bluuebunny/crossref_metadata_2025 huggingface dataset:
A multicenter phase I trial of the DNA-dependent protein kinase (DNA-PK) inhibitor M3814 in patients with solid tumors.
Authors: van Bussel Mark , Mau-Soerensen Morten , Damstrup Lars , Nielsen Dorte , Verheul Henk M.W. , Aftimos Philippe Georges , De Jonge Maja J. , Berghoff Karin , Schellens Jan H.M.
Published: September 2018

2556

Background: Agents that generate breaks in DNA are frequently used as cancer therapeutics. These agents induce different forms of DNA damage including double-strand breaks (DSBs), which are the most lethal if left unrepaired. M3814 targets tumor cell growth and survival by inhibiting DNA-PK, which is part of a critical DSB DNA damage repair mechanism. The purpose of the phase I, first in man trial was to evaluate the dose-limiting toxicity (DLT), establish a recommended phase II dose (RP2D), and assess the pharmacokinetic (PK) profile and single-agent clinical activity of M3814. Methods: Patients (pts) with potential aberrations in the DNA-damage and repair systemwere included. A standard 3+3 design was implemented with a starting dose of M3814 of 100 mg once daily, determined based on non-clinical safety. M3814 was given continuously and DLT was evaluated after 3 weeks. Throughout the trial rich PK sampling was taken. Tumor evaluation was performed every second cycle and treatment continued until progression, unacceptable toxicity, pt wish, or physician decision. Results: A total of 25 pts were enrolled at 6 dose levels (DL). Three pts were enrolled per DL, except at 300 and 400 mg BID where 9 and 4 pts were enrolled, respectively. At 300 mg BID one DLT (several low grade adverse events [AEs] lasting > 1 week) was seen. No DLTs were observed at 400 mg BID, which was declared as the RP2D; further dose escalation was not possible due to an impurity in the drug. An additional 6 pts were included at the RP2D. The most frequent AEs were nausea, vomiting, decreased appetite, constipation, diarrhea, pyrexia, fatigue, and rash, all seen in > 20% of pts. No pts discontinued due to AE and no grade 4 AEs were reported. Six pts (20%) had stable disease for at least 18 weeks; no pt had a partial remission. PK analysis demonstrated high variability of exposure with a tendency for skin rash in pts with the highest exposure. Conclusions: M3814 was found to be safe and tolerable at doses up to 400 mg BID, with limited single-agent activity in the studied population. Clinical evaluation of M3814 is ongoing in combination with radiotherapy as well as chemo-radiotherapy and planned in combination with chemotherapy. Clinical trial information: NCT02316197.
Patterns of failure on Ga PSMA (GaPSMA) and F18 FDG (FDG) PET CT in a prospective phase 2 trial of 177Lu DKFZ PSMA 617 (LuPSMA) in men with castrate resistant metastatic prostate cancer (mCRPC).
Authors: Joshua Anthony M. , Stricker Phillip , Epstein Richard J , Ho Bao , Nguyen Quoc , Kent Robert , Willowson Kathy P , Hofman Michael , Violet John A , Emmett Louise
Published: September 2018

2562

Background: LuPSMA is emerging as an effective therapy in mCRPC, with retrospective series reporting high PSA response rates in men undergoing treatment (tx). However, not all men have prolonged tx responses. We report the prospective imaging (GaPSMA/FDG) and PSA response of men who progress biochemically during LuPSMA tx to gain information on characteristics of failure patterns, to determine optimal future tx strategies. Methods: Men with mCRPC, who had failed androgen blockade, failed/ ineligible/refused chemotherapy, with GaPSMA positive disease were enrolled in a prospective phase 2 trial. All men underwent LuPSMA therapy 6-8Gbq, 4 doses at 6 weekly intervals. Imaging with FDG, GaPSMA, bone scan and CT scans was at screening, at subsequent PSA rise, or 3 months post completion of 4 cycles of therapy. Results: 14 men met eligibility criteria and enrolled. 4/14 (28%) men had progressive disease (no PSA response). 10/14 (72%) PSA reduced by a mean 56% .Overall 9/14 (64%) men had >30% decline in PSA, and 5/15(36%) >50% reduction in PSA. 7/15 men were reimaged with GaPSMA, FDG at biochemical failure or 3/12 post tx completion. Imaging revealed 4 distinct patterns (P) of progression. Conclusions: PSMA acts as both target for radionuclide therapy and biomarker for effective tx response. PSMA and FDG imaging at PSA failure following or during LU PSMA therapy identifies phenotypic patterns of failure that have implications for determining next best tx options in men with mCRPC. [Table: see text]
The utility of genomics and functional imaging to predict irinotecan pharmacokinetics and pharmacodynamics: The PREDICT IR study.
Authors: Michael Michael , Liauw Winston , McLACHLAN Sue-Anne , Link Emma , Matera Anetta , Thompson Mick , Jefford Michael , Hicks Rodney J , Cullinane Carleen , Campbell Ian , Beale Philip James , Karapetis Christos Stelios , Price Timothy , Burge Matthew E.
Published: September 2018

2564

Background: BSA-based dosing of Irinotecan (IR), does not account for its pharmacokinetic (PK) and pharmacodynamic (PD) variability. Given IR’s unique metabolism, functional hepatic nuclear imaging (HNI) with probes for hepatic transporters correlated with its PK. This study further evaluated the utility of HNI combined with extensive excretory/metabolic/PD pharmacogenomics (PG) to predict IR PK and PD in patients (pts) treated with FOLFIRI to enable dose individualization. Methods: Eligible pts had advanced colorectal cancer, suitable for 1st/2nd-line FOLFIRI± Bevacizumab. Pts had blood analyzed by Affymetrix DMET™ Plus Array and additional SNPs were genotyped. For HNI, pts were given IV 250MBq 99mTc-IDA and imaging data analyzed for hepatic extraction/excretion parameters (clearance [CL], 1hour retention [1hRET], deconvulutional CL [DeCL], hepatic extraction fraction [HEF]). Pts treated with chemotherapy, q2-weekly, and restaged after 4 cycles. Blood taken for IR and metabolite (SN38, SN38G) analysis on day 1 cycle 1, PK parameters derived by non-compartmental analysis. Statistical correlations were evaluated between (i) IDA HNI and (2) PGs, with IR PK, toxicity, objective response (ORR) and progression-free survival (PFS). Results: 32 pts analysed, 31 pts completed 4 cycles. (1) PK correlates: (a) HNI CL and 1hRET with SN38 Metabolic CL, (P = 0.04) and (b) HNI DeCL with IR AUC(0-∞) (P = 0.04). (2) Grade 3+ diarrhea (N = 4, 13%) predicted by SN38 AUC(0-∞) and Metabolic CL (P = 0.04), and gene variants for SCL22A2 and -28A3, ABCC2, UGT2B17, CYP2C18 and DPYD (P < 0.05). (3) Grade 3+ neutropenia (N = 9, 28%) predicted by SN38 PK exposure (P < 0.02), HNI CL and 1hRET (P < 0.0001) and variants for SLC7A7-, SLC22A2-, CHST1-, UGT1A1-, -2B7, ABCB1. (4) ORR (N = 6, 20%) predicted by Methylene tetrahydrofolate reductase (MTHFR) 677C > T (P = 0.002), SN38 exposure (P < 0.003), and variants in metabolic/transporter genes (P < 0.05). (5) PFS by SN38 PK exposure, MTHFR 677C > T, HNI CL, HNI HEF and variants in PK genes (P < 0.05). Conclusions: Hepatic functional imaging with extensive pharmacogenomics correlate with Irinotecan PK and PD enabling the development of nomograms to individualize dosing. Clinical trial information: ACTRN12610000898055.
The potential clinical impact of pre-emptive screening of multiple polymorphisms in gene-encoding DPD on patients candidate for fluoropyrimidine based-chemotherapy: An experience of the Northern Italy Cancer Centre.
Authors: Iachetta Francesco , Damato Angela , Bonelli Candida , Romagnani Alessandra , Banzi Maria , Nicoli Davide , Farnetti Enrico , Casali Bruno , Pinto Carmine
Published: September 2018

2567

Background: Dihydropyrimidine dehydrogenase (DPD) is a key enzyme in the metabolism of fluorouracil. Deleterious polymorphisms in gene-encoding DPD ( DPYD) results in a DPD deficiency that causes life-threatening toxicities when the standard dose of fluorouracil is used. DPYD*2A (IVS14+1G > A) is the most common single-nucleotide polymorphism (SNP) associated with critical DPD deficiency. At present, most of the evidence supports screening for at least 3 SNPs (DPYD*2A, c.2846 A > T, c.1679T > G). The aim of this study is to confirm that the detection of additional polymorphisms of DPYD could enhance prevention of fluoropyrimidine toxicity. Methods: In 2011, we began to screen DPYD*2A in patients candidate for fluoropyrimidine based-chemotherapy. As the first step of the evaluation, we selected all cases of DPYD*2A wild type, from 2011 to 2012, who developed CTC-NCI-V.3 toxicity ≥ G3. In these patients, we researched the other 3 SNPs (c.2846 A > T, c.1679T > G, c.2194C > A). Mutational status was analyzed with real Time PCR. Results: From 2011 to 2016 we pre-emptively screened DPD deficiency in 1,863 patients and 32 subjects (1.6%), with results mutated for DPYD*2A. As the first step of the evaluation, 548 subjects were assessed from 2011 to 2012. We found 7 patients who were carriers of the DPYD*2A mutation (1.27%). Of the 541 wild type cases, 114 presented toxicities ≥ G3. In this subgroup, 22 patients (19%) proved to be mutated for the other SNPs of DPYP, as reported in the table below. Conclusions: Preliminary data show that in 22 (19%) of 114 patients who presented severe toxicity which was not correlated with DPYD*2A, we found other polymorphisms of gene encoding DPD. Out of the 3 SNPs evaluated, c.2194 C > A proved to be the most frequent, although it is the polymorphism that is least known and least studied. Such results suggest that the evaluation of additional polymorphisms could enhance the prevention of fluoropyrimidine toxicity. The results are expected to be clarified further in the second step, which is ongoing. [Table: see text]
Molecular markers to predict response to selective fibroblast growth factor receptor inhibitors (FGFRinh) in patients (pts) with FGFR-amplified (amp) or mutated (mut) tumors.
Authors: Hierro Cinta , Serrano Marta , Ruiz-Pace Fiorella , Martin-Liberal Juan , Ochoa de Olza Maria , Azaro Analía , Brana Irene , Vieito Maria , Alsina Maria , Perez Garcia Jose Manuel , Verdaguer Helena , Macarulla Teresa , Sanchez Monica , Serra Violeta , Nuciforo Paolo , Vivancos Ana , Garralda Elena , Dienstmann Rodrigo , Tabernero Josep , Rodon Jordi
Published: September 2018

2581

Background: Several FGFR and ligand (11q) alterations have been described in cancer. While FGFR fusions are recognized biomarkers of response to FGFRinh, it is still unclear to what extent FGFRamp, FGFR mRNA high expression (mRNAh) or FGFRmut predict sensitivity in the clinic. Methods: Retrospective analysis of pts with molecularly-selected FGFRamp/mRNAh/mut tumors treated with FGFRinh in phase 1 trials at our institution. Mut were detected with IlluminaÒ or Foundation OneÒ. FGFR1-2amp were analyzed by in situ hybridization and mRNA levels by qRT-PCR or nCounterÒ. Clinical benefit (ClinBen) was defined as any tumor shrinkage plus disease control for ³ 4 months (m). Time to progression (TTP) was defined as time between start of FGFRinh and end for any cause. Results: From 2011 to 2016, 36 pts with FGFRamp(25)/mRNAh(5)/mut(6) received an FGFRinh (irreversible- [11 cases (c)] or reversible-FGFR1-4inh [23 c], isoform-specific FGFRinh [3 c] or combo with PI3Kinh [1 c]). Median age 55 yrs (34-76); median prior palliative lines was 3 (0-8); tumor types: breast (17), colorectal (3), esophagus (3), liver (3), lung (3), others (7). Median TTP was 1.67 m (CI 95%; 1.40-2.87). In the FGFRamp/mRNAh population (30), 7 pts achieved ClinBen (23%). 4 out of these seven pts had mRNAh (1 FGFR2amp breast with FGFR2 mRNAh, 1 bladder FGFR3 mRNAh and 2 liver FGFR4 mRNAh without known amp), and 2 pts harboured 11q co-amplification (1 FGFR2amp breast, 1 FGFR2amp head and neck). There was no correlation between ClinBen and level of FGFRamp in the overall population (p = 0.51) or in the breast cancer group (p = 0.29). Of 6 FGFRmut pts, one with bladder cancer had ClinBen (clonal oncogenic FGFR3 S249C). The remaining 5 unresponsive FGFRmut pts had subclonal events, some of these FGFRmut were of unknown functional significance, and had coexisting oncogene mut in MAPK or PI3K pathways. Conclusions: Our results suggest that ClinBen with FGFRinh in the FGFRamp setting is enriched in pts with high mRNA expression and/or ligand co-amplification, and in the FGFRmut population may be dependent on clonality and functionality of the event and co-existence of driver mut.
Anticancer and immunostimulatory activity of the imipridone ONC201, a selective DRD2 antagonist, in advanced cancer patients.
Authors: Stein Mark N. , Chan Nancy , Silk Ann W. , Malhotra Jyoti , Aisner Joseph , Aiken Robert , Zloza Andrew , El-Deiry Wafik S. , Newman Jenna , Chesson Charles , Tarapore Rohinton , Allen Joshua E. , Oster Wolfgang , Saunders Tracie , Yu Bangning , Dickerson Siobhan , Rodriguez-Rodriguez Lorna , Haffty Bruce George , Kaufman Howard , Mehnert Janice M.
Published: September 2018

2586

Background: ONC201 is an orally active, small molecule selective antagonist of the G protein-coupled receptor DRD2 that has established a new class of compounds referred to as imipridones. A first-in-human trial of ONC201 defined its recommended phase II dose (RP2D) as 625mg using once every three week administration that was very well tolerated at doses that yielded antitumor effects. ONC201 also showed stimulatory effects on immune cells in preclinical studies, including increased intratumoral NK cell infiltration in xenografts. Based on the exceptional safety profile of ONC201, weekly dosing has been evaluated. Methods: This open-label, 3+3 dose-escalation study used a starting dose of 375mg and escalated to 625mg using a weekly administration schedule. The primary endpoint was to determine the RP2D of ONC201 and secondary endpoints included PD, PK, toxicity, and anti-tumor efficacy. Based on signs of clinical activity and preclinical tumor type sensitivity studies of ONC201, the patient population was enriched for advanced glioblastoma, prostate cancer, and endometrial cancer. Six additional patients were treated at the weekly RP2D. Results: The RP2D for the weekly regimen was defined as 625 mg. Twelve evaluable patients were treated at this dose level and no drug-related AEs > grade 1 occurred. Five patients had stable disease by RECIST criteria for 21-29 weeks. A metastatic prostate cancer who received 375mg ONC201 weekly had significantly diminished intensity in bone scans after 6 doses. PK was consistent with previous reports: Cmax consistently reaches therapeutic micromolar plasma concentrations, ~11 hour half-life, evidence of sustained and delayed activity, no systemic accumulation. In agreement with preclinical observations of ONC201-induced NK cell populations, a 2-10 fold increase in circulating activated NK cells was observed in 5 prostate cancer patients. Conclusions: ONC201 is well tolerated at an oral dose of 625mg weekly, exhibits sustained and late anti-cancer activity, and increases circulating NK cells. Observation in this study, and other clinical studies, warrant further evaluation of the immune oncology effects of ONC201. Clinical trial information: NCT02250781.
Phase 1 study of the bone-targeting cytotoxic conjugate, etidronate-cytosine arabinoside (MBC-11), in cancer patients with bone metastases.
Authors: Zinnen Shawn , Rowinsky Eric Keith , Alexandrov Alexander , Plekhova Larisa , Roudas Marina , Karpeisky Alexander
Published: September 2018

2589

Background: MBC-11 is a first-in-class therapeutic conjugate of the bone targeting bisphosphonate etidronate covalently linked to the antimetabolite cytosine arabinoside (Ara-C). In preclinical studies, MBC-11 localizes at the site of cancer-induced bone disease (CIBD) where it demonstrates both antiresorptive and antitumor activities following local release of Ara-C. Robust efficacy was observed in several rodent models of CIBD, as well as in spontaneous osteosarcoma in dogs. Herein, the results of the first-in-human study of MBC-11 are reported. Methods: Patients with advanced solid cancers and CIBD were treated with escalating doses (0.5-10 mg/kg/day) of MBC-11 administered as an intravenous infusion daily for 5 days every 4 weeks for up to 4 cycles. Fifteen patients (prostate cancer [PC; 7], breast cancer [BC; 7], cervical cancer [1]) received 38 total cycles. The study sought to characterize the safety, pharmacokinetics, and the effects of MBC-11 on bone turnover, and tumor response by 18F-FDG-PET/CT imaging and tumor biomarkers. Results: Myelosuppression was generally grade 1-2, involved all lineages, and was the principal toxicity of MBC-11. Two of three patients treated at the 10 mg/kg dose level had dose-limiting toxicity (DLT), each with both grade 4 neutropenia and thrombocytopenia, the maximum tolerated dose (MTD) was 5 mg/kg. Four of 5 patients with pretreatment elevations of the bone resorption marker Trap5b had persistent decrements. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in 3 patients; one BC patient treated at the 0.5 mg/kg and two CRPC patients treated at 1.0 mg/kg dose levels. An additional 3 patients had stable metabolic responses according to PERSIST. SUV values were reduced by at least 25% in 111 (53.8%) of 206 measurable bone lesions; significant activity was noted at all doses. Conclusions: At doses that were well tolerated and even much lower than the MTD, MBC-11 treatment resulted in substantial reductions in metabolic activity in CIBD patients, providing a foundation for further disease-directed studies to further assess efficacy. Clinical trial information: NCT02673060.
Association of the diversity and composition of the gut microbiome with responses and survival (PFS) in metastatic melanoma (MM) patients (pts) on anti-PD-1 therapy.
Authors: Wargo Jennifer Ann , Gopalakrishnan Vancheswaran , Spencer Christine , Karpinets Tatiana , Reuben Alexandre , Andrews Miles Cameron , Tetzlaff Michael T. , Lazar Alexander , Hwu Patrick , Hwu Wen-Jen , Glitza Isabella Claudia , Tawbi Hussein Abdul-Hassan , Patel Sapna Pradyuman , Lee Jeffrey Edwin , Davies Michael A. , Gershenwald Jeffrey E. , Futreal Andrew , Sharma Padmanee , Allison James Patrick , Jenq Robert R.
Published: September 2018

3008

Background: Significant advances have been made in cancer therapy with immune checkpoint blockade. However, responses in pts with MM are variable, and insights are needed to identify biomarkers of response and strategies to overcome resistance. There is a growing appreciation of the role of the microbiome in cancer, and evidence in murine models that modulation of the gut microbiome may enhance responses to immune checkpoint blockade, though this has not been well studied in pts. Thus we evaluated the microbiome in a large cohort of pts with MM, focusing on responses to anti-PD-1. Methods: We collected oral (n = 234) and gut microbiome samples (n = 120) on a large cohort of of MM patients (n = 221). Of note, the majority of pts were treated with PD-1 based therapy (n = 105). Pts on anti-PD1 were classified as either responders (R) or non-responders (NR) based on RECIST criteria, and 16S rRNA and whole genome shotgun (WGS) sequencing were performed. Immune profiling (via immunohistochemistry, flow cytometry, cytokines and gene expression profiling) was also done in available pre-treatment tumors at baseline. Results: Significant differences in diversity and composition of the gut microbiome were noted in R vs NR to anti-PD-1, with a higher diversity of bacteria in R vs NR (p = 0.03). Differences were also noted in the composition of gut bacteria, with a higher abundance of Clostridiales in R and of Bacteroidales in NR. Immune profiling demonstrated increased tumor immune infiltrates in R pts , with a higher density of CD8+T cells; this correlated with abundance of specific bacteria enriched in the gut microbiome (r = 0.59, 0.014). Other features of enhanced immunity were also noted, and WGS revealed differential metabolic signatures in R vs NR. Furthermore, diversity (p = 0.009; HR = 7.67) and abundance of specific bacteria in R (p = 0.007; HR = 3.88) was associated with improved PFS to anti-PD-1 therapy. Conclusions: Diversity and composition of the gut microbiome differ in R vs NR pts with MM receiving anti-PD-1 therapy. These have potentially far-reaching implications, though results need to be validated in larger cohorts across cancer types.
First-in-human multicenter study of bb2121 anti-BCMA CAR T-cell therapy for relapsed/refractory multiple myeloma: Updated results.
Authors: Berdeja Jesus G. , Lin Yi , Raje Noopur S. , Siegel David Samuel DiCapua , Munshi Nikhil C. , Liedtke Michaela , Jagannath Sundar , Maus Marcela Valderrama , Turka Ashley , Lam Lyh Ping , Hege Kristen , Morgan Richard , Quigley M. Travis , Kochenderfer James
Published: September 2018

3010

Background: To test the safety and efficacy of the CAR T cell modality in relapsed/refractory multiple myeloma (MM), we have designed a second-generation CAR construct targeting B cell maturation antigen (BCMA) to redirect T cells to MM. bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif and a CD3-zeta T cell activation domain. We will report updated safety and efficacy following initial results (Berdeja et al, ENA 2016). Methods: CRB-401 (NCT02658929) is a multi-center phase 1 dose escalation trial of bb2121 in patients with relapsed and/or refractory MM who have received ≥ 3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥ 50% BCMA expression on plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis. Patients undergo lymphodepletion with Flu (30 mg/m2) / Cy (300 mg/m2) daily for 3 days then receive 1 infusion of bb2121. The study follows a standard 3+3 design with planned dose levels of 5, 15, 45, 80 and 120 x 107 CAR+ T cells. Results: As of November 18, 2016, 11 patients had been infused with bb2121 in the first 4 dose cohorts, and 9 patients had reached at least 1 month of follow-up. As of data cut-off, no dose-limiting toxicities and no > Grade 2 neurotoxicities or cytokine release syndrome (CRS) had been observed. Grade 1-2 CRS had been reported in 8/11 (73%) treated patients. All patients treated with doses of 15.0 x 107or higher remained on study and the overall response rate (ORR) in the 6 evaluable patients at these doses was 100%, including 2 sCRs and 2 MRD-negative responses (1 sC, 1 VGPR). CAR+ T cell expansion has been demonstrated consistently. An additional 6 months of follow up on previously reported results and initial data from an additional ~10 patients will be presented. Conclusions: bb2121 shows promising efficacy at dose levels above 5 x 107 CAR+ T cells, including 2 sCRs and ongoing clinical responses at 6 months, with mild and manageable CRS to date. These initial data support the potential of CAR T therapy with bb2121 as a new treatment paradigm in MM. Study sponsored by bluebird bio. Clinical trial information: NCT02658929.
A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors.
Authors: Friedlander Michael , Meniawy Tarek , Markman Ben , Mileshkin Linda R. , Harnett Paul R. , Millward Michael , Lundy Joanne , Freimund Alison E. , Norris Christie , Mu Song , Wu John , Paton Virginia E. , Wang Lai , Gao Bo
Published: September 2018

3013

Background: The release of tumor-associated antigens may enhance the response to immunotherapy. BGB-A317, a humanized IgG4 variant monoclonal antibody engineered to have no Fc gamma receptor binding, targets the programmed cell death-1 (PD-1) receptor. It is being developed in solid and hematologic malignancies at a dose of 200 mg IV Q3W. BGB-290, a potent inhibitor of PARP 1/2, is hypothesized to promote neoantigen release that will potentially increase the efficacy of BGB-A317. A phase 1 study identified 60mg BID as the recommended Phase 2 dose (RP2D) for BGB-290. This study consists of initial dose escalation to determine the maximum-tolerated dose (MTD), safety, PK profile, and preliminary anti-tumor activity of the combination, followed by expansion into ovarian, breast, prostate, gastric, bladder, pancreatic and small cell lung cancers. Methods: Cohorts of 6 -12 pts with advanced solid tumors were treated in each of 5 planned dose levels (DLs). In DLs 1-3, BGB-290 doses ranged between 20-60mg PO BID with BGB-A317 2mg/kg IV Q3W. In DLs 4 - 5, BGB-290 doses were 40 or 60 mg BID; A317 was given at 200 mg IV Q3W based on PK data from a single agent Phase 1 study. Results: As of 16 Jan 2017, 38 pts [median age 59 years (34-75)] were treated in DLs 1-4; enrollment to DL5 is ongoing. One DLT of persistent Gr 2 nausea was reported in DL 4. The most common adverse event (AE) considered related to both study drugs was fatigue (10.5%). Immune-related AEs were Gr 3 hypophysitis (n = 1), Gr 3 or 4 autoimmune hepatitis(n = 2), and Gr 2 elevated AST/ALT (n = 1). Decreases in tumor burden have been observed in 16 pts; 7 achieved a PR (5 with ovarian and one each with uterine and pancreatic cancer) and one CR was observed in ovarian cancer. Six pts had SD for > 6 months including 2 pts with pancreatic cancer who received BGB-A317+BGB-290 for 189 and 281 days. Plasma/serum exposure of BGB-290 and BGB-A317 were consistent with those in single-agent trials. Conclusions: BGB290 and BGB-A317 can be combined. Dose expansion in multiple tumor types is planned to commence in 2017 once the RP2D is determined. Clinical trial information: NCT02660034.
Antibiotics prescription to decrease progression-free survival (PFS) and overall survival (OS) in patients with advanced cancers treated with PD1/PDL1 immune checkpoint inhibitors.
Authors: Derosa Lisa , Routy Bertrand , Mezquita Laura , Naltet Charles , Enot David , Fidelle Marine , Goubet Anne-Gaëlle , Soria Jean-Charles , Massard Christophe , Goldwasser Francois , Zitvogel Laurence , Brosseau Solenn , Escudier Bernard J. , Loriot Yohann , Zalcman Gerard , Besse Benjamin , Albiges Laurence
Published: September 2018

3015

Background: Use of antibiotics (ATB) alters the gut microbiota composition and decreases bacterial diversity. Pre-clinical evidences demonstrated the impact of the microbiota in the efficacy of immune checkpoint blockades (ICB) in cancer. Interaction between ATB and ICB has not been extensively investigated in cancer patients (pts). Our study evaluated the effect of ATB in cancer pts treated with PD-1/PD-L1 inhibitors. Methods: We conducted a retrospective analysis of pts treated with PD-1/PD-L1 inhibitors for advanced Renal Cell Carcinoma (RCC), Urothelial Cancer (UC) and Non-Small Cell Lung Cancer (NSCLC) and data on ATB use were collected. ATB(+)/(-) groups were defined as pts treated or not with ATB before (2 months period) or within the first month of ICB. PFS and OS were compared between both groups among all pts and then according to tumor site. Statistical analyses were performed using the Kaplan-Meier method. Cox regression analyses were performed separately for each cancer type adjusting for its specific risk factors. Results: Among 175 pts included, 51 (29%) received ATB (mostly beta-lactamases and fluoroquinolones). ATB(+) group had shorter PFS and OS when compared to ATB(-) group: 3.4 vs. 5.2 months, p < 0.013, and 12.2 vs. 20.8 months, p < 0.001, respectively. According to tumor type, ATB(+) group translated into decrease OS (7.0 vs. 13.8 months, p < 0.038) in NSCLC. In RCC and UC pts, ATB (+) group had shorter PFS when compared to ATB(-) group (4.3 vs. 7.4 months, p < 0.013 and 1.8 vs. 4.3 months, p = 0.048, respectively). The negative impact of ATB was maintained after multivariate analyses adjusting for risk factors in each tumor type. Conclusions: ATB prescription preceding or concomitant to the first injection of PD-1/PD-L1 inhibitors impaired the outcome in patients with advanced cancers. This reduction in efficacy seems to be independent of classical prognostic factors in RCC, UC and NSCLC. These data should be validated in larger cohort. In addition, the role of gut composition to explain this interaction is ongoing, as well as novel diagnosis tools based on microbiota to predict response/resistance to ICB.
Overall survival prognosis of patients in immuno-oncology phase I trials: The Gustave Roussy score.
Authors: Bigot Frederic , Castanon Eduardo , Baldini Capucine , Aspeslagh Sandrine , Marabelle Aurelien , Massard Christophe , Hollebecque Antoine , Postel-Vinay Sophie , Soria Jean-Charles
Published: September 2018

3029

Background: The evaluation of patient’s life expectancy is crucial to select patients who may benefit from phase I studies. The Royal Marsden Hospital (RMH) prognostic score, based on 3 objective variables (number of metastatic sites, LDH and serum albumin) was validated in patients treated with cytotoxic and targeted therapies. We aimed to determine if those factors were applicable to immunotherapy (IT) phase I trials. Methods: A retrospective analysis for risk factors of survival was conducted in a discovery cohort of 155 patients enrolled into IT phase I trials at our institution. We computed univariate and multivariate analysis (MVA) of demographics, clinical and biological data to assess their prognostic value for overall survival (OS). MVA results were used to build a prognostic score for OS. A validation cohort of 113 patients enrolled in IT phase I trials was used to prospectively re-validate this score. Results: 155 patients receiving an experimental IT between March 2012 and January 2016 were included in the discovery cohort. A MVA assessing the RMH Score variables showed that albumin < 35 g/dL (HR 1.73, 95% CI 1.05-2.86) and LDH > upper normal limit (1.88, 95% CI 1.12-3.15) were independent negative prognostic factors for OS. As opposed to the RMH score, number of metastases was not associated with a poorer outcome for this IT cohort (0.83 95% CI 0.51-1.35). Interestingly, a neutrophil to lymphocyte ratio (N/L) > 6 (1.75, 95% CI 1.04-2.95) was associated with a worse OS. A risk analysis based on the results of the MVA showed that patients presenting a high score (2-3) had a significantly shorter OS (20.4 weeks; 95% CI 5.7-35.2) compared to those with a low score (0-1) (68.9 weeks; 95% CI 50-83.7) (HR = 2.9 95% CI 1.87-4.64). In the validation cohort of 113 patients, the patients presenting a high score showed an inferior OS (HR = 6.3, 95% CI 2.7-14.8). Conclusions: In phase I trials of IT, traditional prognostic variables included in the RMH Score are suboptimal to determine patient’s prognosis. In this context, the N/L ratio, which reflects the immune contexture, is a significant prognostic variable. The new Gustave Roussy Score, based on albumin, LDH and N/L ratio allows to better select patients for IT phase I trials.
Very early molecular marker of tumor response to PD-1 inhibition in plasma of patients with advanced non-small cell lung cancer (NSCLC).
Authors: Hiltermann Thijo Jeroen Nicolaas , Miedema A , Hijmering-Kappelle Lucie , Groen Harry J.M. , Schuuring Ed
Published: September 2018

3030

Background: Nivolumab shows a durable tumor response in 20 % of advanced NSCLC patients. While a PD-L1 immunohistochemistry complementary diagnostic has been approved, there is a need to identify a predictive biomarker with greater diagnostic accuracy. Methods: In an ongoing study of patients, treated with nivolumab every 2 weeks for advanced recurrent NSCLC and a known KRAS mutation in the primary tumor, liquid biopsies were taken by a simple blood draw at baseline (before treatment), 1, 2, 4, 6 and thereafter every 12 weeks until disease progression. Circulating tumor DNA (ctDNA) was extracted from cell free plasma and tested with a specific digital droplet PCR (ddPCR)-KRAS G12/G13 screenings assay (BIORAD). Mutation levels in plasma were compared with tumor response on CT scans by RECIST v.1.1. CT scans were performed at baseline and thereafter every 6 weeks until disease progression. Results: Patient characteristics are shown in table 1. In this prospective analysis specific patterns could be demonstrated in plasma ctDNA testing of KRAS mutation levels. All 4 responders showed an increase of mutant copies/ml plasma in the first week followed by a clear drop to non-detectable KRAS mutations at all CT evaluated tumor responses. The 2 non-responders however, did not show the increase in mutant copies/ml at one week and showed a gradual increase in mutant copies/ml in the following weeks. Conclusions: Specific plasma ctDNA testing seems a very promising early biomarker (1 week) for tumor response to PD-1 therapy. [Table: see text]
Phase 1 safety of ICOS agonist antibody JTX-2011 alone and with nivolumab (nivo) in advanced solid tumors; predicted vs observed pharmacokinetics (PK) in ICONIC.
Authors: Burris Howard A. , Callahan Margaret K. , Tolcher Anthony W. , Kummar Shivaani , Falchook Gerald Steven , Pachynski Russell Kent , Tykodi Scott S. , Gibney Geoffrey Thomas , Seiwert Tanguy Y. , Gainor Justin F. , LoRusso Patricia , Hilbert James , Apgar Josh F , Hua Fei , Burke John M , Lazaro Manny , Clancy Myles , Ding Baoyu , Trehu Elizabeth G. , Yap Timothy Anthony
Published: September 2018

3033

Background: JTX-2011 is an agonist monoclonal antibody that targets ICOS, Inducible CO-Stimulator of T cells. A dual mechanism of action is intended to activate antigen-specific CD4 T effector cells and selectively deplete intratumoral T regulatory cells. JTX-2011 is equally potent across human, rodent, and non-human primate species. Methods: A quantitative systems pharmacology (QSP) model describing target binding by JTX-2011 and target mediated drug disposition in blood, tumor and non-tumor tissues was based on preclinical potency and non-linear PK data across species. The model was translated to predict PK and target engagement (TE) in humans to facilitate dose selection. The QSP model predicts > 95% TE for 21 days at the top planned dose. We present safety and actual/predicted PK from a Phase 1 study of JTX-2011 alone (Part A) and safety in combination with nivo (Part B). Results: 25 subjects have been dosed, 19 in 4 cohorts of JTX-2011 alone at .003, .01, .03, and .1 mg/kg IV q 21 days, and 6 in 2 cohorts of JTX-2011 .01 mg/kg and .03 mg/kg IV plus nivo 240 mg IV q21 days. Safety data from ≥ 1 cycle is available for 12 subjects in Part A (7 ≥ 3 cycles), and 3 in Part B (all ≥ 3 cycles). PK data is available for cycle 1 of Part A. Mean age (±SD) is 60 (±10.6). Mean prior systemic therapies is > 5 (range 1-11). Tumor types include endometrial, triple negative breast, melanoma, lung, pancreatic and colorectal cancers. No dose limiting toxicities have been reported. 3 Grade 3 adverse events (AEs) were reported in 2 Part A subjects: anemia and hypoxia (unrelated SAE) at .003 mg/kg and JTX-2011 related diarrhea at .1 mg/kg. Grade 1-2 AEs in ≥2 subjects are chills, pyrexia, neck pain, dizziness, and nausea. 5 subjects had JTX-2011 related Grade 1-2 infusion reactions up to 6 hours post infusion. Non-linear exposure increase was observed. While PK at lower doses is consistent with model predictions, AUC and t1/2at 0.03 and 0.1 mg/kg doses are higher than predicted, suggesting higher than predicted TE. Conclusions: JTX-2011 has been well tolerated up to 0.1 mg/kg and with nivo at .01 mg/kg IV q 21 days. Greater than linear exposure increase was observed and TE may be higher than QSP model prediction. Clinical trial information: NCT02904226.
The scope of possible combination therapy with immunotherapy and targeted therapy.
Authors: Colli Leandro Machado , Machiela Mitchell J , Zhang Han , Myers Timothy A , Jessop Lea , Delattre Olivier , Yu Kai , Chanock Stephen J.
Published: September 2018

3056

Background: Combination treatment of two recent trends in cancer therapy, namely immunotherapy with checkpoint inhibitors and drugs that target specific gene mutations, could improve cancer survivorship overall. Targeted drugs usually induce rapid tumor death leading to the release of neoantigens, and can affect immune development pathways, which could increase the efficacy of checkpoint inhibitor treatment. Assessment of somatic mutation profiles from large public databases provides an estimate of the prevalence of targetable somatic mutations and the burden of somatic nonsynonymous mutations (NsM), used as a surrogate for overall neoantigen load, which, in turn, correlates with clinical utility of checkpoint inhibitors for melanoma and lung adenocarcinoma. The rational design of these combinations based on somatic genomic profiles offers a prioritization scheme for new clinical trials. Methods: We surveyed 13,349 genomic profiles from public databases for cases with specific mutations targeted by current agents and/or a burden of exome-wide non-synonymous mutations (NsM) that exceeds a recently suggested threshold for response to checkpoint inhibitors. Results: Overall, 8.9% of cases have profiles that could benefit from combination therapy, which corresponds to approximately 11.2% of US annual incident cancer cases; the most commonly targetable mutations were observed in PIK3CA, BRAF, NF1, NRAS, and PTEN genes . Interestingly, cases with mutations in SMO, DDR2, FGFR1, PTCH1, FGFR2, and/or MET appear to be enriched in those with high burdens of NsM, who have a higher likelihood of responding to immunotherapy. Of the 13,349 cases that could benefit from combination therapy, 50.9% had BRAF, NF1, GNAQ and/or GNA11 mutations which can be targeted by Trametinib ; 26.1% by Taselisib (targets PIK3CA mutations); and 19.8% by Afatinib ( EGFR and ERBB2 mutations). Conclusions: Our results indicate a significant proportion of solid tumor patients are eligible for combination therapy and suggest prioritizing specific cancers for combination trials using target drugs and checkpoint inhibitor therapy.
Immune related adverse events (irAE) with platinum chemotherapy (CT) with durvalumab (D) ± tremelimumab (T): CCTG IND226.
Authors: Daaboul Nathalie , Gauthier Isabelle , Tu Dongsheng , Brown-Walker Pamela , Sun Xiaoqun , Hao Desiree , Juergens Rosalyn A. , Bradbury Penelope Ann , Mates Mihaela , Tehfe Mustapha Ali , Kollmannsberger Christian K. , Ellis Peter Michael , Robinson Andrew George , Wheatley-Price Paul , Laurie Scott Andrew , Seymour Lesley
Published: September 2018

3058

Background: CT is immunomodulatory and requires corticosteroids (CS) premedication. We hypothesized that the incidence of irAE may be lower when D ± T is given with CT or CS. Methods: Patients (pts) receive CT (pemetrexed, nabpaclitaxel, etoposide or gemcitabine + cisplatin or carboplatin; usual 4-6 cycles) with D ± T, followed by D ± T alone (1 year total); pts with ≥ g2 (selected) or ≥ g3 irAE discontinued D ± T. Cycles were coded as CT + D ± T or D ± T; pts could contribute to both. CS: high (dexamethasone > 10mg/day for 5 days) or low CS. irAE were D ± T related gastrointestinal (GI), skin, endocrine, neurologic, hypersensitivity, pneumonitis (PN) or other immune (nephritis (GN), pancreatitis, hepatitis). Biochemistry (BIO; all causality): creatinine, transaminases/bilirubin (LFTS) and amylase/lipase was summarised. Results: In this ongoing study, 118 pts received 723 cycles. Pts had good performance status (PS 0-1), 78 had thoracic malignancies and 84 no prior CT. 44 pts continue on D ± T alone; 32 pts continue on CT + D ± T while 76 pts discontinued D ± T primarily due to disease progression; 15 discontinued for ≥ g2 irAE [PN (3), hepatitis (1), GN (2), adrenal (1), myocarditis (1), GI (3), thrombocytopenia (1), hyperthyroidism (1), encephalitis (1), pt decision (1)]. 67 pts had high CS cycles while 78 pts had low. 50% pts had irAE and 10% had ≥ g3 irAE, most commonly skin and GI. GI (15 vs 11%), skin (26 vs 20%) and PN (3 vs 0%) were reported in more pts during CT + D ± T cycles (non significant (NS)) ; hypothyroidism was more common with D ± T alone (18 vs 10%; p = NS). IrAE rates and severity were similar between high (67 pts) or low CS (78 pts) except for GI (19 vs 10%; p = NS). BIO were more common during CT + D ± T (74% of pts vs 48% p = 0.003); rates in high CS were similar to low CS. LFTs (ALT/AST - 41% vs 16%; 38% vs 9%; p = 0.005) and amylase/lipase (18 vs 9%; 19 vs 14%; p = NS) were more common in pts with CT + D ± T cycles vs pts with D ± T alone cycles. Conclusions: There is no evidence that CT or CS abrogates irAE in this exploratory analysis. GI, skin, pneumonitis, LFTS and amylase/lipase were more common during CT + D ± T suggesting additive/multifactorial causes; hypothyroidism is more common in D ± T cycles, which may reflect time on treatment. Clinical trial information: NCT02537418.
Molecular characterization of immune-related severe adverse events (irSAE).
Authors: Balko Justin M. , Al-Rohil Rami N , Wang Daniel Ying , Liang Yan , Ong Giang , Barker Kristi , Compton Margaret , Wang Yu , Beechem Joseph M , Xu Yaomin , Sosman Jeffrey Alan , Mobley Bret , Shi Chanjuan , Moslehi Javid J. , Johnson Douglas Buckner
Published: September 2018

3076

Background: Immune checkpoint inhibitors (ICIs; anti-CTLA-4 and anti-PD-1) have shown clinical success in many cancers, but may cause rare irSAE. The molecular features of irSAE have not been extensively explored. Therefore, we characterized the immune composition of tissue affected by ICI-mediated inflammation with a focus on colitis and neurologic toxicity. Methods: We performed retrospective T-cell receptor (TCRβ) sequencing, RNA-sequencing (HTG EdgeSeq; > 2500 immune-related genes), and digital spatial profiling (NanoString) for 20 protein markers in 10 regions across tissues representing ICI-induced colitis, autoimmune inflammation (e.g. Crohn’s) and normal colon. Matched tumors were also included in a subset. We also analyzed the encephalitic and healthy brain of a unique presentation of anti-PD-1-induced encephalitis. Results: Patient-matched melanoma and colitis biopsies (n = 3) demonstrated shared T cell clones in all samples ranging from several shared clones to several hundred (0.4%, 2.7%, and 3% of rearrangements, respectively), including high-frequency clones. Shared TCRβ sequences were also identified among and between colon-irSAE and Crohn’s specimens. Gene expression patterns of inflammation in colon-irSAE resembled that of Crohn’s disease in principle components and clustering analysis, highlighting likeness between these diseases/SAEs. NanoString digital spatial profiling of regions of inflammation across samples showed higher CD68 and PD-L1 positivity in colon-irSAE specimens versus normal colon or Crohn’s specimens and reduced beta-catenin levels in both Crohn’s and colon-irSAE specimens relative to normal controls. Finally, we detected a high degree of TCR clonality in the encephalitic brain, including a single sequence present in ~20% of > 12,000 T cells, suggesting a distinct antigen-specific response. Conclusions: We report the molecular characteristics of irSAE in colon and brain specimens from patients receiving ICIs. Highly clonal TCRβ sequences were frequently detected, particularly in a unique case of encephalitis-irSAE. Furthermore, we identify molecular distinctions and similarities between autoimmune and colon-irSAEs at the gene expression and proteomic levels.
Interrogating resistance mechanisms to PD-1 blockade therapy with CRISPR.
Authors: Torrejon Davis Yuri , Zaretsky Jesse Meir , Shin Daniel Sanghoon , Onyshchenko Mykola , Abril-Rodriguez Gabriel , Vega-Crespo Agustin , Puig-Saus Cristina , Cheung-Lau Gardenia , Long Chris , Comin-Anduix Begonya , Hu-Lieskovan Siwen , Ribas Antoni
Published: September 2018

3077

Background: We tested the biological significance of the loss of function (LOF) mutations in JAK1 or JAK2 within the IFN-receptor-pathway and in beta-2-microglobulin (B2M), which had been found in patient biopsies with resistance to anti-PD-1 therapy. Methods: We used CRISPR/Cas9 genome editing to generate JAK1, JAK2 and B2M knockout (KO) sublines of HLA-A*02:01 MART-1 or NY-ESO-1 positive human melanoma cell lines, tested using in-vitro T cell co-culture systems and in a syngeneic mouse model (MC38) to analyze the in-vivo antitumor activity with anti-PD1 therapy. Results: The JAK2-KO cell line was insensitive to IFN-gamma induced signaling and growth arrest (p < 0.001 compared with IFN-alpha or beta), while the JAK1-KO cell line was insensitive to all three IFNs. Baseline MHC class I expression after JAK1-KO was unaffected (baseline-MFI 1230 JAK1-KO vs 1570 parental, p = 0.66), but the magnitude of change was lower upon IFN-gamma exposure compared to the parental (MFI change with IFN-gamma, 26% decrease for JAK1-KO vs 50% increase for parental). There was no difference in in-vitro cytotoxicity by NY-ESO-1-TCR transgenic T-cells against JAK1-KO-NY-ESO-1+ melanoma cells compared to the parental (78% vs 82% cytotoxicity at 10:1 E:T ratio, p NS). However, B2M-KO was resistant to killing by MART-1 specific T-cells (2% vs 96% cytotoxicity at 10:1 E:T ratio, p < 0.0001). On the other hand, in the MC38 model the significant antitumor activity of anti-PD-1 against the wild type cells was lost in both JAK2-KO and B2M-KO. The percentage of CD8+ T cells has a trend of increase with anti-PD1 compared to untreated in the MC38 wild type (p = 0.1 d12), and a trend of decrease in MC38 B2M-KO (p = 0.2 d12), but no change in JAK2-KO tumors (p = 0.7 d12). Conclusions: JAK1/2 LOF mutations result in insensitivity to IFN induced antitumor effects, but does not impair T cell recognition and cytotoxicity, while B2M LOF results in lack of antigen presentation to T cells and loss of antitumor activity. However both lead to in-vivo resistance to anti-PD-1 therapy, suggesting they do so by independent mechanisms.
Ensituximab (E) in patients (pts) with refractory metastatic colorectal cancer (mCRC): Results of a phase I/II clinical trial.
Authors: Kim Richard D. , Arlen Philip M. , Tsang Kwong Y. , Mavroukakis Sharon , Zaki Anjum , Cui Karen , Azad Nilofer Saba , Tan Benjamin R. , Poplin Elizabeth , Morse Michael , Beg Muhammad Shaalan
Published: September 2018

3081

Background: E is an investigational, novel, chimeric monoclonal IgG1 antibody derived from an immunogenic neoantigen with sequence homology to MUC5AC that is preferentially expressed with exquisite specificity to pancreatic cancer and CRC. Its mechanism of action is via antibody-dependent cellular cytotoxicity (ADCC). The efficacy and safety of E was evaluated in a single-arm, open-label, phase 1/2 clinical trial of adult pts with refractory mCRC. Methods: Pts were selected based on > 20% expression of tumor antigen, as measured by immunohistochemistry. Based on phase 1 results, E was administered 3 mg/kg IV every 2 weeks until unacceptable toxicity or disease progression. Primary endpoint was overall survival (OS). Serum cytokine levels were analyzed at baseline, day 4, and day 15. E-mediated ADCC of CD16 genotype V/V, V/F, and F/F pt PBMCs was measured with an IN-111 release assay using the E target-expressing ASPC-1 pancreatic cancer cell line. Results: Fifty-seven and 63 pts were evaluable for OS and safety, respectively. Median OS was significantly longer than historical control: 6.8 vs 5.0 months (mo); p = 0.007; 95% CI: 5.39,8.02. Three pts were alive at end of study (21, 21, and 24 mo); 21 pts survived ≥ 12 mo. Pts had a median of 4 prior therapies (range 2-9); 25% had received regorafenib. Forty-seven pts were evaluable by RECIST, and 20 (43%) had stable disease of target lesions at end of first course (day 57). E was well tolerated, with < 2% grade 3 and no grade 4 toxicities. There were no trends in serum cytokine and chemokine levels. Analysis of 56 samples (8 V/V, 26 V/F, 17 F/F, and 5 undetermined) showed that V/V PBMCs had significantly higher E-mediated ADCC than PBMCs harboring other genotypes. No correlation between CD16 polymorphism and pt outcome was observed. Conclusions: E demonstrated excellent tolerability and encouraging OS in this heavily pretreated population. Correlative in vitro data suggest that E can mediate higher levels of ADCC activity in individuals with a V/V versus other genotypes. The lack of correlation between CD16 polymorphism and pt outcomes in this study suggests that other immune-related factors (under investigation) may impact the efficacy of E in vivo. Clinical trial information: NCT01040000.