bluuebunny/crossref_metadata_2025 huggingface dataset:
Osimertinib for patients (pts) with leptomeningeal metastases (LM) from EGFR-mutant non-small cell lung cancer (NSCLC): Updated results from the BLOOM study.
Authors: Yang James Chih-Hsin , Cho Byoung Chul , Kim Dong-Wan , Kim Sang-We , Lee Jong-Seok , Su Wu-Chou , John Tom , Kao Stephen Chuan-Hao , Natale Ronald , Goldman Jonathan Wade , Overend Philip , Vishwanathan Karthick , Ye Xin , Yang Zhenfan , Ahn Myung-Ju
Published: September 2018

2020

Background: LM due to NSCLC progression are associated with poor prognosis. Osimertinib is an oral, CNS-active, irreversible EGFR-TKI selective for sensitizing (EGFRm) and T790M resistance mutations. Methods: In the BLOOM study (NCT02228369), pts with EGFRm advanced NSCLC who had progressed on prior EGFR-TKI therapy and had LM confirmed by positive cerebrospinal fluid (CSF) cytology received osimertinib 160 mg once daily (qd). Response was assessed (by investigator) in 2 cohorts: T790M unselected and T790M positive (by central test); results are presented as a combined analysis set. Analyses were based on CSF cytology, brain MRI imaging, and neurological examination every 6 weeks (wk; relative to first dose) until progression. Adverse events (AEs) were graded according to CTCAE. EGFR-mutant DNA in CSF was determined by ddPCR. Plasma and CSF samples were collected for PK analyses. Results: As of 24 Sep 2016,32 pts had received treatment: 21 T790M unselected; 11 T790M positive. Max treatment duration was 17.5 months (m; median 6.0 m); 21 pts ongoing. 23/32 pts had a 12-wk brain image assessment: 10 had radiological improvement, 13 had stable disease (SD). The same 23 pts had a 12-wk neurological assessment: of 8 symptomatic pts, 7 improved, 1 had SD; of 15 asymptomatic pts, 2 worsened, 13 remained asymptomatic. The geometric mean decrease in EGFR-mutant DNA copy was 57% (95% CI 30, 74) in 22 pts with pre-dose and Cycle 2 Day 1 CSF samples. Most common AEs were skin effects (n = 20), diarrhea (n = 13), nausea (n = 11) and paronychia (n = 9). All were grade (G) 1/2 except 1 case each of diarrhea and nausea (both G3). 9 pts had dose interruptions and 4 had dose reductions to 80 mg qd. Osimertinib mean concentration in CSF was 7.51 nM (range 2.19–21.1 nM) at steady state (N = 16); CSF:free plasma ratio: 16%. Accrual is now complete (n = 41; 21 T790M unselected, 20 T790M positive) and updated data (including overall survival) will be presented. Conclusions: Osimertinib penetrates the blood-brain barrier. Encouraging activity and manageable tolerability in pts with LM from EGFRm NSCLC was observed at 160 mg qd, with a median treatment duration of 6.0 m; continued evaluation is ongoing. Clinical trial information: NCT02228369.
Comprehensive assessment of ATRX mutation, protein expression, and alternative lengthening of telomeres (ALT) phenotype in grade II and III gliomas.
Authors: Becker Aline P. , Bell Erica Hlavin , Fleming Jessica , McElroy Joseph P , Fabian Denise , Beyer Sasha , Salavaggione Andrea L , Graham Mindy K , Heaphy Christopher M , Oehlke Oliver , Staszewski Ori , Prinz Marco , Grosu Anca , Chakravarti Arnab
Published: September 2018

2064

Background: ATRX mutations are key molecular markers for classification of gliomas. We aimed to evaluate ATRXmutations and protein expression and the ALT phenotype as potential biomarkers for grade II and III gliomas. Methods: Retrospective analysis of 156 adult gliomas, with long-term follow up. Gene sequencing ( IDH1/2 and ATRX), Oncoscan array (1p19q co-deletion), FISH assays (1p19q co-deletion and ALT phenotype) and immunohistochemistry (IDH1 R132H and ATRX) were performed and the results were correlated with OS and PFS. Results: Twenty-six out of 94 samples (27.7%) had ATRX mutations, commonly related to IDH1/2 mutant-1p/19q intact tumors (22/26 cases – p < 0.0001), however, 3 (11.5%) mutant tumors had concurrent 1p/19q co-deletions. ATRX loss of expression occurred in 66/150 cases (44%), consistently related to ATRX mutations (p < 0.0001). Intriguingly, 4/25 ATRX mutant tumors (2 frameshift and 2 point mutations with low/medium functional impact) showed weak/heterogeneous expression, while 18/65 (27.7%) ATRX wild type tumors had loss of protein expression. ALT phenotype was detected in 50/150 cases (33.3%), strongly related to ATRX mutations (23/32 cases), loss of protein expression (45/50 cases), and to IDH1/2 mutant-1p/19q intact tumors (35/41 cases). Two ATRX mutant tumors were ALT negative, while nine ATRX wild type tumors with loss of expression had ALT phenotype. ATRXmutations, loss of protein expression, and ALT phenotype were strongly related to longer OS in grade III gliomas (p = 0.006, 0.023 and 0.003, respectively). Further subset analyses were not completed due to small sample sizes. Conclusions: ATRX mutations and loss of protein expression as well as ALT phenotype are potential prognostic factors for grade III gliomas. Importantly, this study highlights possible discrepancies (although infrequent) between ATRX sequencing, immunohistochemistry, and FISH (ALT). In addition, other mechanisms of ATRX gene silencing should be further investigated in grade II and III gliomas. FUNDING: R01CA108633, R01CA169368, RC2CA148190, U10CA180850-01 (NCI), Brain Tumor Funders Collaborative Grant, and The Ohio State University CCC (all to AC).
First-in-class oral ERK1/2 inhibitor Ulixertinib (BVD-523) in patients with advanced solid tumors: Final results of a phase I dose escalation and expansion study.
Authors: Li Bob T. , Janku Filip , Patel Manish R. , Sullivan Ryan J. , Flaherty Keith , Buchbinder Elizabeth Iannotti , Lacouture Mario E. , Varghese Anna M. , Wong Deborah Jean Lee , Sznol Mario , Sosman Jeffrey Alan , Keedy Vicki Leigh , Wang-Gillam Andrea , Ribas Antoni , Tolcher Anthony W. , Patel Sapna Pradyuman , Varterasian Mary Laura , Welsch Dean , Hyman David Michael , Infante Jeffrey R.
Published: September 2018

2508

Background: Aberrant MAPK pathway activation is known to be an oncogenic driver in many solid tumors, making ERK inhibition an attractive therapeutic strategy. Ulixertinib is an oral ERK1/2 inhibitor that demonstrated potent activity in vitro and tumor regression in BRAF and RAS mutant xenograft models. Methods: This multi-center phase I trial enrolled patients (pts) with advanced solid tumors. Dose escalation utilized an accelerated 3+3 design; expansion cohorts included BRAF or NRAS mutant melanoma and other BRAF or MEK mutant cancers. Study objectives were to characterize dose limiting toxicities (DLTs), maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, pharmacodynamics and preliminary anti-tumor activity by RECIST 1.1. Results: A total of 135 pts were enrolled. Dose escalation enrolled 27 pts (10-900 mg BID) and established the MTD and recommended phase 2 dose (RP2D) of 600 mg BID. DLTs included rash, diarrhea, elevated AST, and elevated creatinine. Drug exposure was dose proportional up to the RP2D, which provided near-complete inhibition of ERK activity in whole blood. In the 108 pt expansion cohort, there were no drug related deaths; however, 32% of pts required a dose reduction. The most common adverse events were rash (49%), diarrhea (47%), fatigue (41%), and nausea (37%). In addition to 3 pts with partial responses during escalation (11%), an additional 9 of 83 (11%) evaluable pts at expansion had a partial response: 1 melanoma pt refractory to prior BRAFi/MEKi treatment, 3 NRAS mutant melanoma pts, 2 pts with BRAF V600E mutant lung cancers including response in brain metastases, 1 with BRAF V600E mutant glioblastoma multiforme, 1 with BRAF G469A head & neck cancer, and 1 with BRAFL485W gallbladder cancer. The duration of response ranged from 2 to 24+ months. Conclusions: Ulixertinib at 600 mg twice a day has an acceptable safety profile and has produced durable responses in pts with NRAS mutant melanoma, BRAF V600 and non-V600 mutant solid tumors including melanoma, glioblastoma multiforme, lung cancers with brain metastases, gallbladder and head & neck cancers. These data support further clinical development of ulixertinib. Clinical trial information: NCT01781429.
Preliminary results from a phase 1 study of the antibody-drug conjugate ABBV-221 in patients with solid tumors likely to express EGFR.
Authors: Calvo Emiliano , Cleary James M. , Moreno Victor , Gifford Maryella , Roberts-Rapp Lisa , Ansell Peter J , Mittapalli Rajendar K. , Lee Ho-Jin , Hu Beibei , Barch David , Ocampo Christopher Joseph , Tolcher Anthony W.
Published: September 2018

2510

Background: ABBV-221 is a 2nd-generation antibody-drug conjugate (ADC) targeting EGFR based on the 1st-generation ADC ABT-414. ABT-414 shows efficacy in glioblastoma (GBM) patients (pts) with EGFR amplification in ongoing studies. ABBV-221 is an affinity matured monoclonal antibody against EGFR linked to the toxin MMAE. ABBV-221 has higher affinity for overexpressed EGFR than ABT-414, potentially allowing it to target a broader range of tumor types. Methods: This is a Phase 1, multicenter study to determine maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) of ABBV-221. Pts are required to have an EGFR-dependent cancer to be eligible. Starting dose of ABBV-221: 0.3 mg/kg IV infused over 3 hrs for each 21-day cycle, with alternate dosing schedules utilized (2 wks on, 1 wk off or weekly) to mitigate infusion reactions. Results: As of 11 January 2017, 42 pts were treated (13 colon, 5 head & neck (H&N) cancer, 5 non-small cell lung cancer, 5 GBM, 2 breast, 12 other). Ten dose escalation cohorts have been completed with the last cleared dose 4.5 mg/kg per cycle. Tumor tissue samples were evaluated for EGFR protein expression by IHC, EGFR and EGFR ligand mRNA expression by RNAseq, and the results compared to outcome. The most common adverse event (AE) was infusion reaction in 18/42 pts (43%); 3 pts experienced severe infusion reactions. Several mitigation strategies were used to permit continued dose escalation. The other most common AE was fatigue in 17/42 pts (41%). Only 1 pt had keratitis (Grade 4). Sixteen pts (38%) had stable disease (SD), including 4 pts who remained on study longer than 6 months. One H&N pt who has received 2 cycles of ABBV-221 had an unconfirmed partial response and continues to be treated. This pt had high levels of both EGFR and EGFR ligand. Preliminary pharmacokinetics (PK) analysis suggests ABBV-221 exposures are approximately dose-proportional. Conclusions: Safety, PK, pharmacodynamics, and preliminary efficacy data of ABBV-221 warrant further study in this population. Infusion reactions have been manageable and primarily a first dose phenomenon. The duration of SD in pts with refractory solid tumors is encouraging. Clinical trial information: NCT02365662.
A phase I study of PT-112 in advanced solid tumors.
Authors: Karp Daniel D. , Camidge D. Ross , Bryce Alan Haruo , Jimeno Jose , Infante Jeffrey R.
Published: September 2018

2519

Background: PT-112 is a novel platinum-pyrophosphate agent designed to avoid the toxicity and drug resistance mechanisms of conventional chemotherapy. Pre-clinical models show effects on multiple cell signaling components: p16 mediated G1/S cell cycle arrest; modulation of MDM2/p53 expression; extrinsic apoptosis initiation; and immunogenic cell death (ICD) induction. This Phase I first-in-human, multicenter, open label study assesses PT-112’s safety and pharmacokinetic (PK) profile in advanced solid tumor patients (pts), to determine the RP2D and signals of activity. Methods: Pts with advanced solid tumors and acceptable marrow / organ function received PT-112 IV over 1-hr on days 1, 8, and 15 every 4 wks in a 3+3 dose escalation design. Intra-subject escalation was allowed. PK samples from cycles 1-2 were analyzed by ICP-MS and LC-MS/MS. Results: 44 pts have been treated across dose levels (DL) from 12-300mg/m2. Cumulative dosing ranged from 1 to 60 infusions, and cumulative exposure from 96 to 5,244 mg/m2. PK parameters were dose proportional. Target Cmax and AUC levels were achieved, with constant VD. DLTs were observed at 150mg/m2 (G3 pancytopenia); 250mg/m2 (G2 renal injury in a cervical ca pt with hydro-nephrosis); and 300mg/m2 (G3 rash). The most common treatment-related AEs were G1-2 fatigue (26% pts), nausea (23%), vomiting (14%), constipation (12%), and diarrhea (12%). Numerous signals of activity were observed at DLs ≥ 125mg/m2. These include a confirmed PR in a NSCLC pt with 6 prior lines of therapy and no response to TKI inhibition or PD-1 blockade; PFS > 6 months (7-18 months) in 3 pts; metabolic response via PET scan in bone and liver mets (basal cell and pancreatic ca.); biomarker responses in ovarian and prostate ca.; and nodal/metastatic volumetric reduction in 3 pts. Conclusions: PT-112 is a well-tolerated novel agent with a pleiotropic mode of action and feasibility for long-term and combination treatment. Numerous signals of anti-cancer efficacy in heavily pre-treated pts suggest lack of cross-resistance with conventional agents. MTD has not yet been reached. PT-112’s profile makes it an attractive candidate for further development, including in combination with immunotherapy. Clinical trial information: NCT02266745.
Dose escalation results from a first-in-human, phase 1 study of the glucocorticoid-induced TNF receptor-related protein (GITR) agonist AMG 228 in patients (Pts) with advanced solid tumors.
Authors: Tran Ben , Carvajal Richard D. , Marabelle Aurelien , Patel Sandip P. , LoRusso Patricia , Rasmussen Erik , Juan Gloria , Upreti Vijay V. , Ngarmchamnanrith Gataree , Schöffski Patrick
Published: September 2018

2521

Background: AMG 228 is an agonistic human IgG1 monoclonal antibody that binds to GITR (CD357), a TNFSFR costimulatory molecule expressed by effector/regulatory T cells. Dose escalation of this open label, first in human, phase 1 study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and maximum tolerated dose (MTD) and recommended phase 2 dose of AMG 228 in pts with advanced solid tumors. Methods: Pts with refractory advanced colorectal cancer (n = 13), squamous cell carcinoma of head and neck (n = 10), non–small cell lung cancer (n = 2), urothelial transitional cell carcinoma (n = 4), and melanoma (n = 1) received AMG 228 IV Q3W. Dose escalation was in two stages: single-pt cohorts until AMG 228-related grade > 2 adverse events (AEs), efficacy, or 90 mg dose reached (4 cohorts: 3, 9, 30, and 90 mg), followed by rolling six design (n = 2 to 6) until MTD or highest planned dose of 1200 mg reached (5 cohorts: 180, 360, 600, 900, and 1200 mg). Primary endpoints included incidence of dose-limiting toxicities (DLTs) and AEs and PK. Additional endpoints were objective response (RECIST 1.1) and evidence of biological activity. Results: In total, 30 pts (median age 63 y) were treated (3, 9, 30, and 90 mg, n = 1; 180 mg, n = 6; 360 mg, n = 4; 600 mg, n = 6; 900 mg, n = 4; 1200 mg, n = 6). Twenty-seven (90%) pts had treatment-emergent AEs; the most common were hypophosphatemia (23%), fatigue (23%), anemia (23%), nausea (20%), and pyrexia (20%). No DLTs occurred; the MTD was not reached. AMG 228 exposure was dose-related, with PK profiles at low doses (3 to 90 mg) consistent with target mediated drug disposition; doses > 360 mg achieved serum levels needed for 95% receptor occupancy on activated PBMCs. No evidence of T cell activation was observed despite complete target coverage in both tumor and peripheral blood. Among 29 evaluable pts, none had an objective response. Conclusions: In this population of pts with advanced solid tumors, AMG 228 Q3W was tolerable up to the highest tested dose (1200 mg), showing favorable PK. However, no clinical or immunological activity was observed in this limited number of pts. Clinical trial information: NCT02437916.
A phase I study of LY3022855, a colony-stimulating factor-1 receptor (CSF-1R) inhibitor, in patients (pts) with advanced solid tumors.
Authors: Dowlati Afshin , Rugo Hope S. , Harvey R Donald , Kudchadkar Ragini Reiney , Carvajal Richard D. , Manji Gulam Abbas , Hamid Omid , Klempner Samuel Jacob , Tang Shande , Yu Danni , Kauh John S. , Schaer David Arlen , Tate Sonya Catherine , Wesolowski Robert
Published: September 2018

2523

Background: Binding of CSF-1 to the CSF-1 receptor (CSF-1R) results in proliferation, differentiation, and migration of monocytes/macrophages. Intratumoral infiltration with macrophages correlates with increased invasiveness, growth, and immunosuppression. LY3022855 (LY) is a human IgG1 antibody (mAb) targeting CSF-1R. Methods: Eligible pts (ECOG 0-2) with advanced solid tumors were enrolled. Mandatory pre and post-treatment biopsies were obtained. LY was given on a 6-week cycle. Two escalation regimens (Part A: weight-based dosing; Part B: flat dosing) were investigated in a 3+3 design. Primary objective was to establish the safety and characterize the pharmacokinetics (PK) of LY. Secondary objectives were to establish recommended phase 2 dose (RP2D) and to characterize pharmacodynamics (PD). Results: As of Sept 6, 2016, 35 cancer pts (colorectal 14; lung 4; pancreas 3; others 14) were treated (29 in Part A; 6 in Part B) with median treatment duration 4 weeks (range 1-21). Common treatment-emergent adverse events (TEAEs) were fatigue (54%), hypoalbuminemia (40%), nausea (37%), AST increase (37%), anemia (34%), anorexia (34%), creatine kinase elevation (29%), and constipation (23%). Most common grade (G) 3/4 TEAEs were anemia (11%), fatigue (11%), ascites (9%), and lymphocyte count decrease (9%). 3/28 evaluable pts had DLTs: G3 left ventricular systolic dysfunction (1), G4 rhabdomyolysis and G4 acute renal failure (1), and G3 pancreatitis (1). Eight treatment unrelated deaths were reported. One pt (adenoid cystic carcinoma) had stable disease (~3 mo as of last visit), 19 pts had progressive disease, and 15 pts were non-evaluable for response assessment. PK profile of LY was consistent with IgG1 mAbs. An interim analysis following completion of Part A demonstrated a lack of relationship between weight and clearance, prompting evaluation of non-weight based dosing. PD analyses revealed dose-dependent increases in serum CSF-1 levels as well as suppression of circulating non-classical monocytes (CD14dim CD16bright), indicating biologic activity at studied doses. Conclusions: RP2D for LY monotherapy has been determined. Detailed PK and PD data will be presented. Clinical trial information: NCT01346358.
A call for global harmonization of phase I oncology trials: Results from two parallel, first-in-human phase I studies of DS-7423, an oral PI3K/mTOR dual inhibitor in advanced solid tumors conducted in the United States and Japan.
Authors: Yokota Tomoya , Bendell Johanna C. , LoRusso Patricia , Tsushima Takahiro , Desai Ved , Kenmotsu Hirotsugu , Watanabe Junichiro , Ono Akira , Murugesan Bhavani G. , Silva Joseph , Naito Tateaki , Greenberg Jonathan , Kumar Prasanna , Wang Yibin , Jikoh Takahiro , Shiga Ryota , Ho Alan Loh , Gounder Mrinal M.
Published: September 2018

2536

Background: The aim of this study was to determine the safety, maximum-tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of DS-7423, a novel inhibitor of PI3K/mTOR, in US and Japanese population. We further compared toxicities and recommended phase 2 dose (RP2D) of DS-7423 and approved oncology drugs in the two populations. Methods: We conductedparallel, first-in-human studies in US and Japan in patients with advanced solid tumors. We conducted a Pubmed search of pivotal and corresponding phase I studies to compare the RP2D and final approval doses of molecularly targeted agents (MTA) between US and Japan. Results: 69 patients were enrolled (n = 42 from US and n = 27 from Japan). Between populations, the only difference at baseline was body weight (BW) and body mass index (BMI). Dose-limiting toxicities included grade 3 rash (48 mg), grade 3 stomatitis (240 mg), grade 3 lung infection (240 mg), grade 4 hyperglycemia (240mg), grade 3 fatigue (320 mg), and grade 3 dehydration (320mg). The MTD and RP2D was 240 mg/d in both populations. Frequent treatment-related adverse events included diarrhea, fatigue, decreased appetite, rash, and stomatitis. No remarkable difference in AUC and Cmax were observed between populations. Prolonged stable disease was seen in cholangiocarcinoma, thymic cancer, non-small cell lung cancer, squamous cell carcinomas, carcinoid, and sarcoma. DS-7423 demonstrated PD effects on serum glucose, C-peptide and Akt phosphorylation and 18F-FDG uptake in tumors. The final RP2D of 17 MTA approved in US and Japan from 2001 to 2015 was near identical. The approved doses in both regions were identical. Conclusions: Despite differences in BW, BMI, and ethnicity, DS-7423 showed no difference in PK, PD, toxicity or efficacy between populations. We found near identical RP2D in phase I oncology studies and approved doses in pivotal studies. This supports increased international collaboration in the conduct of phase I oncology trials. Clinical trial information: NCT01364844, Japic CTI, 12766.
Suitability factors of core needle biopsies for pharmacodynamic (PD) studies.
Authors: Parchment Ralph E. , Ferry-Galow Katherine , Makhlouf Hala R. , Wood Brad J. , Levy Elliott B. , Krishnasamy Venkatash P. , Chang Richard , O'Sullivan Coyne Geraldine H. , Meehan Robert S. , Kinders Robert J. , Doroshow James H. , Chen Alice P.
Published: September 2018

2540

Background: There are different requirements of biopsies for diagnosis vs. pharmacologic evaluation of drug mechanism biomarkers. Evaluation of core needle biopsy pairs collected pre-dose and at a defined timepoint post-dose provides insight into the pharmacodynamics of agents in early development. Adequate biopsies are key for quantifying response of the tumor cell population to molecular drug action. Tumor heterogeneity and variable tumor content make many biopsy pairs unsuitable for biomarker evaluation with any assay platform (microscopy, immunoassay, etc.). We analyzed biopsies obtained from the Developmental Therapeutics Clinic (DTC) for suitability for PD assays. Methods: Specimens obtained from 2010-2016 across 4 trials were analyzed. For microscopy measurements, biopsy pairs collected using image guidance are snap-frozen, thawed under fixative, and embedded in paraffin with control tissues. The likelihood of finding optimal regions for analysis is maximized by preparing a series of sections with H&E stained flanking slides, and annotation by an anatomic pathologist. Results: Of 112 biopsies evaluated, 26% were found to contain < 5% tumor, making them inadequate for quantitative microscopy due to a mixture of factors, with the primary factor being predominantly non-neoplastic tissue, followed by extensive mucin content, necrosis, fibrosis, inadequate size and tissue artifact post-collection. Another 20% contained ≤25% tumor, and in this group, tumor segmentation methodology during image analysis increased the rate of evaluable biopsies. 56% of tissues had > 25% tumor and were suitable for analysis. Conclusions: Improved communication between oncologists, radiologists and pathologists is key to a better understanding of factors that affect suitability of biopsies for robust PD biomarker analyses. NCI’s DTC has implemented protocol modifications including increased tissue collection and frequent case reviews by the Phase 1 team, interventional radiologists and PD team aimed at understanding features during image guidance that relate to suitability. Implementation of a scoring system has allowed the assessment of suitability of biopsies for analysis. Funded by NCI Contract No HHSN261200800001E.
Pharmaco-kinetics/dynamics (PK/PD) evaluation and individual patient cross-over studies with growth trajectory assessment to adaptively develop ilorasertib.
Authors: Maitland Michael L. , Sharma Manish , Zhao Binsheng , McKee Mark D. , Karovic Sanja , Thomeas Vasiliki , McIver Malcom , Yang Hao , Piha-Paul Sarina Anne , Falchook Gerald Steven , Karrison Theodore , Kurzrock Razelle , Janisch Linda A. , Hoening Elizabeth , Wong Shekman , Munasinghe Wijith , Ansell Peter J , Ratain Mark J. , Schwartz Lawrence H. , Hong David S.
Published: September 2018

2563

Background: We evaluated PK/PD of the AURK B/VEGFR2 inhibitor ilorasertib. To detect activity in CDKN2A-deficient tumors, we measured changes-in-tumor-burden by CT-volume before, during, and after discontinuation of therapy. Methods: Study 1: open-label, dose-escalation, phase 1 in 58 patients (pts) with advanced solid tumors. Arms I, II, and III assigned: 23 pts (10–180 mg oral QD), 28 pts (40–340 mg oral BID), and 7 pts (8–32 mg i.v. QD), to ilorasertib monotherapy Days 1, 8, and 15 every 28 days. We evaluated PK/PD for validated biomarkers: change-in-diastolic blood pressure (ΔDBP), change-in-plasma [PlGF] (ΔPlGF), and change-in phosphorylated histone H3 (Δ%pHH3) in skin biopsies. Study 2: open-label trial, of 10 solid tumor pts with CLIA-lab-detected CDKN2A disruption. Pts received ilorasertib 250 mg oral BID on same schedule. On CT images collected prior to screening, and ~ study days -7, 49, and 98 individual lesion volumes were determined by central lab semi-automated segmentation algorithms on DICOM files. Pts who tolerated ilorasertib with RECIST-stable disease at day 98 discontinued ilorasertib for 42 days and underwent re-imaging before restarting ilorasertib. Results: Study 1: the DLTs and frequent adverse events reflected VEGFR2 inhibition. PK/PD analysis showed peak VEGFR2 inhibition on ΔDBP and ΔPlGF at lower systemic concentrations than for peak AURKB-inhibition detected with Δ%pHH3. Two pts in Arm II had partial response; one had homozygous deletion of CDKN2Aby FISH. Pre-clinically the CDKN2A-deficient cell lines (OVCAR5, MDA MB 231, A549) were among the most ilorasertib-sensitive. At time of submission, Study II enrolled 10 pts, with 5 evaluable for longitudinal tumor burden assessments. Three pts had sustained negative growth trajectories after ilorasertib therapy; one of these had positive growth after cessation of treatment but restabilization of disease after restarting ilorasertib. Conclusions: The development plan adapted to the in-human PK/PD assessment. We prospectively conducted individual change-in-tumor burden cross-over studies to assess clinically the sensitivity of CDKN2A-deficient tumors. Clinical trial information: NCT02540876 and NCT01110486.
A phase 1 dose escalation study of eFT508, an inhibitor of mitogen-activated protein kinase-interacting serine/threonine kinase-1 (MNK-1) and MNK-2 in patients with advanced solid tumors.
Authors: Falchook Gerald Steven , Infante Jeffrey R. , Meric-Bernstam Funda , Miller Langdon L. , Morison Karen , Vallner Debra , Sperry Sam , Goel Vikas , Chiang Gary Gene , Webster Kevin , Barton Jeremy , Patel Manish R.
Published: September 2018

2579

Background: Dysregulated translation of messenger RNA (mRNA) plays a role in the pathogenesis of multiple solid tumors. eFT508, a potent and highly selective small molecule inhibitor of MNK-1 and 2 blocks activation of eIF4E, a key regulator of mRNA translation, and thereby selectively regulates translation of a small set of mRNAs. In addition to direct antitumor activity, eFT508 triggers an anti- tumor immune response and enhances responses to checkpoint inhibitors in preclinical models. Methods: Using a 3+3 dose escalation schema, cohorts of solid tumor patients (pts) were treated with eFT508 administered orally once daily at doses ranging from 50 mg to 600 mg. Results: 28 pts were treated, and the most common tumor types were colorectal cancer (8), prostate cancer (3), and soft tissue sarcoma (3). Median number of prior therapies was 4. The most common observed adverse events (AEs) included nausea (47%), vomiting (47%), dyspepsia (23%), fatigue (20%), and constipation (20%). Two pts treated at 600 mg experienced Gr 3 related AEs, including one pt with Gr3 nausea and vomiting (met criteria for dose limiting toxicity) and one pt with reversible Gr3 AST/ALT elevation. 6 pts achieved stable disease with duration ranging from 82 to 196 days. Pharmacokinetic analysis revealed that eFT508 is bioavailable and rapidly absorbed, with median Tmax of 2 hours and a mean T1/2 of 12 hours. Minimal accumulation was observed between Days 1 and 14/15, with mean accumulation factor of 1.2-fold. Analysis of eIF4E phosphorylation in peripheral blood cells suggested that doses ≥ 300 mg achieved engagement sufficient for maximal efficacy as predicted by preclinical models. Conclusions: Preliminary results suggest that eFT508 is well tolerated, and dose escalation continues with a cohort of pts providing pretreatment and on treatment biopsies for evaluation of target engagement and immunomodulatory effects. After determination of the recommended phase 2 dose, further evaluation will include monotherapy cohorts in specific tumor types as well as cohorts to evaluate efficacy and tolerability in combination with checkpoint inhibitors. Clinical trial information: NCT02605083.
Phase I dose escalation study of CVM-1118, a novel anti-vascular mimicry agent, in patients with advanced cancers.
Authors: Tolcher Anthony W. , Su Wu-Chou , Lakhani Nehal , Gutheil John , Melink Teresa J. , Chu Yi-Wen , Chen Yen-Ling , Chien Du-Shieng
Published: September 2018

2580

Background: CVM-1118 is an oral NCE that demonstrated potent anti-tumor effects in several tumor xenograft models, via multiple MOAs including induction of cancer cell cycle arrest and apoptosis, and reducing vasculogenic mimicry (VM) network formation in cancer cells, providing a promising therapeutic means in the treatment of malignant tumors that have metastatic potential. Methods: Patients with advanced tumors are being enrolled into 2 ongoing open-label Phase I dose escalation studies in both US (CVM-001) and Taiwan (CVM-002) to evaluate ethnic differences in drug responses. CVM-1118 capsules are administrated orally QD/BID in a 28-day cycle for 4 cycles. The primary objectives are to evaluate the safety, tolerability and pharmacokinetics (PK) and establish the Recommended Phase 2 Dose (RP2D). The secondary objective is to evaluate the therapeutic response after receiving treatment. Beyond 4 cycles, patients showing clinical benefit with CVM-1118 may enter extension cohort to continue the treatment. Results: To date, 28 pts (16 M/12 F)received CVM-1118 across 6 dose levels (50 to 800 mg daily). Median number of days was 52 (range 2 to 135). For CVM-001, 2 DLTs (grade 5 dehydration and grade 3 fatigue) were reported at cohort 6 (800 mg/daily) and the MTD is currently under evaluation. For CVM-002, 3 cohorts (100 to 400 mg/daily) have been completed without DLT. Enrolment to cohort 5 (600 mg/daily) is in progress. From both studies, the most common drug-related AEs included manageable diarrhea, nausea, and vomiting. Rapid oral absorption was observed with Tmax < 2 hr. Bioconversion to active metabolite, CVM-1125, occurred rapidly and the drug exposure increased with increasing dose levels. However, patients in US study showed higher drug exposure than those in Taiwan study. Two patients at 200 mg/daily cohort in Taiwan completing 4-cycle treatment and showing stable disease continued into extension cohort with higher dose. Conclusions: In this ongoing study, Asian patients in Taiwan appear to have better tolerance for CVM-1118 than those in US, likely due to lower drug exposure at same dose level, and some patients have experienced clinical benefit. Clinical trial information: NCT02507544; NCT02703298.
Proof-of concept phase I study of everolimus, letrozole and trastuzumab in hormone receptor-positive, HER2-positive/amplified or mutant metastatic breast cancer or other solid tumors: Evaluating synergy and overcoming resistance.
Authors: Pant Shubham , Wheler Jennifer J. , Fu Siqing , Hong David S. , Karp Daniel D. , Subbiah Vivek , Tsimberidou Apostolia Maria , Holley Veronica R. , Brewster Abenaa M. , Koenig Kimberly Higginbotham , Ibrahim Nuhad K. , Murthy Rashmi Krishna , Meric-Bernstam Funda , Janku Filip
Published: September 2018

2583

Background: Preclinical models suggested synergistic antineoplastic activity of anti-estrogen therapy with HER2 and mTOR inhibitors. Methods: We designed a 3+3 dose escalation phase I study of the aromatase inhibitor letrozole 2.5mg PO daily, mTOR inhibitor everolimus 2.5-10mg PO daily and HER2 antibody trastuzumab 4-8mg loading dose followed by 2-4mg maintenance dose IV on day 1 of 21-day cycle in patients with hormone-receptor positive, HER2-positive/amplified or mutant advanced cancers (confirmed by immunohistochemistry and/or FISH and/or next-generation sequencing). The primary objectives were to determine maximum tolerated dose (MTD), dose limiting toxicities (DLT), overall safety and response. Results: A total of 18 patients (men, 1; women, 17; HER2 amplification, 14; HER2 mutation, 4; breast cancer, 15; ovarian cancer, 1; cervical cancer, 1; gastroesophageal junction cancer, 1), median age 56 years, median of 6 prior therapies (including letrozole [9] or other aromatase inhibitor [8]; everolimus [3]; trastuzumab [14] or other HER2 targeted therapy [1]) were enrolled in the planned 6 dose levels. The MTD has not been reached and grade 3 (G3) mucositis at the dose level 4 was the only DLT. Other G3 or G4 drug-related toxicities included G4 hyperglycemia in 1 patient, G3 hyperglycemia in 3 patients, G3 thrombocytopenia in 1 patient, G3 anemia in 1 patient and G3 headache in 1 patient. Of 18 patients, 3 (17%) had a partial response (all with heavily-pretreated breast cancer with HER2 amplification [2] or HER2A775_G776insYVMA mutation [1]), 11 (61%) stable disease (SD) including 7 (39%) patients with SD > 6 months (all with heavily-pretreated breast cancer), 3 (17%) progressed and 1 had pending evaluation. The median change in size of target lesions per RECIST 1.1. was -11% (-68% to +47%). Median progression-free survival was 9 months (95% CI 5.8-12.2). Conclusions: The combination of letrozole, everolimus and trastuzumab is well tolerated with encouraging activity in heavily-pretreated patients with HER2-amplified or mutant advanced breast cancer. Clinical trial information: NCT02152943.
Phase I study combining the aurora kinase A (AURKA) inhibitor alisertib (Ali) with mFOLFOX in gastrointestinal (GI) cancer.
Authors: Goff Laura Williams , Azad Nilofer Saba , Stein Stacey , Whisenant Jennifer , Vaishampayan Ulka N. , Hochster Howard S. , Connolly Roisin M. , Weise Amy M. , LoRusso Patricia , El-Rifai Wael , Berlin Jordan
Published: September 2018

2593

Background: Overexpression and cellular mis-localization of AURKA in GI cancers results in chromosomal instability, activation of several oncogenic pathways, and inhibition of pro-apoptotic signaling. Inhibition of AURKA causes mitotic delays, severe chromosome congression, and activation of p53/p73 causing cell death. Our preclinical data showed synergy of Ali and platinum agents in GI cells and xenografts, and suggested an optimal timing window of the combination. The purpose of this study was to assess safety of Ali + mFOLFOX, as this is a standard platinum-based therapy for GI cancers. Methods: This CTEP-sponsored, investigator-initiated, study (NCT02319018) used standard 3+3 dose escalation to determine the maximum tolerated dose (MTD) of Ali + mFOLFOX. Eligible patients (pts) had metastatic or unresectable GI cancer where standard therapies did not exist or were no longer effective, or for whom FOLFOX was appropriate. Pts received escalating doses of Ali starting at 10 mg twice daily (D1-3), with leucovorin + oxaliplatin (85 mg/m2) on D2 followed by continuous 5FU (2400 mg/m2) infusion on D2-4 in 14-day cycles. Dose-limiting toxicity (DLT) was any treatment-related non-hematologic ≥Gr3 toxicity (except diarrhea or nausea, vomiting, controllable with meds) or ≥Gr4 hematologic toxicity observed during the first 28 days. Results: 13 pts were enrolled and 2 dose levels explored; 2 pts were not evaluable for DLT and replaced. Zero DLTs observed in first 3 pts. Ali was escalated to 20 mg where 2/6 had a DLT [Gr3 fatigue (n = 2); Gr3 nausea, vomiting, dehydration with hospitalization (n = 1)]. Ali was de-escalated and 2 of 3 pts have been enrolled; 0 DLTs observed thus far. Most frequent toxicities (%) were nausea (54), fatigue (46), neuropathy (46), anorexia (38), and anemia (38), most ≤Gr2. One of 10 evaluable pts had a partial response, and 6 had stable disease for a 70% disease control rate. Conclusions: The MTD will be 10 mg Ali (D1-3) + oxaliplatin (D2, 85 mg/m2) + continuous 5FU (D2-4, 2400 mg/m2). The combination was tolerable, and preliminary clinical activity was seen in a majority of pts. Correlative biomarker studies to evaluate AURKA target inhibition are ongoing and will be reported. Clinical trial information: NCT02319018.
A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours.
Authors: Glasspool Rosalind Margaret , Blagden Sarah Patricia , Lockley Michelle , Paul James , Hopkins Carol , Thomson Fiona , Brown Jennifer , Fernandes Ricardo , Douglas Nivea , Pou Chantevy , Hanif Aishah , Campbell Craig , Multani Pratik S. , Tucker Trevor , McNeish Iain A. , Evans T.R. Jeffry
Published: September 2018

2594

Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.
Clinical results with combination of anti-CD27 agonist antibody, varlilumab, with anti-PD1 antibody nivolumab in advanced cancer patients.
Authors: Sanborn Rachel E. , Pishvaian Michael J. , Kluger Harriet M. , Callahan Margaret K. , Weise Amy M. , Lutzky Jose , Yellin Michael Jay , Rawls Tracey , Vitale Laura , Halim Abdel , Keler Tibor , Davis Tom , Rizvi Naiyer A.
Published: September 2018

3007

Background: A phase 1 trial to assess the safety and immunological activity of the combination of varlilumab (V) and nivolumab (N), and recommend a dose of V for the phase 2 study was conducted. Methods: The study was performed using the approved dose of N (3 mg/kg Q2W) and escalating doses of V (0.1, 1, or 10 mg/kg Q2W) in anti-PD-(L)1 naïve patients with advanced cancer. Results: A total of 36 patients (21 CRC, 8 ovarian [OVA], 4 melanoma and 3 SCCHN) were enrolled. Toxicity was consistent with the safety profile of each agent individually; no unexpected toxicities were seen with the combination. No MTD was identified. An OVA cancer patient in the 10 mg/kg cohort had a DLT: hepatitis (G4) and acute kidney injury (G3). A CRC patient in the 10 mg/kg cohort had a drug-related SAE of mixed motor sensory neuropathy (G2) and a CRC patient in the 1 mg/kg cohort had rash (G3). No additional drug related SAEs or DLTs were reported. The majority of tumors were PD-L1 negative (24/27) by IHC at baseline. For patients with post treatment biopsies, PD-L1 expression was observed in 43.5% (10/23) and correlated with increases in CD8 T cell infiltration, consistent with the generation of anti-tumor immunity. Other treatment related biomarker changes included transient increases in serum chemokine levels, and a prominent decrease in circulating Tregs. Biomarker analysis did not clearly differentiate between dose levels, or delineate an optimal V dose. Three patients had objective PR by RECIST [CRC MSI-low (1 mg/kg V), SCCHN (10 mg/kg V) and OVA (10 mg/kg V, uPR)]. The response in the CRC patient is ongoing with a 94% decrease in target lesion diameter and a PFS of 19+ months. There were also 11 patients with SD. Phase 2 cohorts are ongoing in RCC, SCCHN, OVA, CRC and GBM. The Phase 2 portion includes exploration of different dose/regimens of V, including high and low exposure, to better characterize the optimal dosing strategy for V, in combination with a fixed dose of N (240 mg Q2W). Conclusions: The combination of V and N was well tolerated, associated with strong biological signals, and has evidence of clinical activity in subsets of patients with tumor types that are typically resistant to PD-1 inhibitor monotherapy. Clinical trial information: NCT02335918.
A phase I/II clinical trial of E6 T-cell receptor gene therapy for human papillomavirus (HPV)-associated epithelial cancers.
Authors: Hinrichs Christian S. , Doran Stacey L. , Stevanovic Sanja , Adhikary Sabina , Mojadidi Michelle , Kwong Mei Li , Faquin William C , Feldman Steven , Somerville Robert , Sherry Richard Mark , Yang James C. , Rosenberg Steven A.
Published: September 2018

3009

Background: Engineered T-cell therapy has shown promise in B-cell malignancies and melanoma, but clinical investigation in epithelial cancers has been limited. Methods: We conducted a phase I/II clinical trial of T cells genetically engineered to express a T-cell receptor that targets an HLA-A*02:01-restricted epitope of E6 (E6 TCR T Cells) for patients with metastatic HPV-16+ carcinoma. The cell dose was escalated in cohorts of single patients (1 x 109, 1 x 1010, and 1-2 x 1011cells). Patients received a nonmyeloablative conditioning regimen of cyclophosphamide and fludarabine, a single infusion of E6 TCR T Cells, and systemic high-dose aldesleukin. Results: Twelve patients were treated, 9 at the highest cell dose, plus one retreatment. The cancer types were 6 cervical, 4 anal, 1 oropharyngeal, and 1 vaginal. No dose-limiting toxicity, autoimmune adverse events, or cytokine storm were observed. Two patients with anal cancer treated at the highest cell dose experienced partial tumor responses lasting 6 and 3 months after treatment. The patient with a 6-month response had complete regression of one tumor and partial regression of two tumors that were resected upon progression; she has no evidence of disease 22 months after treatment. T-cell receptor gene transfer efficiency was 45 and 51% in the responding patients, and 47-76% (median 61%) in the non-responding patients. Responding patients showed robust levels of E6 TCR T cell memory (30 and 46% of circulating T cells 1-month after treatment). Non-responding patients showed wide-ranging levels of E6 TCR T cell memory (range 4-53%, median 29%). Expression of programmed cell death protein 1 (PD-1) by circulating E6 TCR T Cells 1-month after treatment was low in all patients ( < 5%). The patient with a 6-month response had 7% E6 TCR T Cells in a resected tumor 10 months after treatment, 25% of which expressed PD-1. A patient with no response had no detectable E6 TCR T Cells in a resected tumor 3 months after treatment. Conclusions: E6 TCR T-cell therapy was safe at doses up to 2 x 1011 cells. Regression of metastatic HPV+ carcinoma occurred in two patients following treatment, suggesting that TCR T-cell therapy can mediate epithelial cancer regression. Clinical trial information: NCT02280811.
Safety of epacadostat 100 mg bid plus pembrolizumab 200 mg Q3W in advanced solid tumors: Phase 2 data from ECHO-202/KEYNOTE-037.
Authors: Hamid Omid , Bauer Todd Michael , Spira Alexander I. , Smith David C. , Olszanski Anthony J. , Tarhini Ahmad A. , Lara Primo , Gajewski Thomas , Wasser Jeffrey S. , Patel Sandip P. , Borges Virginia F. , Balmanoukian Ani Sarkis , Schmidt Emmett V. , Zhao Yufan , Jones Mark M. , Gangadhar Tara C.
Published: September 2018

3012

Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.