bluuebunny/crossref_metadata_2025_split huggingface dataset:
GMI-1271, a novel E-selectin antagonist, combined with induction chemotherapy in elderly patients with untreated AML.
Authors: DeAngelo Daniel J. , Jonas Brian Andrew , Becker Pamela S. , O'Dwyer Michael , Advani Anjali S. , Marlton Paula , Magnani John , Thackray Helen M. , Liesveld Jane 
Published: September 2018

2560 Background: The outcomes for elderly patients (pts) with acute myeloid leukemia (AML) remain poor, therefore newer and less toxic therapies are urgently needed. The binding of E-selectin (E-sel), an adhesion molecule expressed in the bone marrow, to the leukemic cell surface activates survival pathways and promotes chemotherapy resistance. GMI-1271, a novel E-sel antagonist, enhances chemotherapy responses and protects from common toxicities in preclinical models (Becker ASH 2013; Winkler ASH 2013 and 2014). We report interim Phase 2 data for GMI-1271 plus chemotherapy in elderly untreated pts with AML. Methods: Pts ≥ 60 yrs with untreated AML, ECOG 0-2, and adequate renal and hepatic function were eligible. Prior treatment of MDS was allowed. GMI-1271 (10 mg/kg) was given 24 hrs prior, during and 48 hrs post induction with infusional cytarabine and idarubicin (7+3). Safety, tolerability, and anti-leukemia activity were assessed. Two cycles of induction were allowed and responders could receive consolidation with GMI-1271 plus intermediate dose cytarabine. Dose-limiting toxicity (DLT), defined as myelosuppression in the absence of disease or related Grade 3 (Gr) non-hematologic toxicity beyond day 42, was assessed in the first 3 pts. Results: 24 pts have been enrolled to date and 17 are evaluable for response. The median age was 68 years (range, 60-79) with 58% male pts, 50% secondary AML (sAML) pts and 25% with high-risk cytogenetics (by SWOG). The first 3 pts had no DLT, allowing enrollment to proceed. Common Gr 3/4 AEs included febrile neutropenia (47%), pneumonia (20%), pulmonary edema (13%) and non-fatal respiratory failure (13%). 2 pts died of sepsis within 60 days. The remission rate (CR/CRi) was 12/17 (71%). CR/CRi rate was 75% for pts with de novodisease and 67% for pts with sAML. E-sel ligand was expressed at high levels on blasts in the majority of pts. Conclusions: The addition of GMI-1271 to anthracycline-based induction chemotherapy in untreated elderly pts with AML demonstrates a high remission rate with acceptable side effect profile and low induction mortality. This study compares favorably to previous studies (Lancet, ASCO 2016). A randomized trial is being planned. Clinical trial information: NCT02306291.
Phase 1 results of PTC596, a novel small molecule targeting cancer stem cells (CSCs) by reducing levels of BMI1 protein.
Authors: Infante Jeffrey R. , Bedard Philippe L. , Shapiro Geoffrey , Bauer Todd Michael , Prawira Amy , Laskin Oscar , Weetall Marla , Baird John , Branstrom Art , O'Mara Edward , Spiegel Robert J. 
Published: September 2018

2574 Background: PTC596 is an oral investigational new drug that reduces levels of BMI1, a protein required for CSC survival. PTC596 reduced the number of CSCs in preclinical models and slowed growth rates of tumor xenografts in rodent models. The primary objectives of this first-in-human trial of PTC596 were to determine safety, dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and pharmacokinetics (PK). Secondary objectives included exploratory assessments of biological efficacy, pharmacodynamic changes and anti-tumor activity. Methods: A Phase I multi-center, open-label study was conducted in patients with advanced solid tumors using a modified 3+3 design, followed by a dose-confirmatory 10-patient expansion. PTC596 was administered using bodyweight-adjusted twice-per-week (biw) oral dosing in 4 week cycles. Dose escalation and MTD were based on observed cycle 1 DLTs. Anti-tumor activity was assessed by RECIST 1.1. Results: A total of 31 patients with a broad range of tumor types were enrolled at dose levels of 0.65 (N = 3), 1.3 (N = 3), 2.6 (N = 3), 5.2 (N = 11), 7 (N = 8) and 10 mg/kg (N = 3). Nausea, vomiting, and diarrhea were the most common all grade adverse events, though usually mild and manageable. At 10 mg/kg one patient experienced DLTs of neutropenia, mucositis, and thrombocytopenia. The other two patients at this dose level also experienced poor tolerability with Grade 2 nausea, vomiting, and diarrhea that may be partially due to the overall pill burden and excipients. The recommended dose for the expansion and further study was 7 mg/kg. Over the dosing range, plasma concentrations of PTC596 increased in an approximately dose-proportional manner and at doses of 2.6 mg/kg and above exceeded those associated with activity in vitro and in vivo models. Best response was stable disease in 5 patients including two with minor radiographic reductions in tumor volume. Conclusions: PTC596 is tolerable with manageable gastrointestinal side effects. At 7 mg/kg biw exposures exceeded those associated with preclinical activity and future clinical studies are planned for this first-in class molecule that targets CSCs. Clinical trial information: NCT02404480.
Clinical next generation sequencing for precision oncology in rare cancers.
Authors: Groisberg Roman , Hong David S. , Janku Filip , Tsimberidou Apostolia Maria , Javle Milind M. , Meric-Bernstam Funda , Subbiah Vivek 
Published: September 2018

2582 Background: Rare tumors receive little financial support or interest from major drug developers or clinical investigators. They are by nature difficult to study even in a large academic medical center. As such, no standard of care exists for many of these cancers and treatment is often extrapolated. ESMO defines rare tumors as 5/100,000 persons per year. We examined patients with rare tumors for potentially targetable genomic alterations using next generation exome sequencing (NGS). Methods: We reviewed charts of patients with rare tumors per the ESMO definition. Sarcomas were excluded. Patients were referred to investigational therapeutics department and underwent CLIA certified comprehensive genomic profiling (Foundation Medicine). Actionable alterations were defined as targeted by a drug available on-label, off-label, or in clinical trials. Results: Among the 95 patients analyzed median age was 51 years (range 2-75). M:F ratio 46:49. Overall, there were 47 different subtypes in our dataset with the most common being adenoid cystic (13%), cholangiocarcinoma (7%), metaplastic breast (6%), gallbladder (5%), and carcinoid (4%). Eighty-seven out of 96 patients (92%) had at least one genomic alteration identified with mean of 2.6 mutations per patient. Of the patients with identifiable mutations, the most common were TP53 (23%), KRAS (10%), PIK3CA (9%), CDKN2A/B (8%), BRAF (7%), MLL (7%), and ARID1A (6%). Thirty-six patients (38%) had at least one potentially actionable alteration in 21 different tumors (eg: PI3K in metaplastic breast and adenoid cystic carcinomas and BRAFV600Ein Erdheim-Chester disease). Nine patients received targeted therapy. Of these 9 patients, 3 had PR, 4 had SD, and 2 had PD as best response (table). Conclusions: The addition of CGP to management of rare tumors adds a potential line of therapy especially in RAF pathway altered ultra-rare cancers that have no standard of care. [Table: see text]
A dose-escalation study of imipridone ONC201 administered every one (QW) or three weeks (Q3W) in advanced solid tumors and multiple myeloma.
Authors: Olszanski Anthony J. , Dotan Efrat , Hall Michael J. , vonMehren Margaret , Ross Eric A. , Viereck Amanda M , Denlinger Crystal Shereen 
Published: September 2018

2592 Background: ONC201 is an orally active, first-in-class small molecule activator of the integrated stress response that selectively upregulates ATF4 to trigger tumor cell death. A phase I study of ONC201 exploring different dosing regimens and drug exposure was conducted to determine the maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Methods: A modified accelerated-titration dose escalation design was employed to enroll patients onto 2 sequential dose-escalation arms: ONC201 Q3W and QW. Dose escalation proceeded with the following order: 125, 250, 500, and 625mg (Q3W) and 250, 375, 500 and 625 (QW). Dose exposure ranged from 125 mg/6 wks to 1875 mg/3 wks. Key eligibility: advance/refractory solid tumor or myeloma, ECOG 0/1, and no active CNS disease. Adverse events, SAEs, laboratory values, physical exam findings, EKGs and bio-samples (for PK/PD) are collected. Pre and post ONC201 dose biopsies are being obtained from the 500mg weekly cohort and above. Results: 17 pts (12F:5M) with treatment-refractory tumors have been enrolled to date. Dose/#pts Q3W: 125/6, 250/1, 500/1, and 625/1; QW: 250/4, 375/4. Two patients have been enrolled at 500mg QW after database lock and not included in this assessment. Median (range) age: 57 yrs (27-72). ECOG 0/1: 2/15. MTD has not been reached. No DLTs observed. Tumor types: 8 CRC, 3 pancreatic, 2 sarcoma and 1 each cervical, endometrial, NSCLC (adeno) and small bowel. Of 17 pts, 10 (59%) had ≥1 tx-related adverse events (TRAEs), possibly related. Most common TRAEs (≥15% pts): fatigue (9,53%), anorexia (5,29%), nausea (4,24%), vomiting (4,24%), abdominal pain (3,18%), and arthralgias (2,12%). Grade ≥ 3 TRAEs were observed in 3 pts (18%). Pharmacokinetic and pharmacodynamic analysis is ongoing. Fresh frozen and paraffin-embedded biopsies (baseline and week 2) are being assessed for tumor markers implicated in the mechanism of action. No objective responses by RECIST have been seen. Final cohort is enrolling. Conclusions: ONC201 was well tolerated throughout the Q3W dosing and weekly dosing has been well tolerated to date without an apparent increase in AEs. Final enrollment summary, AEs and PK/PD data will be presented. Clinical trial information: NCT02609230.
Updated results from ZUMA-3, a phase 1/2 study of KTE-C19 chimeric antigen receptor (CAR) T cell therapy, in adults with high-burden relapsed/refractory acute lymphoblastic leukemia (R/R ALL).
Authors: Shah Bijal D. , Wierda William G. , Schiller Gary J. , Bishop Michael Russell , Castro Januario E. , Sabatino Marianna , Bot Adrian , Mardiros Armen , Rossi John , Jiang Yizhou , Navale Lynn , Stout Shanna , Aycock Jeff , Wiezorek Jeffrey S. , Jain Rajul K. 
Published: September 2018

3024 Background: Promising results have been observed with KTE-C19, an anti-CD19 CAR T cell therapy, in refractory aggressive NHL in the ZUMA-1 trial (Blood 2016;128:LBA-6). We present here updated results from the ZUMA-3 phase 1 trial of KTE-C19 in adult patients (pts) with R/R ALL. Methods: Adult (≥18 y) pts with R/R ALL (Ph+ eligible), ≥25% bone marrow (BM) blasts, adequate organ function and ECOG status 0-1 received 1 or 2×106 CAR T cells/kg after conditioning with cyclophosphamide + fludarabine. Phase 1 primary endpoint is incidence of dose-limiting toxicity (DLT). Secondary endpoints include efficacy outcomes and biomarker associations. Results: As of Nov 1, 2016, 11 pts were enrolled; 10 received KTE-C19. One pt had a serious adverse event (SAE) prior to dosing and was not treated. KTE-C19 was successfully manufactured in all pts across a broad range of baseline absolute lymphocyte counts in 6 days in a centralized facility, with an approximate 2-week turnaround time. Pts were 60% men with 1-4 prior lines of therapy and high disease burden (median, 70% BM blasts). No pt (0/3) experienced a DLT at the 2×106 dose. Phase 1 was expanded to 6 pts at the same dose; 1 grade (Gr) 5 AE (multiorgan failure due to cytokine release syndrome [CRS]) was observed. Subsequent pts (4) received 1×106 CAR T cells/kg. Overall, the most common Gr≥3 AEs were cytopenias (80%), febrile neutropenia (50%), pyrexia (40%), and transaminitis (40%). Gr≥3 CRS and neurologic events (NEs) were reported in 20% and 40% of pts, respectively. Cerebral edema was not observed. All CRS (except Gr5) and 5 of 6 NEs (1 Gr3 ongoing at cut-off) resolved. Of the 8 efficacy evaluable pts, 6 achieved an MRD-negative (MRD–) complete response (CR, or CR + partial or incomplete hematopoietic recovery). Updated results will include additional pt follow-up and biomarker data. Conclusions: No DLTs were observed with KTE-C19 in adult pts with high BM disease burden; one pt had G5 CRS after the DLT cohort. Manufacturing was successful in all pts; most pts achieved an MRD– CR. Based on these results, ZUMA-3 continues to enroll pts with additional measures implemented to further enhance safety. Clinical trial information: NCT02614066.
Epitope mapping of PD-L1 primary antibodies (28-8, SP142, SP263, E1L3N).
Authors: Schats Kelly , Van Vre Emily A. , Schrijvers Dorien , De Meester Ingrid , Kockx Mark 
Published: September 2018

3028 Background: Currently, programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) assays received approval in combination with an anti-PD-1 or anti-PD-L1 compounds. However, the FDA blueprint and other publications revealed differences in staining pattern between PD-L1 IHC assays. More precisely the SP142 assay detects less tumor cells (TC), but more immune cells (IC), while the 28-8 assay is more sensitive for TC and less appropriate for IC detection. SP263 stains TC and IC equally well. E1L3N IHC reveals IC and slightly more TC staining than SP142. This study investigates whether these staining discrepancies can be partly explained by specific epitope recognition. Methods: Linear epitope mapping was performed for PD-L1 antibody clones 28-8, E1L3N, SP142 and SP263. In brief, the PD-L1 sequence (Q9NZQ7, Uniprot) was split into 15 amino acid (AA) peptides with a peptide overlap of 14 AA . Each peptide was printed in duplicate on the PD-L1 microarray. The microarray was exposed to different concentration of the four PD-L1 antibodies. For the detection, sheep anti-rabbit IgG DyLight800 was used. Results: Epitope mapping for the E1L3N antibody revealed a linear epitope in the intracellular domain. The other clones showed weaker binding to multiple peptides. The 28.8 clone demonstrated binding to predominantly intracellular epitopes, while SP142 and SP263 clones showed binding to both intracellularly and extracellularly located epitopes. Blasting the epitope sequences of the PD-L1 antibodies did not disclose identity with another (non-PD-L1) human protein. Conclusions: Different binding characteristics were found for all four PD-L1 antibody clones in a linear epitope mapping experiment. This could lead to particular staining patterns depending on PD-L1 conformation (folding) or isoform expression. Two PD-L1 isoforms are known, with isoform 2 lacking AA 19-132 of the extracellular domain. Especially SP142 binding can be impacted in the case of dominant isoform 2 presence, since epitopes were observed in this spliced domain. Further investigation is needed into the potentially conformational epitopes of SP142, SP263 and 28.8 antibody clones as well as in the PD-L1 conformation and isoform expression in TC and IC.
Excision repair cross complementation group 1 (ERCC-1) gene polymorphisms and response to nivolumab in advanced non-small cell lung cancer (NSCLC).
Authors: Aiello Marco M. , Vigneri Paolo Giovanni , Bruzzi Paolo , Verderame Francesco , Paratore Sabrina , Restuccia Nunzio , Albanese Valeria , Soto Parra Hector J. 
Published: September 2018

3032 Background: Anti PD1 antibodies showed significant clinical activity in different cancer types. Recently, it was observed that cancers with higher somatic mutation burden, as tumors with genome instability due to DNA repair defects, develop more elevated anti PD1 induced neoantigen specific T cell reactivity which results into increased susceptibility to PD1 blockade. We hypothesize that NSCLC pts with single nucleotide polymorphisms (SNPs) of the ERCC-1 gene, a key enzyme of DNA nucleotide excision repair pathway, may be more responsive to PD-1 blockade due to their genetic instability. Methods: We evaluated the rs11615 and rs3212986 ERCC1 SNPs by pyrosequencing analysis on tumor DNA of stage IIIb-IV previously treated NSCLC patients receiving Nivolumab (Nivo) 3 mg/kg q2w. To be eligible for this study, pts had to have a complete record of clinical and radiological parameters. Objective tumour response was assessed according to RECIST 1.1 criteria. Results: Between Jul 2015 and Jan 2016, 45 NSCLC pts received Nivo. Pts characteristics were as follows: M/F = 37/8; median age (range) = 64 (38-80); ECOG PS, 0/1/2 = 33/9/3; Stage IIIb/IV = 8/37; sqNSCLC/non sq NSCLC = 11/34; current-former smokers/non-smokers = 40/5; EGFR status, mutant/wildtype/unknown = 4/35/6; median cycles (range) = 12 (1-28). Only two pts presented the rs11615 SNP. 16 pts were positive for the rs3212986 SNP. ORR for all pts was 26.6% (95% CI, 10 to 47). The ORR was significantly higher in NSCLC pts positive for the rs3212986 SNP than for wild-type NSCLC patients (62.5% vs. 6.9%. p = 0.0001). For all pts median PFS was 4.3 mos (95% CI, 1.2 to 7.4)and median OS not-reached. Among pts positive for the rs3212986 SNP, median PFS and OS were 8.2 mos and not-reached respectively. In contrast wild-type patients presented a median PFS of 3.1 mos (HR = 0.21 95% CI, 0.07 to 0.57; p = 0.02) and a median OS of 6.5 mos (HR = 0,403 95% CI = 0,131-1,237 p = 0.11). Multivariate analyses confirmed the effect of rs3212986 SNP after adjustment for age, PS, sex and disease stage for PFS. Conclusions: This study suggests that genetic instability due to tumor ERCC1 SNPs in advanced NSCLC pts may be of value to predict clinical benefit from Nivo.
A phase I study of anti-GPC3 chimeric antigen receptor modified T cells (GPC3 CAR-T) in Chinese patients with refractory or relapsed GPC3+ hepatocellular carcinoma (r/r GPC3+ HCC).
Authors: Zhai Bo , Shi Donghua , Gao Huiping , Qi Xingxing , Jiang Hua , Zhang Yuan , Chi Jiachang , Ruan Huaying , Wang Huamao , Ru Qinhua Cindy , Li Zonghai 
Published: September 2018

3049 Background: HCC was commonly diagnosed and identified as leading causes of cancer death in China. Using a 10% cutoff score, GPC3 was detected in 63.6% of HCCs. Safety and preliminary efficacy of a GPC3 CAR-T was evaluated in 13 Chinese patients (pts) with r/r GPC3+ HCC in a Phase I trial. Methods: Pts between 18 and 70 yrs old with histopathological confirmed r/r GPC3+ HCC, Child-Pugh score≤B7, ECOG≤1, lymphocyte ≥ □0.7 x109, post-transduction positive T cells □ ≥30%, amplification by α CD3/CD28 ≥5 □, and without ascites and HIV infection were enrolled. Eligible pts undergo leukapheresis or whole blood colletion, which further developed into GPC3 CAR-T via lentiviral transduction. Standard release tests were conducted before administering GPC3 CAR-T in pts. Adverse events were graded per NCI CTCAE v.4.03. Efficacy was evaluated per modified RECIST (mRECIST). Results: All 13 pts, who received at least one infusion of GPC3 CAR-T, tolerated the treatment well. No dose-limiting toxicity (DLT) was identified, and only one SAE of grade 3 fever was reported. Preliminary analysis compared the clinical outcomes in pts who received GPC3 CAR-T without lymphodepleting conditioning (LDC) (Group A) vs. with LDC (Group B) at baseline. In Group A (N = 5), all pts developed progressive disease (PD) shortly after received a total infusion of GPC3 CAR-T ranging from 0.92x107 to 8.72 x107 cells/kg. In Group B (N = 8), following the LDC with fludarabine and cyclophosphamide, pts received a total infusion of GPC3 CAR-T ranging from 0.013x107 to 14.68 x107 cells/kg. Except two non-evaluable pts, the best response for the rest 6 pts are 1 PR, 3 SD, 2 PD. As of Feb 1, 2017, the PR pt remains alive for 385 days; 2 SD pts remain alive for 384 and 562 days, respectively; and one SD deceased at 108 days. Also worth to mention, one pt in Group A decided to remain on the study after PD, further received a total of 6.23 x107cells/kg infusions following a LDC given around Day 150, remains stable for 571 days as of Feb 1, 2017. Conclusions: Phase I trial shows GPC3 CAR-T is feasible and safe for Chinese pts with r/r GPC3+ HCC, and holds promising antitumor potential when LDC is applied along with GPC3 CAR-T. Clinical trial information: NCT02395250.
Atezolizumab (A) + cobimetinib (C) in metastatic melanoma (mel): Updated safety and clinical activity.
Authors: Miller Wilson H. , Kim Tae Min , Lee Carrie B. , Flaherty Keith T. , Reddy Sunil , Jamal Rahima , Chow Laura Q. , Rooney Isabelle Anne , Pitcher Bethany , Cha Edward , Infante Jeffrey R. 
Published: September 2018

3057 Background: A, an anti–programmed death-ligand 1 (PD-L1) monoclonal antibody, inhibits PD-L1/programmed death-1 (PD-1) and PD-L1/B7.1 binding and shows promising clinical activity in patients (pts) with cutaneous mel (objective response rate [ORR] 33%; median progression-free survival [mPFS] 5.5 months; Hodi et al SMR 2014). C promotes intratumoral T-cell infiltration, major histocompatibility complex 1 upregulation, and PD-L1 expression via targeted MEK inhibition in preclinical models (Ebert et al Immunity 2016) and tumor biopsy specimens (Bendell et al ASCO 2016). Therefore, clinical benefits may be enhanced by combining A + C vs A. This Phase Ib dose-escalation and -expansion study (NCT01988896) suggested higher ORR/disease control rate (DCR, ORR + stable disease) and longer PFS may be achieved with A + C vs A or C alone in mel. We present updated safety and efficacy data. Methods: Oral C, escalated 20 mg→40 mg→60 mg, was given qd for 21 days followed by 7 days off. Intravenous (IV) A was given at 800 mg q2w. Tumor-specific expansion cohorts were enrolled at maximum tolerated doses (C 60 mg/d 21/7; A 800 mg IV q2w). No prior anti–PD-L1 or –PD-1 therapy was allowed. Results: Data cut-off was Oct 12, 2016; 22 patients were safety-evaluable (two ocular, 20 non-ocular [ten each BRAF-mutant and -wild-type]). Median safety follow-up was 14.4 months (range 2.1–23.2). Adverse events (AEs) were experienced in all pts (diarrhea [20 pts, 90.9%] and rash [15 pts, 68.2%] were most common); related grade (G)3–4 AEs in 54.5% (diarrhea [three pts, 13.6%] and dermatitis acneiform [two pts, 9.1%] were most common; no related G5 AEs); related serious AEs in 13.6%. All were manageable. One pt discontinued A + C due to an AE. RECIST v1.1-confirmed ORR was 45.0% in pts with non-ocular mel (median duration of response was not reached); DCR was 75.0%; mPFS was 12.0 months (95% CI 2.8–not evaluable). ORR was similar for pts with BRAF-mutant and wild-type mel. Conclusions: Updated results confirm previous findings that suggest higher ORR/DCR and longer PFS may be achieved with A + C vs A or C monotherapy for mel. Together with biomarker data from other cohorts, our data suggest that the immune contexture may be altered by C, enhancing A activity. Clinical trial information: NCT01988896.