bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary results from CLASSICAL-Lung, a phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC.
Authors: Shafique Michael Rahman , Fisher Terrence Lee , Evans Elizabeth E. , Leonard John E. , Pastore Desa Rae Electa , Mallow Crystal L. , Smith Ernest , Zauderer Maurice , Schröder Andreas , Chin Kevin M. , Beck J. Thaddeus , Baumgart Megan Ann , Govindan Ramaswamy , Sanborn Rachel E. , Goldman Jonathan Wade
Published: May 2019

2601

Background: Rational combination therapies are needed to overcome resistance mechanisms in NSCLC. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D (SEMA4D, CD100). In vivo preclinical models demonstrated antibody blockade of SEMA4D promoted immune infiltration and reduced function and recruitment of immunosuppressive myeloid cells within the tumor. Importantly, preclinical combinations of anti-SEMA4D with various immunotherapies enhanced T cell activity and tumor regression. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This ongoing phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) NSCLC (NCT03268057). The trial is split into dose escalation (n = 12) and dose expansion (n = 50) phases and includes 2 cohorts; 1) pts who are immunotherapy naïve, and 2) pts whose tumors progressed during or following immunotherapy (IO failure). Pts in the dose escalation cohorts received ascending doses of pepinemab i.v. (5, 10, 20 mg/kg, Q2W) in combination with avelumab i.v. (10mg/kg, Q2W). Results: Dose escalation is complete and the RP2D was selected as 10mg/kg pepinemab, Q2W. No pts experienced a TRAE leading to study discontinuation or death. The most frequent related AEs were grades 1 or 2 fatigue, pyrexia, or chills; no grade 3 AEs occurred in more than one subject. One DLT, a grade 3 pulmonary embolism occurred in the 10mg/kg pepinemab cohort, and resolved without reoccurrence. The disease control rate for pts treated > 2 months is 90% (19/21), and, at this early stage, a PR with a 49% reduction in target lesion was observed in at least 1 of 8 pts in the IO failure cohort. Updated data from the dose expansion phase will be presented. Conclusions: Preliminary data suggest the combination is well tolerated and shows initial signals of antitumor activity. Dose escalation is complete and the expansion phase is ongoing. Clinical trial information: NCT03268057.
Phase I safety and pharmacokinetic study of KN035, the first subcutaneously administered, novel fusion anti-PD-L1 antibody in Japanese patients with advanced solid tumors.
Authors: Shimizu Toshio , Nakajima Takako Eguchi , Lu Ni , Xue Shilin , Xu Wenlian , Fu Meng , Cao Walt , Lu Haolan , Liu David , Dong RuiPing , Wang Xiaoxiao , Wang Pilin , Zhu Danming , Xu Ting , Gong John
Published: May 2019

2609

Background: KN035 is a novel fusion protein of humanized anti-PD-L1 single domain antibody and human IgG1 Fc, formulated for subcutaneous (SC) injection. A phase I safety and pharmacokinetic (PK) study was conducted in Japanese patients. Methods: Patients with advanced solid tumors were treated with KN035 SC once every-7-days (QW) or once every-14-days (Q2W) schedules with the dose limiting toxicities (DLT) evaluation period of 28 days. For the QW schedule, the starting dose was 1 mg/kg (n=3) with escalations to 2.5 (n=4), and 5 (n=3) mg/kg. For the Q2W schedule, 6 patients were planned at the dose levels of 2.5 and 5 mg/kg. Results: No DLT was observed up to the highest dose level of 5 mg/kg QW. No maximum tolerated dose (MTD) was reached. Among evaluable treated subjects (n=14), there were two confirmed partial responses. Preliminary PK analysis suggested that after SC administration, KN035 was slowly absorbed (Tmax ∼ 4 d) and the mean residual time (MRT) was 21 days. Apparent clearance (CL/F) and volume of distribution (Vz/F) were on average 0.58 L/day and 11 L, respectively. Plasma levels generally decreased mono-exponentially with an average terminal elimination half time around 13 days after reaching the peak concentration post SC administration. Exposures of KN035 increased approximately proportionally with dose. Trough concentrations were maintained above 15 µg/mL post administration of 5 mg/kg Q2W. No apparent exposure-body weight relationship was observed. Conclusions: KN035 exhibits a favorable safety profile in patients with advanced malignancies and preliminary results demonstrate encouraging anti-tumor activity. Based on PK data from the Q2W schedule, a fixed dose with less frequent dosing schedule of every 3 or 4 weeks is presently being evaluated. Clinical trial information: NCT03248843.
A phase 1/2a study of GEN-009, a neoantigen vaccine based on autologous peptide immune responses.
Authors: Cohen Roger B. , Johnson Melissa Lynne , Twardowski Przemyslaw , Stein Mark N. , Vaishampayan Ulka N. , Dobson Jason R. , Foti James , Agnihotri Parul , Dowal Louisa , Broom Wendy , McNeil Lisa , Davis Thomas A. , Flechtner Jessica
Published: May 2019

2611

Background: Tumor-specific neoantigens provide individualized targets for immunotherapy. In silico selection methods are sub-optimal at predicting immunogenic targets, missing up to 70% of true neoantigens. ATLAS is a powerful tool that screens all candidate neoantigens for pre-existing patient-specific CD4 or CD8 responses in an HLA agnostic assessment. ATLAS also identifies inhibitory peptides that may suppress tumor immunity and accelerate tumor progression. The GEN-009 vaccine contains stimulatory but no inhibitory peptide antigens. Methods: GEN-009-101 is a first-in-human phase 1/2a study testing platform feasibility, safety, immunogenicity and clinical activity in selected solid tumors. After next-generation tumor sequencing and cytokine-based ATLAS assessment using autologous T cells and APCs, up to 20 stimulatory synthetic long peptides are used in each personalized vaccine. GEN-009 is administered with poly-ICLC on weeks 0, 3, 6, 12 and 24. Part A, a safety and immunogenicity pilot, has completed target enrollment of patients without evidence of disease to receive GEN-009; Part B has 5 tumor-specific cohorts of up to 15 pts naïve to PD-1 blockade who will receive GEN-009 with a SOC immunotherapy; Part C: up to 15 pts refractory to PD-1 inhibitors will receive GEN-009 monotherapy. Results: GEN-009 has been successfully generated for patients. Repeated dosing has been well tolerated with mild local discomfort and no DLT. ATLAS screening results below show notable interpatient variability; one subject had only CD4 neoantigens, one had only CD8, another had a strong CD8 bias, and one patient had prominent inhibitory peptides. Conclusions: GEN-009 is a neoantigen vaccine that personalizes tumor specific targets and the individual patient’s capacity to respond. Immunogenicity data will assess CD4 and CD8 T cell responses to each vaccine neoantigen. Clinical trial information: NCT03633110. [Table: see text]
Interim analysis of a phase II study of nivolumab combined with ipilimumab in patients with pediatric solid tumors in adulthood (GETHI021).
Authors: Mielgo Xabier , Diaz-Beveridge Robert , Sepulveda Juan Manuel , Pineda Estela , Lecumberri Maria Jose , De Las Penas Ramon , Rodriguez Salas Nuria , Valverde Claudia , López Castro Rafael , Vaz Maria Angeles , Lopez Lopez Carlos , Virizuela Juan Antonio , Medina Javier , Lopez Rafael , Rodríguez-Antona Cristina , Berraondo Pedro , Rodriguez-Moreno Juan Francisco , Moreno Diana , Martin Hernandez Raquel , Garcia-Donas Jesus
Published: May 2019

2613

Background: Solid pediatric tumors that appear in adulthood are a heterogeneous group characterized by a low incidence, lack of standard therapeutic options and reduced survival. We have designed the first phase II clinical trial of nivolumab and ipilimumab in this setting, Here, we present the results of the first cohort with 30 evaluable patients. Methods: This is a multicenter, open-label, single arm Phase II study conducted in 15 centers of the Spanish Group for Rare Cancer (GETHI). We aimed to evaluate efficacy and safety of the combination of nivolumab and ipilimumab in adult patients ( 18 years) with locally advanced or metastatic childhood malignancies that have progressed or are not candidates to standard therapy. Treatment consisted on nivolumab 3 mg/kg IV q2w + ipilimumab 1 mg/kg IV q6w for 6 months or until progression/unacceptable toxicity, for a maximum of 24 months. Primary endpoint was overall response rate (ORR) according to RECIST v1.1 criteria. We used a Simon optimal two-stage design, with a first stage including first 30 evaluable patients. Results: 20 patients were male and median age was 43 (range 20-75). Most frequent histologies were medulloblastoma (4) neuroblastoma (4) and Ewing family tumors (3). 90% had received prior systemic therapy with 37% presenting progressive disease as best response. Median previous treatment lines were 3 (range 1-9). 27 patients were PS0-1, and 3 PS2. 6 patients have been treated for ≥6 months . Only one discontinued for adverse events. With a median follow up of 4,3 months (range 0,4-11,3), 1 patient has achieved a deep partial response (PR) (3,6%), 10 stable disease (SD) (35,7%) and 17 progressive disease (PD) (60,7%). 2 patients died before radiologic evaluation. Clinical benefit rate (CR+PR+SD) was 39,3%. Median progression free survival (PFS) was 1,8 months (95% CI 1,3-2,3), with a 3-months-PFS of 32,7% and 6-months-PFS of 20%. Median overall survival (OS) was 6,8 months (95% CI 3,3-10,2). 12 (40%) patients presented adverse events (AE) of any grade and 6 (20%) experienced a grade AE deemed as possibly related to treatment. Conclusions: The combination of nivolumab and ipilimumab showed significant clinical benefit in this population with little therapeutic options. One case of metastatic esthesioneuroblastoma, achieved a dramatic tumor response and represents the first patient with this extremely rare histology treated with immunotherapy. Clinical trial information: EudraCT 2016-003946-99.
Overestimation of tumor mutational burden (TMB) using algorithms compared to germline subtraction.
Authors: Parikh Kaushal , Huether Robert , White Kevin , Hoskinson Derick , Dong Haidong , Adjei Alex A. , Mansfield Aaron Scott
Published: May 2019

2621

Background: TMB is an emerging predictor of survival with immunotherapy. TMB is determined by taking the difference between somatic and germline datasets when tumor-normal pairs are available. In the case of commonly utilized tumor-only sequencing, additional steps are needed to estimate the somatic alterations. Computational tools have been developed that determine germline contribution based on sample copy state, purity estimates and occurrence of the variant in population databases. Given the potential bias of population datasets, we hypothesized that tumor-only filtering approaches may overestimate the actual TMB. Methods: We assessed the TMB from 50 tumors in 10 diseases including all missense, indels, and frameshift variants with an allelic fraction (AF) ≥5% and Coverage ≥100X within the tumor. Tumor-only TMB was evaluated against the gold standard of matched germline subtracted TMB at three levels. Level 1 removed all the tumor-only variants with AF in the non-TCGA ExAC database ≥1%. Level 2 removed all variants observed in population databases simulating a naive approach of removing germline variation. Level 3 used an internal tumor-only pipeline for calculating TMB. Results: There were significantly higher estimates of TMB with Level 1, Level 2 and Level 3 tumor-only filtering approaches than that determined by germline subtraction, resulting in significant bias. Whereas there was no correlation between TMB estimates and tumor-germline TMB for Level 1 filtering, there were improvements in correlations for Level 2 and Level 3. Conclusions: The tumor-only approaches that filter variants in population databases overestimate TMB compared to that determined by germline subtraction. Despite improved correlations with more stringent filtering approaches, these falsely elevated estimates may result in the inappropriate categorization of tumor specimens and negatively impact clinical trial results and patient outcomes. [Table: see text]
TMB standardization by alignment to reference standards: Phase II of the Friends of Cancer Research TMB Harmonization Project.
Authors: Merino Diana M. , McShane Lisa , Butler Matt , Funari Vincent Anthony , Hellmann Matthew David , Chaudhary Ruchi , Chen Shu-Jen , Chen Wangjuh Sting , Conroy Jeffrey M. , Fabrizio David , MacConaill Laura E , Pallavajjala Aparna , Papin Arnaud , Sausen Mark , Weigman Victor J , Xie Mingchao , Zehir Ahmet , Zhao Chen , Williams Paul M. ,   Friends of Cancer Research TMB Harmonization Team
Published: May 2019

2624

Background: Tumor mutational burden (TMB) is a predictive biomarker of response to immune checkpoint inhibitors across multiple cancers. In Phase 1 of the Friends of Cancer Research Harmonization Project, we demonstrated a robust correlation between TMB estimated using targeted next-generation sequencing (NGS) gene panels and whole exome sequencing (WES) applied to MC3-TCGA data. These findings demonstrated variability in TMB estimates across different panels. Phase 2 evaluates sustainable TMB reference standard materials for TMB alignment to assess this variability. The goal of this effort is to establish best practices for estimating TMB in order to improve consistency across panels, for the sake of optimizing clinical application and facilitating integration of datasets generated from multiple assays. Methods: Fifteen laboratories with targeted panels at different stages of development participated. We identified a set of reference standards consisting of 10 well-characterized human-derived lung and breast tumor-normal matched cell lines. WES was performed using a uniform bioinformatics pipeline agreed upon by all team members (WES-TMB). Each laboratory used their own sequencing and bioinformatics pipelines (tumor-only and tumor-normal) to estimate TMB according to genes represented in their respective panels (panel-TMB). The association between WES-TMB and each panel-TMB was investigated using regression analyses. Bias (relative to WES-TMB) and variability in TMB estimates across panels were rigorously assessed. All analyses were blinded. Results: The set of reference standards spanned a clinically meaningful TMB range (4.3 to 31.4 mut/Mb). Preliminary data from 12 laboratories shows a good correlation between panel-TMB and WES-TMB in this empirical analysis. Across panels, regression R2 values range 0.77-0.96 with slopes ranging 0.60-1.26. Calibration analyses that seek to minimize variability of TMB estimates across panels using the established set of reference standards are ongoing, as well as investigating cancer type dependence on the relationship between panel-TMB vs. WES-TMB, which will be available at the time of presentation. Conclusions: Preliminary findings demonstrate feasibility of using sustainable reference control cell lines to standardize and align estimation of TMB across different targeted NGS assays. Future studies aim to validate reference standard material as a reliable alignment tool by using formalin-fixed paraffin-embedded human tumor samples.
Association of genetic variations within the T-cell costimulatory LIGHT gene with outcome in stage II and III colon cancer.
Authors: Berger Martin D. , Cao Shu , Zlobec Inti , Miyamoto Yuji , Suenaga Mitsukuni , Hanna Diana L. , Soni Shivani , Puccini Alberto , Tokunaga Ryuma , Naseem Madiha , Battaglin Francesca , Zhang Wu , Lugli Alessandro , Lenz Heinz-Josef
Published: May 2019

2633

Background: T-cell activation plays a key role in maintaining an effective host immunity and antitumor control. Targeting costimulatory immune checkpoint proteins can lead to increased antitumor immunity. We hypothesize, that variations in genes encoding for T-cell activation molecules may predict outcome in stage II and III colon cancer patients. Methods: The impact of 4 functional single nucleotide polymorphisms (SNPs) within the LIGHT, ICOS, CD80 and GITR genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 41.6% / 58.4%; 111 patients had stage II, and 98 stage III colon cancer. The LIGHT rs3760746 SNP showed significant association with recurrence rate in the overall population. Patients harboring any G allele had a lower 3-years recurrence rate compared to those with a A/A genotype (16% vs 30%) in both univariate (HR 0.53, 95% Confidence intervall (CI) 0.29-0.96, p = 0.033) and multivariate analyses (HR 0.52, 95% CI 0.29-0.95, p = 0.034). This trend was most evident among patients with stage III colon cancer. Here again, G allele carriers had both a lower 3-years recurrence and a longer 5-years overall survival rate compared to those having a A/A genotype (21% vs 40% and 77% vs 43%) in both univariate (HR 0.42, 95% CI 0.19-0.90, p = 0.021 and HR 0.51, 95% CI 0.25-1.03, p = 0.046) and multivariate analyses (HR 0.43, 95% CI 0.20-0.93, p = 0.033 and HR 0.30, 95% CI 0.14-0.65, p = 0.002). Conclusions: Our results provide the first evidence that polymorphisms within the T-cell costimulatory LIGHT gene might serve as prognostic markers in patients with stage II and III colon cancer. Targeting LIGHT might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.
Phase I trial of a modified vaccinia ankara (MVA) priming vaccine followed by a fowlpox virus (FPV) boosting vaccine modified to express brachyury and costimulatory molecules in advanced solid tumors.
Authors: Collins Julie Marie , Donahue Renee Nicole , Tsai Yo-Ting , Palena Claudia , Marte Jennifer L. , Madan Ravi Amrit , Karzai Fatima , Heery Christopher Ryan , Strauss Julius , Gatti-Mays Margaret Elena , Cordes Lisa M. , Schlom Jeffrey , Gulley James L. , Bilusic Marijo
Published: May 2019

2640

Background: Brachyury, a transcription factor, plays an integral role in epithelial-to-mesenchymal transition, metastasis, poor prognosis, and resistance to chemotherapy. It is expressed in many tumor types, and rare in normal tissue, making it an ideal immunologic target. BN-Brachyury comprises heterologous vaccination with recombinant MVA priming followed by FPV boosting, each encoding transgenes for brachyury and three costimulatory molecules (B7-1, ICAM1, and LFA-3). Heterologous prime boost approach is intended to optimize immunogenicity, as previously observed. Methods: Pts with metastatic solid tumors were treated with 2 monthly doses of MVA-brachyury SC at the previously tested dose, 2.2 x 109 infectious units (IU), followed by FPV-brachyury SC, 1 x 109 IU, for 6 monthly doses and then every 3 months for up to 2 years. The primary objective was to determine safety and tolerability and establish the RP2D. Immune assays were conducted to evaluate immunogenicity. Results: In 10 pts (3 chordoma, 6 GI, 1 papillary thyroid), no dose-limiting toxicities or serious treatment-related adverse events (TRAEs) were observed. The only Grade 3 TRAE was sedation associated with fever, which resolved spontaneously and did not recur with subsequent cycles. All other TRAEs were Grade 1 or 2; the most common was injection-site reaction in all patients. Five pts have had stable disease for > 24 wks (per RECIST v1.1) and remain on treatment. One pt with chordoma, for which BN-Brachyury was granted orphan drug designation, has had a 13.2% reduction in tumor size. As previously demonstrated, brachyury-specific T cell responses were observed, as were responses against cascade antigens (non-encoded antigens) CEA and MUC-1. Conclusions: Heterologous MVA- and FPV-brachyury is well tolerated and induced immune responses to brachyury and cascade antigens, suggesting induction of immunologically relevant tumor cell destruction. These data have informed combining BN-Brachyury with checkpoint inhibition (NCT03493945) and radiation (NCT03595228) to evaluate potential for synergetic activity in selected populations. Clinical trial information: NCT03349983.
Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors.
Authors: Fakih Marwan , O'Neil Bert , Price Timothy Jay , Falchook Gerald Steven , Desai Jayesh , Kuo James , Govindan Ramaswamy , Rasmussen Erik , Morrow Phuong Khanh H. , Ngang Jude , Henary Haby A. , Hong David S.
Published: May 2019

3003

Background: The KRASG12C mutation is found in approximately 13% of lung adenocarcinomas and 1–3% of other solid tumors, but there is no approved therapy that targets this mutation. AMG 510 is a novel small molecule that specifically and irreversibly inhibits KRASG12C by locking it in an inactive GDP-bound state. Methods: This phase 1, first-in-human, open-label, multicenter study (NCT03600883) is evaluating the safety, tolerability, PK, and efficacy of AMG 510 in adult patients (pts) with locally-advanced or metastatic KRASG12C mutant solid tumors. The primary endpoint is safety; key secondary endpoints include PK, ORR (assessed every 6 weeks [wks]), DOR, and PFS. Key inclusion criteria: KRASG12C mutation identified through DNA sequencing, measurable or evaluable disease, ECOG PS ≤2, life expectancy >3 months (mo). Key exclusion criteria: active brain metastases, myocardial infarction within 6 mo. A dose exploration will determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). A dose expansion will enroll pts with NSCLC, CRC, and other advanced solid tumors carrying the KRASG12C mutation. AMG 510 will be given PO until disease progression, intolerance, or withdrawal of consent. Results: 22 pts (8 men, 14 women; median age 55.5 y) were enrolled in the first 3 dose cohorts. Tumor types: 6 NSCLC, 15 CRC, 1 other. Most pts (n=17) had ≥3 prior lines of treatment (tx). Median tx duration was 28 d (range: 8–134). 5 pts reported 10 treatment-related AEs (grade 1, n=9; grade 2, n=1); there were no DLTs. Tumor response was evaluated in 9 pts (4 with ≥2 assessments); 13 pts have not reached their first assessment.1 pt had a PR (NSCLC at wks 6 and 12, tx ongoing), 6 pts had SD (4 CRC and 2 NSCLC; median tx duration 9.7 wks [range: 6.3–19.1], tx ongoing), 2 pts had PD. 20 pts are continuing to receive AMG 510. A second PR (NSCLC at wk 6, tx ongoing) was reported after data cutoff. Conclusions: AMG 510 has been well tolerated at the dose levels tested and has shown antitumor activity when administered as monotherapy to patients with advanced KRAS G12C mutant solid tumors. MTD has not been determined, and enrollment into the dose exploration is ongoing. Clinical trial information: NCT03600883.
Single agent ONC201 in adult recurrent H3 K27M-mutant glioma.
Authors: Arrillaga Isabel , Kurz Sylvia , Sumrall Ashley , Butowski Nicholas A. , Harrison Rebecca A. , De Groot John Frederick , Shonka Nicole A. , Lieberman Frank S. , Odia Yazmin , Tarapore Rohinton , Merdinger Krystal , Allen Joshua E. , Oster Wolfgang , Mehta Minesh P. , Cloughesy Timothy Francis , Chi Andrew S. , Lassman Andrew B. , Batchelor Tracy , Wen Patrick Y.
Published: May 2019

3005

Background: H3 K27M-mutant glioma is associated with a poor prognosis and there is no effective therapy following radiation. We report the clinical experience with single agent ONC201, the first small molecule DRD2 antagonist in oncology, in adults with recurrent H3 K27M-mutant glioma. Methods: Twenty-nine adult patients with recurrent H3 K27M-mutant glioma have been treated with single agent ONC201 as of January 20, 2019: 19 patients on NCT03295396; 8 patients on NCT02525692; 2 patients on compassionate use protocols under the Sponsor’s IND. Median age was 57 years old (range: 17-74), median prior lines of therapy was 2 (range: 1-4) and all patients received prior radiation (median 8.5 months from radiation completion to ONC201 initiation). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. Results: As of February 5, 2019, 13 of 29 patients remain on-trial within median follow up of 6.5 months (range: 0.6-33.6), 8 patients are alive but off-trial with median follow up of 2.4 months (range: 0.2-9), and 8 patients have expired. Nine of 29 patients (31%) remain progression-free on ONC201 with a median follow up of 6.5 months (range 0.6-33.6). No dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Three patients have experienced durable partial responses by RANO (4.3-28.5 months). In addition, one patient experienced complete regression that continues for > 14 months of all < 1 cm tumor lesions that are not measurable by RANO. Furthermore, 10 patients had a best response of stable disease by RANO, 12 patients experienced progressive disease, and 3 patients are not yet evaluable. Among the patients with a best response of stable disease by RANO, one patient had > 50% tumor regression in the basal ganglia that did not qualify as a partial response by RANO due to a new lesion on a confirmatory scan. Another patient with stable disease by RANO has had 37% tumor regression so far in the brainstem and remains on-treatment for 6 months. All tumor regressions remain durable to date and some were associated with improvements in disease-associated neurological symptoms. Conclusions: Single agent ONC201 is well tolerated and clinically active in adult recurrent H3 K27M-mutant glioma patients. Clinical trial information: NCT03295396; NCT02525692.
Phase 1/2 trial of FF-10502-01, a pyrimidine antimetabolite, in patients with advanced cholangiocarcinoma and solid tumors.
Authors: Janku Filip , Sen Shiraj , Pant Shubham , Bramwell Lindsay , Subbiah Vivek , Way Tracey , Javle Milind M. , Stone Cassie , Prajapati Bhumika , Hagiwara Shinji , Johansen Mary , Madden Timothy , Maier Gary , Subach Ruth Ann , Saeki Kazunori , Suzuki Takeaki , Wages David S. , Wheeler Catherine A. , Falchook Gerald Steven
Published: May 2019

3008

Background: FF10502 is a synthetic pyrimidine nucleoside similar to gemcitabine (gem) with a sulfur in the pentose ring. FF10502 is a more potent inhibitor of DNA polymerase Beta than gem with activity in gem resistant patient (pt) derived xenograft models. FF10502 is avidly taken up into DNA and has greater activity against quiescent cells than gem. Methods: Pts > 18 years old with advanced disease who had progressed on standard of care were enrolled into 9 dose levels to determine maximum tolerated dose (MTD) and dose limiting toxicities (DLTs) and subsequently into two expansion cohorts: biliary or solid tumors (ST). FF10502 at doses of 8 to 135 mg/m2 was administered iv on days 1, 8, 15 of a 28-day cycle until progressive disease or toxicity. PK/PD evaluations were performed on all pts. Response was assessed by RECIST 1.1. Results: 76 pts were treated; 35 pts in dose escalation, including 7 cholangiocarcinoma pts. MTD was 90 mg/m2. DLTs included 2 pts with hypotension at 135mg/m2 (G3 and G4) and 1 pt each with G3 fatigue and G2 rash at 100mg/m2. In expansion, 19 cholangiocarcinoma, 3 gallbladder and 19 other pts (13 pancreatic, 2 urothelial, and 1 each ovarian, prostate, NSCLC, SCCHN each) were treated. 1 pt with prior rituximab for ITP developed PML. G3 treatment-related low platelets occurred in 3 pts at 90mg/m2 after cycle 1. There were 5 partial responses (PRs), including 4 pts who had progressed on prior gemcitabine: 3 of 26 pts with cholangiocarcinoma, 1 urothelial carcinoma and 1 chondroblastic osteosarcoma. 7 cholangiocarcinoma pts stayed on therapy for ≥6 months. FF10502 incorporation intoperipheral blood cellular DNA was seen, andbiomarkeranalysisdata to identify pts with higher potential for clinical response will be presented. Conclusions: FF10502 is well tolerated in pts with advanced cancers refractory to standard therapies. Early signals of efficacy warranting further exploration were seen in heavily pretreated cholangiocarcinoma pts (median: 4 prior therapies). Patient selection based on differential effects of FF10502 on DNA polymerases will be explored. Clinical trial information: NCT02661542.
Results of the phase 1b study of ABBV-399 (telisotuzumab vedotin; teliso-v) in combination with erlotinib in patients with c-Met+ non-small cell lung cancer by EGFR mutation status.
Authors: Camidge D. Ross , Barlesi Fabrice , Goldman Jonathan Wade , Morgensztern Daniel , Heist Rebecca Suk , Vokes Everett E. , Spira Alexander I. , Angevin Eric , Su Wu-Chou , Hong David S. , Strickler John H. , Motwani Monica , Sun Zhaowen , Parikh Apurvasena , Noon Elysa , Wu Jun , Kelly Karen
Published: May 2019

3011

Background: Telisotuzumab vedotin (ABBV-399; teliso-v [T]) is a c-Met–targeted antibody and MMAE drug conjugate. Activity of T was shown in late-line c-Met+ non-small cell lung cancer (NSCLC) irrespective of EGFR mutation (M+) status. We present mature data from the T+ erlotinib (E) cohort of a phase 1b study (NCT02099058) by EGFR M+ status. Methods: T was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg IV Q3W, and E at 150 mg PO QD/prior tolerated dose in adult patients (pts) with advanced NSCLC. Efficacy-evaluable pts were c-Met+ (central lab IHC H-score ≥150 or local lab MET amplification/Ex 14 skipping) and had ≥1 postbaseline scan or discontinued study. EGFR M+ was defined as del19 or L858R by local lab. PK was assessed. Results: As of Dec 2018, 42 NSCLC pts received T+E; 37 were c-MET+ (36 evaluable; 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 pts (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (Gr; ≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Gr 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Gr ≥3 (≥10%) AE: pulmonary embolism (14%). PK of T+E was similar to single-agent T. The table presents efficacy data. Conclusions: These data suggest acceptable safety and promising activity of T+E and support further study in EGFR M+ c-Met+ NSCLC pts for whom frontline EGFR TKI failed. Clinical trial information: NCT02099058. [Table: see text]
Genome-wide cell-free DNA fragmentation profiling for early cancer detection.
Authors: Leal Alessandro , Cristiano Stephen , Phallen Jillian , Fiksel Jacob , Adleff Vilmos , Bruhm Daniel C. , Jensen Sarah Østrup , Medina Jamie E. , Palsgrove Doreen N. , Niknafs Noushin , Anagnostou Valsamo , Forde Patrick M. , Brahmer Julie R. , Fijneman Remond , Johansen Julia S. , Nielsen Hans J. , Meijer Gerrit A. , Andersen Claus Lindbjerg , Scharpf Robert B. , Velculescu Victor E.
Published: May 2019

3018

Background: Analyses of cell-free DNA (cfDNA) in the blood provide a noninvasive diagnostic avenue for patients with cancer. However, cfDNA analyses have largely focused on targeted sequencing of specific genes, and the characteristics of the origins and molecular features of cfDNA are poorly understood. We developed an ultrasensitive approach that allows simultaneous examination of a large number of abnormalities in cfDNA through genome-wide analysis of fragmentation patterns. Methods: We used a machine learning model to examined cfDNA fragmentation profiles of 236 patients with largely localized breast, colorectal, lung, ovarian, pancreatic, gastric, or bile duct cancer and 245 healthy individuals. Estimation of performance was determined by ten-fold cross validation repeated ten times. Results: cfDNA profiles of healthy individuals reflected nucleosomal patterns of white blood cells, while patients with cancer had altered fragmentation patterns. The degree of abnormality in fragmentation profiles during therapy closely matched levels of mutant allele fractions in cfDNA as determined using ultra-deep targeted sequencing. The sensitivity of detection ranged from 57% to > 99% among the seven cancer types at 98% specificity, with an overall AUC of 0.94. Fragmentation profiles could be used to identify the tissue of origin of the cancers to a limited number of sites in 75% of cases. Combining our approach with mutation-based cfDNA analyses detected 91% of cancer patients. Conclusions: This effort is the first study to demonstrate genome-wide cell-free DNA fragmentation abnormalities in patients with cancer. Results of these analyses highlight important properties of cfDNA and provide a facile approach for screening, early detection, and monitoring of human cancer.
A phase I study of pazopanib with weekly paclitaxel and carboplatin in advanced solid tumors.
Authors: Chan Nancy , Portal Daniella E. , Moss Rebecca Anne , Silk Ann W. , Stein Mark N. , Aisner Joseph , Malhotra Jyoti , Shih Weichung , Lin Hongxia , Kane Michael P. , Mehnert Janice M. , Tan Antoinette R.
Published: May 2019

3021

Background: Pazopanib (pazo) is an oral tyrosine kinase inhibitor of VEGFR, PDGFR and c-Kit. It is a weak inhibitor of CYP3A4 and CYP2C8 and may decrease paclitaxel (P) clearance. Daily pazo with P and carboplatin (C) every 21 days was not feasible on a previous study. We hypothesized that pazo dosed intermittently and on a different day from P and C may be tolerable. We sought to determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics (PK) of pazo with weekly P and C. Methods: Using a 3+3 standard design, a schedule of P 60-80 mg/m2 and C AUC2 on days 1, 8, and 15 with pazo 400-800 mg on days 2-5, 9-12, and 16-26 on a 28-day cycle was evaluated. Pazo alone could be continued if P and C were omitted due to maximal benefit or toxicity. PK was collected during cycles 1 and 2. Results: 34 patients (pts) were treated over 6 dose levels (Table). Mean age 57 (37-79). Tumor types: breast (22), lung (3) and other (9); 27 had prior platinum. Delay in starting cycle 2 due to grade 3 neutropenia was a DLT at dose level 2 and 5. Pts on 5A missed dosing during C1 and C2 due to neutropenia and required subsequent growth factor, and this was deemed unlikely to be sustainable long-term. All grade toxicities included anemia (62%), neutropenia (59%), and thrombocytopenia (56%). Protocol-defined MTD was not determined. PK analysis showed a dose proportional increase in pazo concentration, consistent with previous reports. Pazo did not alter the PK of C. Cmax of P was higher C2D1 vs C1D1; mean Cmax ratio between C2D1:C1D1 was 1.63 (95% CI:1.29-1.96). There were 11 objective responses (3 CRs, 8 PRs). Five breast pts were on pazo alone for a median of 9 cycles (2-52) with CR (2), PR (2) and SD (1); a squamous cell of unknown primary in CR received 22 cycles. Clinical trial information: NCT01407562. Conclusions: PK confirm that pazo is a weak inhibitor of CYP3A4 and CYP2C8. Myelosuppression was a major adverse event at all dose levels. MTD was not determined. Antitumor activity was achieved with this alternate combination schedule and sustained responses from sequential pazo monotherapy was observed.[Table: see text]
A phase I dose-finding and pharmacokinetics study of CPC634 (nanoparticle entrapped docetaxel) in patients with advanced solid tumors.
Authors: Atrafi Florence , Dumez Herlinde , Mathijssen Ron H.J. , Menke Catharina Wilhelmina , Costermans Jo , Rijcken Cristianne J.F. , Hanssen Rob , Eskens Ferry , Schoffski Patrick
Published: May 2019

3026

Background: CPC634 is a novel product with docetaxel temporarily entrapped within stabilized CriPec nanoparticles. We performed the first-in-human study with CPC634 (NCT02442531). Methods: Patients (≥18 years) received CPC634 intravenously either 3-weekly (Q3W) (part 1, 15-100 mg/m2), 2-weekly (Q2W) (part 2, 45 mg/m2) or Q3W with dexamethasone premedication (part 3) following a 3+3 design. Primary objectives were to assess safety, establish the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and to evaluate the pharmacokinetic (PK) profile of CPC634. Results: Thirty-three patients (part 1; n = 24, part 2; n = 3, part 3; n = 6) were treated. Skin toxicity was dose limiting at doses > 60 mg/m2 in part 1, and at a 45 mg/m2 dose in part 2. Skin toxicity was cumulative but resolved after ceasing treatment. The MTD in part 1 was set at 70 mg/m2. In part 3, the 60 mg/m2 was explored which resulted in improved skin tolerability even after repeated administrations without dose limiting toxicities. The RP2D was therefore set at 60 mg/m2 with dexamethasone premedication. Grade ≥3 adverse events (CTCAE version 4.03) were skin toxicity (21%), fatigue (8%), neutropenia (6%), peripheral sensory (8%) and motor neuropathy (4%), stomatitis (4%), infections (4%) and hypomagnesemia (3%). Alopecia grade 1 was reported in 15% of patients. CPC634 exhibited a dose-proportional PK profile. One partial response and sixteen cases of stable disease (RECIST 1.1) were confirmed in part 1 and in part 3 as best response. Conclusions: CPC634 could be administered safely but showed cumulative, though reversible skin toxicity at high doses. The RP2D was set at 60 mg/m2 Q3W with dexamethasone premedication. Additional studies assessing the intratumoral exposure to CPC634 (NCT0371243) and a phase II efficacy study of CPC634 in patients with platinum resistant ovarian cancer (NCT03742713) is currently ongoing. Clinical trial information: NCT02442531.
Phase I trial of chloroquine (CQ)/hydroxychloroquine (HCQ) in combination with carboplatin-gemcitabine (CG) in patients with advanced solid tumors.
Authors: Abdel Karim Nagla Fawzy , Ahmad Imran , Gaber Ola , Eldessouki Ihab , Olowokure Olugbenga Olanrele , Farooq Maria , Morris John Charles
Published: May 2019

3027

Background: Autophagy is a catabolic process triggered in cells during periods of stress to enable their survival. Established tumors utilize autophagy to survive periods of metabolic or hypoxic stress. Inhibition of early stage autophagy can rescue cancer cells, while inhibition of late stage autophagy will lead to cell death due to accumulation of damaged organelles. The antimalarial drugs CQ and HCQ inhibit late phase autophagy. The goal of our study is to assess the safety, tolerability and activity of combining CQ/HCQ with CG in advanced solid tumor patients who either progressed on other therapies or in whom CG is a therapeutic option. Methods: This single institution phase 1 dose-escalation study was designed to evaluate the maximum tolerated dose (MTD) of CQ, later substituted with HCQ, in combination with CG in patients with previously treated advanced solid tumors. Secondary objectives were to determine ORR, PFS and OS. A starting dose of 50 mg of CQ/HCQ was used in conjunction with CG, and increased in increments of 50 mg in each dose cohort. Grade 3 or greater toxicity that is treatment-related, and was not self-limited, or controlled in less than 7 days was considered dose limiting toxicity (DLT). Results: Twenty-three patients were enrolled with a median follow up of 6 months. HCQ 100 mg was found to be the MTD in combination with CG with ≥Grade 3 thrombocytopenia and/or neutropenia as dose-limiting. Median OS was 11 months, and the 1- and 3- year overall survival rates were 30% and 7%, respectively. Median progression free survival was 5 months and the 6-, 12-, and 18-months progression-free survivals were 48%, 21% and 14%, respectively (Table). Conclusions: The MTD identified for CQ/HCQ was lower than previously reported with concomitant use of chemotherapeutic regimes, likely due to the myelosuppressive nature of CG. Clinical trial information: NCT02071537. [Table: see text]
Associations of insulin-like growth factor binding proteins and adiponectin with disease progression and mortality in metastatic colorectal cancer: Results from CALGB/SWOG 80405 (Alliance).
Authors: Guercio Brendan John , Venook Alan P. , Zhang Sui , Ou Fang-Shu , Niedzwiecki Donna , Lenz Heinz-Josef , Innocenti Federico , Pollak Michael N. , Nixon Andrew B. , Mahoney Michelle R. , O'Neil Bert , Shaw James Edward , Polite Blase N. , Denlinger Crystal S. , Atkins James Norman , Goldberg Richard M. , Mayer Robert J. , Blanke Charles David , Fuchs Charles S. , Meyerhardt Jeffrey A.
Published: May 2019

3035

Background: Energy balance-associated biomarkers such as insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) have been associated with risk and prognosis of various malignancies. Their relationship to disease progression and mortality in metastatic colorectal cancer (mCRC) requires further study. Methods: In a prospective cohort study, baseline plasma IGFBP-3, IGFBP-7, C-peptide, IGF-I, and adiponectin were measured at trial registration among 1,086 patients participating in a National Cancer Institute-sponsored clinical trial of first-line therapy for mCRC. We used Cox proportional hazards regression to adjust for confounders and examine associations of biomarkers with overall (OS) and progression-free survival (PFS). Results: Higher plasma IGFBP-3 was associated with longer OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .003). Compared to patients in the lowest IGFBP-3 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 0.58 (95% CI 0.42 to 0.78) and for disease progression or mortality of 0.60 (95% CI 0.45 to 0.82). Higher plasma IGFBP-7 was associated with shorter OS (adjusted Ptrend < .001) and PFS (adjusted Ptrend = .02). Compared to patients in the lowest IGFBP-7 quintile, patients in the highest quintile experienced an adjusted HR for all-cause mortality of 1.52 (95% CI 1.24 to 1.88) and for disease progression or mortality of 1.28 (95% CI 1.05 to 1.57). C-peptide and IGF-I were not significantly associated with patient outcomes (adjusted Ptrend = .73 and .30 for OS). Adiponectin was not associated with OS; there was a U shaped association between adiponectin and PFS, wherein low and high values were associated with shorter PFS ( Pnon-linear trend = .03). Conclusions: In patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with reduced risk of disease progression and mortality. These data suggest that energy-balance associated biomarkers may offer prognostic and biologic insights into mCRC. Support: U10CA180821, U10CA180882, BMS, Genentech, Pfizer, Sanofi; https://acknowledgments.alliancefound.org .
Predictive and prognostic values of circulating tumor DNA (ctDNA) clearance in osimertinib treated advanced non-small cell lung cancer cohort.
Authors: Song Yong , Ma Shenglin , Shi Meiqi , Xu Xingxiang , Chen Xueqin , Wang Yong , Yang Zhenhua , Zhang Tengfei , Li Min , Li Haiyan , Zhang Lu , Mao Xinru
Published: May 2019

3036

Background: Although growth advantage of certain clones would ultimately translate into a clinically visible disease progression, radiological imaging does not reflect clonal evolution at the molecular level. CtDNA, validated as a tool for mutation detection in lung cancer, reflects dynamic molecular changes. Here, we evaluated the potential of ctDNA in monitoring molecular changes and predicting clinical outcomes of EGFR T790M-positive osimertinib treated NSCLC pts. Methods: This prospective multicenter study, enrolled 72 T790M positive osimertinib-treated advanced NSCLC pts who progressed on prior EGFR-TKI to evaluate the potential of ctDNA in monitoring, is part of the ongoing ASTRIS study (NCT02474355). Longitudinal plasma samples, collected from 52 pts, were subjected to sequencing using a panel consisting of 168 lung cancer-related genes. Results: Genomic profile prior to the initiation of osimertinib revealed that mutations participating in cell cycle (14 pts, p = 0.004) and P53 pathways (43 pts, p = 0.032) were associated with shorter OS ( p53 was excluded from analysis due to high mutation frequency). Interestingly, pts with undetectable ctDNA at first follow-up (within 50 d, n = 41) were correlated with longer PFS (p = 0.009) and OS (p = 0.022). With a median follow-up of 168 d (ranged from 40 - 550 d), 32 pts experienced radiological disease progression. Among them, 11 (34%) experienced molecular progression reflected by emergency of new mutation or increased allelic frequency of existing mutation prior to radiological progression, with an average leading time of 74 days. Pts with molecular PD prior to radiological PD were more likely to harbor any gene copy number amplification (CNA, p = 0.035) and p53 (p = 0.023) mutations at radiological PD. In addition, pts with CNA at radiological PD had shorter PFS (p = 0.002) and OS (p = 0.052). Conclusions: This clinical trial study demonstrates that ctDNA clearance at first follow-up can serve as a predictive and a prognostic marker for pts undergoing osimertinib treatment. Furthermore, it revealed the potential of ctDNA in early detection of disease progression, preceding imaging modalities with an average lead time of 74 days.
Can the enumeration of circulating tumor cells (CTCs) and the characterization of circulating tumor DNA (ctDNA) provide insight into organ tropism in metastatic breast cancer (MBC)?
Authors: Gerratana Lorenzo , Zhang Qiang , Shah Ami N. , Davis Andrew A. , Zhang Youbin , Wehbe Firas , Qiang Wenan , Flaum Lisa E. , Finkelman Brian , Gradishar William John , Platanias Leonidas C. , Behdad Amir , Cristofanilli Massimo
Published: May 2019

3038

Background: Liquid biopsy provides real-time data about prognosis and actionable mutations in MBC. The aim of this study was to explore the combination of ctDNA analysis and CTCs enumeration in estimating target organs more susceptible to MBC involvement. Methods: This retrospective study analyzed 85 MBC patients (pts) characterized for both CTCs and ctDNA at baseline. CTCs were isolated through the CellSearch kit (Menarini Silicon Biosystems, PA), while ctDNA was analyzed using the Guardant360 NGS-based assay (Guardant Health, CA). Pts with ≥ 5 CTC/7.5 ml of blood were defined as Stage IV aggressive as previously reported (Cristofanilli et al 2019). Statistical associations were explored through uni- and multivariate logistic regression and Fisher’s exact test. Results: 37% of pts were diagnosed with hormone receptor positive (HRpos) MBC, 26% with HER2-positive MBC and 37% with triple negative MBC (TNBC), 28 pts (33%) were defined as stage IV aggressive. The most observed metastatic sites were bone (37%), lymph nodes (29%), lung (27%) and liver (25%). In multivariate analysis, IBC and ESR1 mutations were the only significant factors associated with liver metastases (respectively, OR 0.12, P = 0.038 and OR 24.01, P = 0.019), while no associations were found with respect to lung localizations. Intriguingly, all HRpos MBC pts with ESR1 mutations had bone metastases (P = 0.022), while IBC and Stage IV aggressive were independently associated with bone metastases (respectively OR 0.10, P = 0.006 and OR 19.92, P = 0.003). FGFR1 and NF1 were associated with lymph node localizations (OR 3.68, P = 0.046, OR 4.39, P = 0.031, respectively), while CDK6 and TP53 alterations were associated with serosal involvement (OR 14.34, P = 0.029, OR 0.08, P = 0.031, respectively). Notably, TNBC and IBC were both associated with soft tissue spreading (respectively OR 3.7, P = 0.011, OR 2.79, P = 0.018). Conclusions: These results suggest that ctDNA and CTCs enumeration could give useful insights on MBC organotropism, suggesting a possible role for future monitoring strategies that dynamically focus on high-risk organs defined by tumor biology.