clinical Oncology (2009)

7066 Background: There continues to be no effective second-line therapy for refractory AML or ALL and the cure rate with current therapy has not significantly improved in decades. The first-line therapy for adult AML has remained the same 7 + 3 that it was a generation ago. Annamycin was specifically synthesized to overcome MDR and to have little to no cardiac toxicity when given as a nanomolecular liposomal entity. Methods: We performed a phase I multi-center, open-label, MTD study of nanomolecular liposomal annamycin in patients with refractory ALL. The secondary objective was to study the MDR-1 encoded P-1u70 glycoprotein expression in correlation with CD34 expression and MDR-1 MRP mRNA levels in refractory ALL patients before and after receiving liposomal annamycin. Results: Thirty patients were enrolled on the study. The MTD was determined to be 150 mg/m2/day for 3 days. Eight of the patients completed 1 cycle of the 3 days of treatment. Of these 8 subjects, 5 (62%) had an efficacy signal. All 5 completely cleared circulating blasts. Three subjects also cleared bone marrow blasts. Of these 3, 1 went on to a successful bone marrow transplant. The other 2 had tumor lysis syndrome and unfortunately expired. Other than the tumor lysis syndromes, there was only 1 SAE definitely related to the study drug which was a grade 3 mucositis but there were also 3 other SAEs of grade 3 or 4 mucositis probably related to the study drug which comprised the MTD determination. There were no reports of cardiac toxicity. Conclusions: Nanomolecular liposomal annamycin appears to be effective through its innate resistance to MDR even as a single agent in refractory adult ALL. We are now testing it in a phase I study in children and young adults with refractory ALL or AML. [Table: see text]
Brain metastasis are more frequent in EGFR mutated than in wild-type lung adenocarcinoma.
Authors: Marcus Paulo Fernandes Amarante, Renata D'Alpino D'Alpino, Jessica Ribeiro Gomes, Raphael Brandao Moreira, Tercia Tarciane Soares de Sousa, Carolina Kawamura, Marcelo Rocha De Sousa Cruz, Fernando C. Maluf, Antonio C. Buzaid, Marcos Andre De Sa Barreto Costa
Journal: Journal of Clinical Oncology (2015)

e19069 Background: Brain metastasis (BM) are an event relatively frequent in the clinical course of patients with lung adenocarcinoma. Despite all advances in therapeutical approach, it still has a dismal prognosis. I Identifying subgroups with a higher propensity for BM may be useful to follow those patients closer and therefore offer them earlier brain treatment. We aimed at evaluating whether patients harboring EGFR activating mutations are at a higher risk for BM compared to those without such mutations Methods: We retrospectively reviewed data of 306 patients with lung adenocarcinoma at Sao Jose Hospital in Sao Paulo, Brazil, in the past 5 years. Results: Of the 306 patients analyzed, 52 (16,9%) had EGFR mutations and we identified BM in 19 of them (36,5%). Amongst the other 254 patients, we excluded 151 because records were not well-documented for BM or EGFR status, remaining 103 patients certainly EGFR negative and that underwent a brain image. Of those 103, BM were identified in 26 (25,2%). There was a trend towards a higher proportion of BM in EGFR mutated tumors (p = 0.11). Conclusions: This study showed that patients with EGFR activating mutations have a trend towards a higher proportion of BM comparing to those without these mutations.
Glutathione-S-transferase genes polymorphisms predict response and progression free survival in head and neck cancer patients treated with cisplatin based chemoradiotherapy
Authors: M. H. Federico, K. C. Brunialti, G. Castro, F. S. Pasini, S. Maistro, F. R. Mangone, R. C. Villar, I. Snitcovsky
Journal: Journal of Clinical Oncology (2007)

21127 Background: Alterations in the function of DNA repair genes and detoxification genes may influence response to cisplatin based chemoradiotherapy in patients (pts) with head and neck cancer. Our purpose was to evaluate the prognostic ability of polymorphisms of three genes glutathione S-transferase (GST), ERCC1 and XPD in patients with head and neck squamous cell carcinoma (HNSCC). Methods: A polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) or multiplex PCR approach was used to determine the frequency of the XPD Lys751Gln (n=29), ERCC1 Asn118 (n=50), GSTP1 Ile105Val (n=22) and GSTT1/GSTM1 (n=66), in DNA of peripheral lymphocytes. A total of 50 pts were treated with platinum based chemoradiotherapy exclusively and 16 pts received the same regimen in the adjuvant setting. Median follow-up was 6.4 months and 17 pts had tumor progression and 2 died, with a progression free survival (PFS) of 18 months. Results: The frequencies (%) of the distinct genotypes were, respectively, for the homozygous common allele and heterozygous plus homozygous polymorphic variant: 40 and 60 for ERCC1; 48 and 52 for XPD; 36 and 64 for GSTT/GSTM1, 41 and 59 for GSTP1. We did not observe any association between ERCC1, XPD, GSTM1/GSTT1 polymorphisms and response, but for GSTP1, the polymorphic variant was associated with tumor response, as compared to wild type (p=0.069 χ 2 test). In relation to PFS, no associations were found between XPD, ERCC1 and GSTP1, however, for GSTM1/GSTT1, the null or heterozygous genotype (median survival: not reached, n=43) was associated with a better PFS, as compared to the wild type (18 months, n=23; p=0.087, Log-rank). Conclusions: Among the polymorphic variants studied here, our impression is that GST is the most powerful prognostic factor of favorable response and PFS to cisplatin based chemoradiotherapy in HNSCC. Supported by CAPES. No significant financial relationships to disclose.
A phase 1 exploratory study of RX-3117 to determine oral bioavailability in cancer subjects with solid tumors.
Authors: Istvan Udvaros, Agnes Rethy, Istvan Lang, Erika Hitre, Christine Peterson
Journal: Journal of Clinical Oncology (2015)

e13545 Background: RX-3117 (fluorocyclopentenylcytosine) is a novel antimetabolite, that requires activation by uridine-cytidine kinase (UCK) , a cancer cell specific kinase, that interferes with cancer cell division and nucleic acid synthesis, causes cellular arrest in the G1 phase and induces apoptosis. Methods: This study was a first-in-human, open-label, exploratory pharmacokinetic study of RX-3117. The study duration was 14-15 days (7-day screening period; 3-day treatment period; 4 (+1)-day safety follow-up period). Nine adult male and female subjects with histologically confirmed, solid tumors were enrolled and completed the study. Subjects received RX-3117 (n = 3 subjects per dose) as a single oral dose (50 mg or 100 mg) or a single intravenous dose (20 mg). Results: Pharmacokinetics (PK): The absolute bioavailability (F) for oral RX-3117 was 55.67% and 33.42% for the 50 and 100 mg doses, respectively. The mean Tmax was 2.16 hours and 2.49 hours for the 50 and 100 mg doses, respectively. The mean Cmax was 303.3 ng/mL and 311.43 ng/mL for the 50 and 100 mg doses, respectively. The greater absolute bioavailability and Cmax results of the 50 mg dose compared to the 100 mg dose suggests that oral bioavailability of RX-3117 in plasma may not be dose-proportional or due to the low subject number tested. The t1/2for the 50 mg and 100 mg doses was 13.95 hours and 20.92 hours, respectively, indicating that RX-3117 may show dose proportionality on some parameters but not on others at the doses tested. The plasma PK profile of intravenous RX-3117 differed from the plasma PK profile of oral RX-3117. The 20 mg dose of intravenous RX-3117 recovered rapidly after bolus infusion (Tmax = 0.25 hours). The 20 mg dose of intravenous RX-3117 had a mean Cmaxof 1143.63 ng/mL, which was approximately a 4-fold increase over the peak concentrations of the oral doses. RX-3117 was safe and well-tolerated at the doses tested in all subjects. No AEs, TEAEs or SAEs occurred. Conclusions: This exploratory first-in-human study shows that RX-3117 was orally bioavailable and well-tolerated at the doses tested. The results support the study of higher and multiple doses in a standard Phase 1 study
AR-V7 detection by a novel junction-specific RNA in situ hybridization (RISH) test.
Authors: Yezi Zhu, Adam Sharp, Courtney M Anderson, John Silberstein, Maritza N. Taylor, Angelo Demarzo, Emmanuel S. Antonarakis, Mindy Wang, Yuling Luo, Nan Su, Ines Figueiredo, Daniel Nava Rodrigues, Emily Park, Xiao-Jun Ma, Ilsa Coleman, Colm Morrissey, Stephen R Plymate, Peter Nelson, Johann S. De Bono, Jun Luo
Journal: Journal of Clinical Oncology (2017)

191 Background: Previous studies have reported an association between blood-based detection of androgen receptor splice variant-7 (AR-V7) and resistance to abiraterone/enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC). Further characterization of AR-V7 and its clinical correlates are necessary but depend on the development of methods that allow for reliable and specific measurement of AR-V7. In this study, we developed and evaluated a novel junction-specific AR-V7 RNA in situ hybridization (RISH) test. Methods: We developed a novel RISH assay targeting single exon-exon junction, allowing for highly-specific detection of mature cytoplasmic AR-FL and AR-V7 mRNA in native cell and tissue environment. We compared quantitative RISH AR-V7 results generated from an automated scoring system with AR-V7 levels quantified by RT-PCR in a panel of cell lines. Using the validated assay, we quantified AR-V7 signals in 58 prostate tumor biopsies. We conducted preliminary evaluation of the clinical correlates of AR-V7 detected. Results: The novel AR-V7 RISH test specifically detected mature cytoplasmic AR-V7 mRNA and did not detect nuclear pre-mRNA. AR-V7 RISH results were highly concordant with RT-PCR results. We generated quantitative AR-FL and AR-V7 data from 93.1% of the clinical specimens examined (54 of 58). Positive AR-V7 signals were detected in 23 specimens, all of which also co-expressed AR-FL. The median AR-V7/AR-FL ratio was 4.6%. Positive detection of AR-V7 was significantly correlated with prior treatment with second-line AR targeting agents and serum PSA ( p &lt;0.05), but not with any other baseline clinical variables. Notably, all castration-sensitive prostate cancer specimens (CSPC) (n = 9) were AR-V7 negative by this method. Association between AR-V7 and treatment outcome has yet to be fully evaluated. Conclusions: We demonstrate for the first time a highly specific and quantifiable AR-V7 RISH test for detection of clinically significant levels of AR-V7 mRNA in prostate tissue specimens. This test may be applied to liquid biopsy specimens to expand the utility. Prospective studies can be designed to evaluate the potential utility of this novel test in drug development and patient management.