bluuebunny/crossref_metadata_2025 huggingface dataset:
Bevacizumab (Bev) to reduce the negative impact of glioblastoma (GBM) tumor size on survival from first recurrence.
Authors: Nguyen Huy Tram N. , Liu Liang Yen , Nguyen Nhung T , Lenchner Daniel , Dovek Laura , Harris Robert J. , Ellingson Benjamin M. , Ozer Byram H , Ravelo Arliene , Sommer Nicolas , Sim Myung Shin , Elashoff Robert M. , Green Richard M. , Nghiemphu Phioanh Leia , Cloughesy Timothy Francis , Lai Albert
Published: September 2018

2052

Background: Bev was FDA approved for recurrent GBM in 2009. However, the survival benefit from Bev in GBM remains to be demonstrated. Methods: We retrospectively identified 168 primary GBM patients diagnosed between 2001-2015 at UCLA and Kaiser Permanente LA, who received upfront radio-chemotherapy, followed with Bev and/or Lomustine (CCNU) at 1st recurrence. We measured tumor size at 1st recurrent treatment initiation, using bi-dimensional (2D) and volumetric (3D) techniques. We analyzed overall survival (OS) from 1st recurrence by Kaplan-Meier analysis. Results: Three groups of patients diagnosed from 2009-2015 were identified: patients treated with Bev alone (n = 49), CCNU alone (n = 36), and concurrent Bev/CCNU (n = 53). Patients were statistically different in performance status at 1st recurrence and tumor size; the CCNU alone group had smaller tumor sizes at diagnosis compared to the Bev groups. The CCNU group showed substantially greater survival (median OS (mOS) = 14.1 mo) compared to the Bev and Bev/CCNU groups (mOS = 6.9 and 7.1 mo, respectively), which may be explained by the imbalance in tumor sizes among the groups, and high rate of crossover (69%) to Bev in subsequent recurrences. To minimize selection bias, we identified another control group (n = 30) diagnosed from 2001-2004 who received CCNU only (CCNU 01-04). These patients had tumor size and KPS more comparable to both Bev groups, and a low rate of crossover (7%). OS for CCNU 01-04 (mOS = 5.7 mo) was similar to the Bev groups. Across all patients, we observed poor OS associated with larger 2D size vs. those with small tumors (mOS = 6.7 vs. 8.8 mo; p = 0.003). In separate stratification of each treatment group by tumor size, this association was retained in the CCNU 01-04 group (mOS = 4.0 vs. 8.4 mo, p < 0.001), but not in either Bev (mOS = 6.7 vs. 7.3 mo) or BEV/CCNU (mOS = 7.0 vs. 8.8 mo). Analysis of effect of tumor size by 3D measurement yielded similar results. Conclusions: Bev appears to reduce the negative impact of large tumor size on GBM patient survival from 1st recurrence. 2D and 3D measurements were correlated, suggesting the adequacy of use of conventional tumor bi-dimensional measurement to predict benefit of Bev in patients based on tumor size.
Immunological targeting of CD133 in recurrent glioblastoma: A multi-center phase I translational and clinical study of autologous CD133 dendritic cell immunotherapy.
Authors: Rudnick Jeremy David , Fink Karen L. , Landolfi Joseph C. , Markert James , Piccioni David Eric , Glantz Michael J. , Swanson Steven J. , Gringeri Anthony , Yu John
Published: September 2018

2059

Background: A hallmark of glioblastoma is the high incidence of tumor recurrence, thought to be triggered by cancer stem cells. These tumorigenic cells are resistant to irradiation and chemotherapeutic agents. The target antigen, CD-133, was chosen because it has been reported as a cancer stem cell antigen overexpressed in glioblastoma tumors and associated with shorter survival. Recent clinical trials suggest that the mean overall survival for these patients is roughly 5-9 months, emphasizing the important unmet medical need in this disease requiring additional strategic approaches. Dendritic cell immunotherapies such as ICT-121 could provide benefit to patients by educating their immune systems to induce the formation of cytotoxic T cells that attack tumor cells bearing the target antigen. In addition to immediate attack on tumor cells present at dosing, a long-term memory response effective against tumor recurrence might be induced. Immunotherapy, such as ICT-121, that targets cancer stem cells could be an important treatment for this disease. Methods: This Phase I multi-center trial of ICT-121 targeting CD133 was designed to assess safety and tolerability (primary endpoint) and to monitor overall survival and progression-free survival (secondary endpoints). ICT-121 is comprised of autologous dendritic cells that are loaded with two HLA-A2 restricted epitopes of the CD133 antigen. CD133 is overexpressed on glioblastoma cancer stem cells. The HLA-A2 patients that had undergone resection for recurrence of glioblastoma were treated with ICT-121 once a week for 4 weeks during the induction phase and then once every 2 months during the maintenance phase until disease progression, death, ICT-121 depletion or discontinuation. Results: A total of 20 patients were treated and eight of these patients are still alive. Immune response data with cytokine mRNA expression demonstrated a response to the CD133 epitopes. A total of 20 patients were treated and eight of these patients are still alive. Conclusions: The results from this Phase I trial suggest that ICT-121 is both safe and well-tolerated with an immune response seen in a subset of patients. Clinical trial information: NCT02049489.
Phase I trial of dimethyl fumarate, temozolomide, and radiation therapy in glioblastoma multiforme.
Authors: Shafer Danielle A. , Chen Zhi-jian , Harris Timothy , Tombes Mary Beth , Shrader Ellen , Strickler Kathryn , Ryan Alison A. , Dent Paul , Malkin Mark Gordon
Published: September 2018

2060

Background: Evidence is increasing for altered immune responses in malignant gliomas. Tumor-associated microglia/macrophages infiltrate human glioma tissue and produce cytokines that promote glioma growth, invasion and angiogenesis. Dimethyl fumarate (DMF), approved for relapsing-remitting multiple sclerosis, is toxic to in vitro activated microglial cells. Based on pre-clinical data demonstrating synergism with radiation (RT) and temozolomide (TMZ), we conducted a phase I study of DMF in patients with newly-diagnosed glioblastoma (GBM) in combination with RT and TMZ. Methods: Using a standard 3+3 dose escalation design (3 dose levels: 120 mg bid, 240 mg bid and 240 mg tid), newly-diagnosed GBM patients received daily DMF with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant DMF (continuously) and TMZ for up 6 maintenance cycles (150-200 mg/m2 on days 1-5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤ 1/6 dose-limiting toxicities (DLT). The MTD was determined by evaluation of DLTs during the first 6 weeks of therapy. Results: Twelve patients were treated at the three dose levels, and no DLT was identified. There were no unexpected toxicities. The most common toxicities were lymphopenia (11 grade 3/4 events) and thrombocytopenia (2 grade 3/4 events). The only grade 3/4 non-heme toxicity was a grade 3 hemorrhoid event. Of the 12 evaluable patients, one remains on active treatment in maintenance phase. Three patients completed all treatment (concurrent and maintenance) with stable disease. Two patients had a partial response (RANO criteria) but then experienced disease progression during maintenance. Five patients had disease progression during study treatment and one patient chose to withdraw from the study during maintenance. Conclusions: These data suggest that DMF may be safely combined with RT and TMZ in GBM patients. A phase II study is under consideration. Clinical trial information: NCT02337426.
VXM01 phase I study in patients with resectable progression of a glioblastoma.
Authors: Wick Wolfgang , Wick Antje , Nowosielski Martha , Sahm Felix , Riehl Dennis , Arzt Marlene , von Deimling Andreas , Bendszus Martin , Kickingereder Philipp , Bonekamp David , Beckhove Philipp , Schmitz-Winnenthal Friedrich Hubertus , Jungk Christine , Wieckowski Sébastien , Herold-Mende Christel , Lubenau Heinz , Unterberg Andreas , Platten Michael
Published: September 2018

2061

Background: VXM01 consists of an attenuated Salmonella typhi Ty21a carrying a plasmid encoding for VEGFR-2. The bacterium is serving as a vector via the oral route of administration carrying the plasmid into the Peyer’s plaques. The vaccine construct elicits a systemic T-cell response targeting VEGFR-2. This trial was set up to examine safety and tolerability, clinical and immunogenic response to VXM01 after treatment with at least four vaccinations [106 or 107colony-forming units (CFU)] in patients with recurrent glioblastoma who have failed at least radiochemotherapy with temozolomide. Methods: Patients with progressive resctable glioblastoma were subjected to single oral administration of VXM01 each on day 1, 3, 5, and 7. In addition, VXM01 was allowed to be administered in 4-weekly single doses every 4 weeks during the tumor follow-up period after reoperation. Follow-up was done by weekly safety laboratories and physical examinations in the treatment period and 4-weekly thereafter, MRI including perfusion maps (days 15 and 30 and six-weekly thereafter), 12-weekly T-cell immunomonitoring in the peripheral blood, and brain tumor immunohistochemistry. Results: Eight patients have been treated according to the schedule and surgery has been performed in seven of them. Under VXM01 treatment 47 adverse events, mostly unrelated to VXM01, were observed after a median of 7 doses per patient. Four out of eight patients (50%) showed a VEGFR-2 specific T cell response. In four patients there was a relevant increase in cerebral blood volume and apparent diffusion coefficient on post-vaccination MRI. In one patient there was an objective and durable T1 response, whereas three further patients remained stable prior to surgery and thereafter. Evaluation of infiltrating T cells in the tissue from re-operation revealed an increase in CD8+ T-cells in 5 out of 7 patients relative to the primary tumor tissue. Conclusions: VXM01 was safe and produces specific peripheral immune responses as well as enumeration of tumor-infiltrating T-cells in post-vaccine tumor tissue. Post treatment MRI imply vascular normalization and there was one patient with an objective response. As a consequence of this data, an expansion cohort of this trial has been launched. Clinical trial information: NCT02718443.
Apparent diffusion coefficient (ADC) decrease to predict longer survival in glioblastoma patients treated by dendritic cell immunotherapy plus standard of care.
Authors: Eoli Marica , Cuccarini Valeria , Aquino Domenico , Anghileri Elena , Servida Maura , Schettino Carla , Pellegatta Serena , Bruzzone Maria Grazie , Finocchiaro Gaetano
Published: September 2018

2065

Background: The MRI follow –up of patients affected by glioblastoma (GBM) and treated with immunotherapy may be difficult, as immune responses may mimic tumor progression. To explore the potential contribution of quantitative MRI to the identification of patients with clinical benefit benefit, we used advanced MRI to study GBM patients treated with dendritic cell (DC) immunotherapy added to standard treatment (surgery, radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant TMZ; DENDR1 trial, EUDRACT N° 2008-005035-15). Methods: A retrospective analysis was performed on longitudinal MRIs obtained soon after radiotherapy, within two days before the first vaccination (basal MRI) and every two months, in 22 patients enrolled in DENDR1. The following parameters were collected: tumor volume of contrast–enhanced lesions, mean rCBV, maximal rCBV, mean ADC, minimal ADC, ADC skewness. Receiver Operating Characteristic (ROC) curves were used to determine optimal sensitivity and specificity in differentiating patients as responder or not responder. Association with PFS (as per RANO criteria) and OS was analyzed using log-rank test and Cox regression. Results: Ten patients with PFS > 12 months were defined as responders Their basal mean ADC was significantly higher than in non responders (1.34 ± 0.17 vs 1.14 ± 0.34, p = 0.03). After four DC vaccinations mean ADC significantly decreased in responders only from 1.34 ± 0.17 to 1.23 ±0.23 (p = 0.028); the decrease persisted during immunotherapy. A basal mean ADC value ≥ 1.07 and a decrease in mean ADC value ≥ 0.13 were significant predictors of longer PFS (15.4 vs 9 m p = 0.0006; 17.2 vs 10.2 p = 0.04) and OS (29 vs 12.5 mo p = 0.002; 33 vs 19.9 p = 0.04 No significant correlations between the other parameters and the outcome were observed. Conclusions: Association with prolonged survival may suggest that in DENDR1responders decreased ADC is partly contributed by immune cells infiltrating the tumor.
Detection of tumor-derived DNA mutations in cerebrospinal fluid of patients with primary or metastatic brain tumors.
Authors: Wang Jianfei , Han Wenbo , Tian Chen , Hu Ying , Chen Yanhui , Li Xiangru , Guo Ruihan , Wang Haibo , Zhang Henghui
Published: September 2018

2070

Background: Because detecting tumor-derived cell free DNA (cfDNA) in the blood of patients with primary or metastatic brain tumors is challenging, here we studied whether cerebrospinal fluid (CSF) could be serve as an alternative “liquid biopsy” by enabling measurement of circulating DNA within CSF to characterize tumor specific mutations. Methods: The paired cfDNA in CSF and plasma were collected from 20 patients with brain tumors and was subjected to enrichment for a 1.15M size panel cover exon regions from 1,086 genes. Followed by next generation sequencing on an Illumina X10 platform, the captured sequencing data was further processed using bioinformatics analysis to identify somatic mutations, including single nucleotide variants (SNV) and short insertions/deletions (indels). Results: The mutation profiles of 48 tumor associated genes in cfDNA were compared between the CSF and plasma. Our results showed that both average somatic mutation number and frequency identified in the cerebrospinal fluid was much higher than that in the corresponding plasma samples (25 vs. 18 & 1.39% vs. 0.55%). Among the twenty cases, one more potential actionable mutation, EGFR exon 19 deletion mutation with a 25.38% allele frequency variation, was only detected in the CSF cfDNA of a patient with brain metastasis lung cancer. Conclusions: Tumor mutations were detectable in CSF cfDNA of patients with different primary and metastatic brain tumors. Thus cerebrospinal fluid cell free DNA analysis could be a potential alternative analysis for patients with primary or metastatic brain tumors.
Linac-based radiosurgery for multiple brain metastases: A quality assurance and feasibility study.
Authors: Pfeffer Raphael M. , Levin Daphne , Spiegelmann Roberto
Published: September 2018

2077

Background: The classical treatment for multiple brain metastases is whole brain radiotherapy (WBRT). For patients with 1-3 brain metastases stereotactic radiosurgery (SRS) results in better response, similar survival and less short and long term toxicity such as neurocognitive dysfunction than WBRT. For patients with > 3 metastases there is little prospective data of SRS partly due to the technical and logistic difficulties of delivering SRS to multiple metastases. We present a new SRS planning program (MMM) that allows the planning and delivery of linac-based SRS to up to 10 brain metastases simultaneously in less overall time than for WBRT. Methods: Between August 2014 and August 2016, patients referred for RT with 2 or more brain metastases were offered treatment with MMM. System QA included ArcCheck diode array and film dosimetry and gel dosimetry based on a patient derived phantom. Individual QA included replanting treatment arcs on an independent system. Results: 94 patients with 2-10 (median 5) metastases and a combined volume of 0.01-8.64 cc were treated. Planning time including image fusion, target delineation and RT plan generation required on average 20 minutes minutes. SRS was delivered using 4-5 (is more 7-10 since return arcs do not address the same targets) non-coplanar arcs and a single isocenter at the center of mass of the metastases. Treatment time to deliver 18-24 Gy to all metastases was 25 mins (beam on time ~6 minutes) for a total time of 45 minutes. This is the same as the time for each individual metastasis on earlier planning systems and compares to 20 minutes planning time and 12 mins delivery time for each of 10 fractions for a conventional 2 field WBRT plan WBRT (total 140 minutes). At 6 months follow up, 88% of treated metastases had decreased in size, 10% were stable and 2% grew. Acute toxicity was mild except for one patient with intractable seizures. Conclusions: Linac based SRS for multiple brain metastases is efficient, requiring the same resources as for treatment of a single metastasis and less resources than for WBRT, with a high rate of local control. Appropriate equipment is available in most radiotherapy departments which will allow more prospective studies of SRS for multiple metastases.
Debio 1347, an oral FGFR inhibitor: Results from a first-in-human, phase I dose-escalation study in patients with FGFR genomically activated advanced solid tumors.
Authors: Voss Martin Henner , Hierro Cinta , Heist Rebecca Suk , Cleary James M. , Meric-Bernstam Funda , Gandhi Leena , Ishii Nobuya , Kirpicheva Yulia , Nicolas-Metral Valerie , Pokorska-Bocci Anna , Purcea Daniela , Vaslin Anne , Moulon Corinne , Zanna Claudio , Flaherty Keith , Tabernero Josep , Baselga Jose
Published: September 2018

2500

Background: Oncogenic alterations in fibroblast growth factor receptors (FGFR) are seen across multiple solid tumor malignancies. Debio 1347 is an orally available, highly selective panFGFR inhibitor with potent antitumor effect in preclinical models bearing FGFR1-3 genetic alterations. Methods: Patients harboring defined FGFR 1, 2 or 3 alterations received escalating doses of Debio 1347 starting from 10 mg once daily. Dose escalation followed a 3+3+3 algorithm based on a modified Fibonacci sequence. The MTD was defined as the level where ≥ 3/9 patients suffer a DLT. Pharmacokinetics (PK) and pharmacodynamic were serially evaluated in blood, skin and/or tumor tissue. Results: Fifty-six patients were enrolled, including patients with mutations (n = 17), amplifications (n = 28) and fusions (n = 11). The dose was escalated up to 150 mg over 8 cohorts. DLTs were experienced by 4/56 patients, including G2 intolerable dry mouth + eyes at 60 mg, G3 hypercalcemia + hyperamylasemia at 80 mg, and G3 bilirubin increase at 110 mg. At data cut-off, the most common treatment-emergent adverse events (TEAE) were hyperphosphatemia (73%), fatigue (41%), diarrhea (39%), nausea (37%), and inappetence (32%). Fifteen patients (27%) experienced a grade ≥ 3 related TEAE. Twenty-five patients (47%) required dose modification, primarily due to hyperphosphatemia and cutaneous toxicity. An MTD has not been reached. PK appeared overall linear, with a half-life of 14 hours; hyperphosphatemia was dose-dependent. Among the 54 response-evaluable patients, 4 confirmed and 1 unconfirmed partial responses were observed in patients with cholangiocarcinoma (FGFR2 mutant), uterine (FGFR2 and FGFR1 amplified), colon (FGFR2 fusion), and urothelial cancer (FGFR3 fusion); an additional 10 patients had target regression < 30%. Conclusions: Debio 1347 had a tolerable and manageable safety profile. Encouraging antitumor activity was seen in several tumor types, mainly in patients with FGFR2 or 3 gene alterations, including fusion events, treated at 80 mg and 110 mg daily. Efficacy will be further explored in disease-specific and molecularly defined expansion cohorts. Clinical trial information: NCT1948297.
Results from the biomarker-driven basket trial of RO5126766 (CH5127566), a potent RAF/MEK inhibitor, in RAS- or RAF-mutated malignancies including multiple myeloma.
Authors: Chenard-Poirier Maxime , Kaiser Martin , Boyd Kevin , Sriskandarajah Priya , Constantinidou Anastasia , Harris Samuel John , Serrano Fandos Sonia , Ryan Alison , Witt Karolina , Dawes Joanna C , Parmar Mona , Turner Alison Joanne , Tovey Holly , Hall Emma , Perez Lopez Raquel , Tunariu Nina , Lopez Juanita Suzanne , De Bono Johann S. , Banerji Udai
Published: September 2018

2506

Background: RO5126766 is a potent RAF and MEK inhibitor with activity in xenografts models of RAS and RAF-mutated cancers. We present data from the RAS/RAF-mutated advanced solid tumor cohort and the initial results for the multiple myeloma (MM) cohort. Methods: Patients with KRAS, NRAS or BRAF-mutant tumours were treated with RO5127566 using a novel schedule:4mg twice weekly in 4-week cycles. For MM patients, it was given 3 weeks out of 4 and co-administration of weekly dexamethasone was authorised. Response assessment was completed using RECIST 1.1 criteria for solid tumours and the International Myeloma Working Group (IMWG) criteria were used for MM. Results: A total of 20 patients with solid tumours (10 NSCLC, 5 gynaecological cancers and 5 miscellaneous cancers) and 1 MM patients were evaluable. Among the 10 KRAS-mutant NSCLC patients, tumour regression was seen in 6/10 (60 %), of which 3/10 (30 %) were partial responses. Two of these patients had maintained response for over 1 year and one patient is still on study after 30 cycles. Of the gynaecological cancers, 3/5 patients (60%) achieved a partial response ( KRAS-mutant endometrial and ovarian cancer and BRAF-mutant ovarian). Of these patients, 1 of the KRAS mutants had received 2 previous lines of MEK inhibitors and the BRAF mutant had previously received a BRAF inhibitor. In the miscellaneous group, 4 patients with colorectal cancer (2 BRAF and 2 NRAS) and 1 patient with NRAS-mutant melanoma were treated and none responded. Two patients with MM have been treated so far (1 KRAS, 1 KRAS+NRAS). The one evaluable patient has had an IMWG partial response (PR) after 1 cycle (FLC-λ from 324 mg/L to 161mg/L, ratio 0.03 to 0.08) without concomittant dexamethasone. This patient was previously treated with an immunomodulatory drug, a proteasome inhibitor and two ASCTs. Conclusions: RO5126766 has shown exciting preliminary activity across a wide range of RAS- and RAF-mutated malignancies, with significant response rates in lung and gynaecological cancers. To our knowledge, the PR seen in our MM patient represents one of the first responses to a single-agent RAF/MEK inhibitor in multiple myeloma in a trial context. Clinical trial information: NCT02407509.
First-in-human phase 1/2 study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3: Final phase 1 data and preliminary activity in HER2+ metastatic breast cancer (MBC).
Authors: Alsina Maria , Boni Valentina , Schellens Jan H.M. , Moreno Victor , Bol Kees , Westendorp Martine , Sirulnik L. Andres , Tabernero Josep , Calvo Emiliano
Published: September 2018

2522

Background: MCLA-128 is a novel IgG1 bispecific antibody with enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) activity targeting HER2 and HER3 receptors. We report final phase 1 single agent escalation data, and safety and preliminary activity at the recommended phase 2 dose (RP2D). Methods: In the phase 1 part, patients (pts) with advanced solid tumors received MCLA-128 every 3 weeks (q3w) IV over 1-2 hr from 40 to 900 mg. In the phase 2 part, pts with selected metastatic indications were treated at the RP2D. Antitumor activity was assessed as per RECIST 1.1. Clinical benefit rate (CBR) was defined as CR + PR + SD ≥12 weeks. Results: As of January 2017, 28 advanced solid tumor pts were treated in the escalation part. No dose limiting toxicities were seen. The RP2D was established as 750 mg q3w (flat dose, corticosteroid premedication) based on safety and PK data. Fifteen pts with HER2 amplified tumors were treated at the RP2D (8 MBC, 4 gastric, 2 ovarian, 1 colorectal). Median age was 52 years (range 33-71), ECOG PS 0/1: 3/12, all ≥2 metastatic sites. The safety profile at the RP2D confirmed dose escalation data; the most common AEs were infusion related reactions in 6 pts (40%; G1-2 in 5 pts, G4 in 1 pt), and G1-2 diarrhea, rash, fatigue in 2 pts each (13%). No congestive heart failure or significant LVEF decreases occurred. The 8 MBC pts had a median 5.5 prior lines of metastatic therapy (range 4-14), all had progressed on 3 prior Her2 inhibitor therapies and received a median of 4.5 MCLA-128 cycles (range 2-12); 1 had a confirmed PR, 5 had SD (including 2 sustained, 11 and 12 cycles). SD was also seen in 2 evaluable MBC pts treated at 480 mg in the phase 1 part (7 and 4 cycles). Overall, CBR in these 10 MBC pts was 70%. Evaluation of other indications is ongoing. Conclusions: MCLA-128 showed a well tolerated safety profile. Consistent antitumor activity was seen in heavily pretreated MBC patients progressing on HER2 therapies. Further exploration of MCLA-128 based combinations with chemotherapy or trastuzumab in less pretreated MBC patients progressing after ≥2 prior Her2 inhibitors including TDM-1 is planned. Clinical trial information: NCT02912949.
Adherence to novel oral anticancer therapies in the phase I setting: The Royal Marsden experience.
Authors: Chenard-Poirier Maxime , Ang Joo Ern , Harris Samuel John , Ingles Garces Alvaro Henrique , Seeramreddi Satyanarayana , Sundar Raghav , Collins Dearbhaile Catherine , Ameratunga Malaka , Lopez Juanita Suzanne , De Bono Johann S. , Banerji Udai
Published: September 2018

2542

Background: The use of oral anticancer therapies has increased substantially in recent years. Nonadherence can impair the efficacy of such therapies as well as confound the interpretation of toxicity and pharmacokinetic data in phase I trials. However, there is a paucity of data regarding adherence patterns and barriers in this specific setting. Methods: We included patients treated in Phase I trials involving oral investigational medicinal products (IMPs) in the Drug Development Unit, Royal Marsden Hospital, UK, between 2012 and 2014. Patient, disease and treatment characteristics as well as compliance data from prospectively collected trial diary cards and drug accountability were recorded. Relationships between adherence rate and other variables were explored using logistic regression. Results: We collected data for 2819 patient-weeks, pertaining to 169 patients treated on 18 different phase I trials. Median age was 61 years (range 18-79), females predominated (60%), median number of previous systemic therapy was 3 (0-12) and median time on trial was 9 weeks (0.3-212.4). Hundred-percent adherence rate was 88% in the first cycle and 79% overall. Nonadherence occurred in 83 of 2819 patient-weeks (3.0%); including 75 (2.7 %) missed doses and 8 (0.3 %) overdoses. In univariate analysis, longer time on trial and a continuous treatment schedule were associated with poorer adherence, whereas fasting requirements pre- or post-dosing was associated with improved adherence. Known intracranial metastases, number of concomitant medications and opiates or anti-emetics use were not significantly associated to adherence. In multivariate analysis, fasting requirements (OR 5.347, 95%CI : 1.443-20.019, p = 0.012) and longer time on trial (OR 0.98, 95%IC : 0.961-0.996, p = 0.017) were statistically significant. Conclusions: This is the first report on adherence rates to oral anticancer IMPs in a large phase I trial population. Our observed adherence rates are at the higher end of published data in the general cancer population. Factors influencing adherence in phase I trials appear to be distinct, with fasting requirements being a unique finding. These findings may impact future early-phase trial design and conduct.
Pharmacokinetics (PK) and pharmacodynamics (PD) of a novel carcinoembryonic antigen (CEA) T-cell bispecific antibody (CEA CD3 TCB) for the treatment of CEA-expressing solid tumors.
Authors: Melero Ignacio , Segal Neil Howard , Saro Suarez Jose M. , Ros Willeke , Martinez Garcia Maria , Calvo Emiliano , Moreno Victor , Ponce Aix Santiago , Marabelle Aurelien , Cleary James M. , Hurwitz Herbert , Eder Joseph Paul , Jamois Cancize , Belousov Anton , Bouseida Said , Sandoval Federico , Bacac Marina , Nayak Tapan K. , Karanikas Vaios , Argiles Guillem
Published: September 2018

2549

Background: CEA CD3 TCB (RO6958688) targets CEA on tumor cells and is agonistic for CD3e on T cells. In mouse models, CEA CD3 TCB displays potent anti-tumor activity, leads to increased intra-tumoral T cell infiltration and activation and up-regulates the PD-1/PD-L1 pathway. Methods: Biodistribution was assessed in mice using SPECT/CT. Patient (pts) samples correspond to 2 dose-escalation studies in CEA+ solid tumors. Study 1 (S1): single agent weekly (qW) (0.052 to 600 mg, iv, n = 80), and Study 2 (S2): combination of RO6958688 qW (5 to 160 mg, iv) with 1200mg atezolizumab q3W (n = 38). Analytical methods: PK - population modeling approach; anti-drug antibodies (ADA) - ELISA; immunophenotyping in peripheral blood (PB) by flow cytometry (FCM), in pre- (BSL) and on-treatment (OT) biopsies by immunohistochemistry (IHC) and FCM; plasma cytokines - multiplex assays; PD-L1 - SP142 assay. Results: In mice, RO6958688 preferentially accumulated in CEA+ tumors. In pts with no ADAs tested thus far in both studies (S1 29; S2 21), RO6958688 showed near linear PK and exposure. In S1, OT biopsies demonstrated a statistically significant increase in density and activation profile of T cells (CD3: 2.6-fold, n = 21; CD3/CD8: 3.7 fold, n = 17; CD3/Ki67: 4-fold, n = 20; CD8/PD1: 1.7-fold, n = 15) without dose-dependence. In S2, preliminary data of T cell density (5-80mg) were similar to S1 (2-fold). In S1, a significant correlation was observed between treatment-induced tumor lesion reduction and increases of OT CD8/CD25 fluorescence intensity from BSL (p = 0.028). PD-L1 expression increased in OT biopsies in both studies. In S1, from week 4, a moderate expansion of activated CD8 T cells (HLA-DR/Ki67) but not of CD4, was detected in PB at doses > 60mg ( > 3.3 fold). Transient increases of several cytokines were seen in both studies with levels peaking within 24hrs. Conclusions: PK and PD results consistent with tumor inflammation and mechanism of action support that RO6958688 is the first tumor-targeted T cell bispecific to show intra-tumoral biological activity in pts with CEA+ solid tumors. Updated data will be presented. Clinical data are reported separately.
An open-label expanded-access study to evaluate the safety, tolerability, and pharmacokinetics of trifluridine/tipiracil in patients with advanced solid tumors and hepatic impairment.
Authors: Saif Wasif M. , Rosen Lee S. , Rudek Michelle A. , Sun Weijing , Shepard Dale Randall , Becerra Carlos , Yamashita Fumiaki , Bebeau Paul , Winkler Robert
Published: September 2018

2559

Background: The Phase 3 RECOURSE study showed that trifluridine/tipiracil (FTD/TPI) was effective in the treatment of refractory metastatic colorectal cancer (Mayer et al. N Engl J Med 2015;372:1909-19). A Phase 1 open-label study evaluated the safety and pharmacokinetics of FTD/TPI in patients with advanced solid tumors and varying degrees of hepatic impairment to inform dosing recommendations for these patients. Methods: Patients aged ≥18 years with advanced solid tumors, an Eastern Cooperative Oncology Group performance status ≤2, normal hepatic function, and mild, moderate, or severe impaired hepatic function according to the National Cancer Institute criteria were enrolled. Patients received FTD/TPI 35 mg/m2 orally twice daily on days 1-5 and days 8-12 of each 28-day cycle, except for those with severe impaired hepatic function (dose was to be determined). Results: 24 patients were enrolled to normal (n=8), mild (n=10), and moderate (n=6) groups. Study enrollment was stopped as 5/6 patients in the moderate group experienced elevated bilirubin levels (grade ≥3). The other baseline characteristics were similar across groups. Overall, 12 patients (50%) had at least 1 adverse event leading to study discontinuation: 2 in normal, 5 in mild, and 5 in the moderate hepatic impairment groups. Pharmacokinetic results are summarized in the table. Conclusions: The exposure to FTD or TPI was not increased by hepatic impairment and the patients who experienced grade 3 and 4 increased total bilirubin were not overexposed to FTD or TPI. Clinical trial information: NCT02301104. [Table: see text]
Vitamin K epoxide reductase complex subunit 1 (VKORC1): A pharmacogenomic predictor of response and survival in patients (pts) on triplet hepatic artery infusion (HAI) and intravenous cetuximab (IV-Cet) for initially unresectable liver metastases from colorectal cancer (uLM-CRC) (EU trial OPTILIV).
Authors: Levi Francis , Saffroy Raphael , Karaboue Abdoulaye , Desterke Christophe , Boige Valerie , Hebbar Mohamed , Smith Denis Michel , Bouchahda Mohamed , Innominato Pasquale , Taieb Julien , Carvalho Carlos , Guimbaud Rosine , Focan C. N. J. , Ducreux Michel , Adam Rene , Lemoine Antoinette
Published: September 2018

2569

Background: The HAI of Irinotecan-Oxaliplatin-5-Fluorouracil (IFO) with IV-Cet achieved 29.7% complete uLM-CRC resections (R0+R1) and an overall median survival (OS) of 25.7 months in previously treated pts (Lévi, Ann Oncol 2016). Methods: To identify pharmacogenomic predictors of outcomes, 207 single nucleotide polymorphisms (SNPs) from 34 pharmacology genes were analysed in blood mononuclear cells (ADME PGx, MassArray platform, Sequenom, USA). Relations between SNPs and tumor response, R0+R1, survival, and toxicities were tested using adjusted Mann Whitney, Fisher Exact, Log Rank tests and Hardy-Weinberg Equilibrium. Results: Pts (16F;36M; 33-76 yo; WHO performance status 0-1) received protocol treatment as 2nd (21 pts) or 3-4thline (31 pts). VKORC1 SNPs in promoter (rs9923231) and intron (rs9934438) were consistently associated with early and objective responses, and overall survival. For rs9923231, T/T (N = 8) as compared to C/T (N = 21) had greatest chance of achieving early response (50% vs 5%, p = 0.029) or 4-y survival (46% vs 0%, p = 0.006). VKORC1 SNPs also related to HA thrombosis (rs992331, T/T, 77% vs C/C, 30%, p = 0.04). In contrast, NAT2 SNPs (rs1041983 and rs1801280) were associated with up to 5-fold differences in R0-R1 resection rate. Statistically significant associations (p < 0.05) of SNPs with clinical outcomes were found for oxydo-reduction (CYP2E1 and HA thrombosis; CYP2C9 and diarrhea; CYP2C19 and diarrhea, fatigue, and early response), conjugation (UGT1A1 and diarrhea; NAT2 and fatigue); and transport (ABCB1 or SLC0B3 and neutropenia; SLC22A1 and diarrhea; SLC 15A2 and early response). Conclusions: VKORC1 was highlighted for the first time, as a pharmacogenomic predictor of HAI efficacy for LM-CRC. Conversion-to-resection was associated with NAT2 polymorphism. VKORC1 γ-carboxylates vitamin K-dependent proteins. Its polymorphism guides personalized warfarin dosing. VKORC1 SNPs determination could help identify the uLM-CRC pts who best benefit from intensive HAI therapy. Clinical trial information: NCT00852228.
TAX-TORC: A phase I trial of vistusertib (AZD2014) in combination with weekly paclitaxel with integrated pharmacodynamic (PD) and molecular characterization (MC) studies.
Authors: Sundar Raghav , Basu Bristi , Wilson Richard H. , Spicer James F. , Jones Robert Hugh , Krebs Matthew , Brada Michael , Talbot Denis Charles , Steele Nicola , Hall Emma , Tovey Holly , Carreira Suzanne , de Oliveira Flavia M , Swales Karen E , Balarajah Geetha , Dawes Joanna C , Parmar Mona , De Bono Johann S. , Banerji Udai
Published: September 2018

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Background: In ovarian cells isolated from ascites, p-S6K levels were found to correlate with resistance to chemotherapy. We hypothesised that inhibiting p-S6K signalling with dual m-TORC1/2 inhibitor vistusertib (V) in addition to paclitaxel (P) would improve outcomes of patients with high-grade serous ovarian cancer (HGSOC). Methods: In the dose escalation part, weekly P 80mg/m2IV (6/7 weeks) was evaluated in combination with two schedules of V; Schedule A: V (25, 50 or 75mg) BID PO on day(D) 1-3/week and Schedule B: V (75 or 100mg) BID PO D1-2/week. This was followed by an expansion cohort in 25 HGSOC patients. Results: Dose limiting toxicities in Schedule A were fatigue and mucositis and in Schedule B were diarrhoea, rash and fatigue. The AUC, Cmax and half-life of V in the 50mg-cohort were 2821ng.hr/ml, 926ng/ml and 3hrs, comparable to single agent studies. PD analysis (from six 50mg-cohort patients) in platelet-rich plasma showed increased phosphorylation of Ser473 AKT following P induction (1.4 fold, p = 0.1378). Following addition of V to P, phosphorylation levels 4hrs post-treatment with V fell significantly to 53% of pre-dose levels (p = 0.0495). This was 61% lower than the corresponding time point following P alone. Based on toxicity, pharmacokinetic and PD evaluation, recommended phase 2 dose was established as P 80mg/m2 D1 and V 50mg BID D1-3 for 6/7 weeks. In the HGSOC expansion, 96% of patients had relapsed within 12 months of last platinum therapy and 100% had received previous paclitaxel, with a median of 3 previous lines of treatments. RECIST and GCIG CA125 response rates were 13/25 (52%) and 15/25 (60%) respectively, with median progression free survival of 5.5 months. MC was performed on archival tumor tissue of 24/25 HGSOC expansion cohort patients, with the most common mutations occurring in p53 (100%), BRCA (17%), and MUC16 (17%). ATM mutations occurred in 17% (n = 4), 3 of whom had a response. Conclusions: We report a highly active combination of paclitaxel with an intermittent schedule of vistusertib in patients with HGSOC. This combination is now being evaluated in a randomised controlled trial for this indication. Clinical trial information: NCT02193633.
Investigating novel resistance mechanisms to third generation EGFR TKI osimertinib in non-small cell lung cancer patients using next generation sequencing.
Authors: Ou Qiuxiang , Wu Xue , Bao Hua , Tong Xiaoling , Wang Xiaonan , Zhang Xian , Chang Zhili , Mao Yu , Shao Yang , Zhou Caicun
Published: September 2018

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Background: Third generation epithelial growth factor receptor ( EGFR) tyrosine kinase inhibitor (TKI) osimertinib (AZD9291) has proven effective in Non-small cell lung cancer (NSCLC) patients who have developed EGFR T790M-mediated resistance to other EGFR TKIs. Unfortunately, a majority of patients still undergo progressed disease after receiving osimertinib treatment. Acquired EGFR C797S mutation has been identified as one major mechanism; however, resistance mechanisms of remaining cases are still largely unknown. Methods: Using next generation sequencing (NGS) targeting 416 cancer-relevant genes, we analyzed the mutation profiles of 99 NSCLC patients that were clinically resistant to osimertinib. Results: In addition to the notable EGFR C797 variants (22%), L792 mutations were identified in 10% of patients, and a further 7% cases carry L718 mutations. Further analysis of 14 patients with paired pre-treatment samples confirmed that these EGFR mutations were acquired during treatment. Interestingly, all L792 mutations are in cis with T790M and in trans with C797 mutations (when present in the same patient). 2 out of 10 L792-positive patients and 6 out of 7 L718-positive patients did not have co-existing C797 mutations, suggesting C797-, L792- and L718-mutated cells may represent different resistant clones. In vitro experiments demonstrated that L792 and L718 mutants also increase osimertinib IC50, and therefore confer their resistance. Besides secondary EGFR mutations, alterations in other key genes such as MET, KRAS, ERBB2 and PIK3CA may also contribute to osimertinib resistance. Notably, MET and KRAS amplifications are present only in patients without above EGFR secondary mutations. Conclusions: In this study, we identified secondary mutations on C797, L792 or L718 residues of EGFR in 29% of osimertinib-resistant patients. Combined with in vitro study, our data strongly suggest that L792 and L718 mutations are likely to alternatively cause osimertinib resistance. Furthermore, MET and KRAS amplification may serve as bypass resistance mechanisms in patients who are EGFR C797-, L792- and L718-wild type.
Phase 1 study of the p53-MDM2 inhibitor AMG 232 combined with trametinib plus dabrafenib or trametinib in patients (Pts) with TP53 wild type (TP53WT) metastatic cutaneous melanoma (MCM).
Authors: Moschos Stergios J. , Sandhu Shahneen Kaur , Lewis Karl D. , Sullivan Ryan J. , Johnson Douglas Buckner , Zhang Yilong , Rasmussen Erik , Henary Haby A. , Long Georgina V.
Published: September 2018

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Background: Large sequencing studies in MCM have shown a TP53WT incidence of approximately 80%. In preclinical TP53WT melanoma models, the oral p53-MDM2 inhibitor AMG 232 exhibited synergistic, cytotoxic-type antitumor activity when combined with MAPK inhibitors. This phase 1 study assessed the toxicity (CTCAE 4.03), maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity (RECIST 1.1) of AMG 232 plus trametinib (T) and dabrafenib (D) (BRAFV600-mutant) or T (BRAFV600-WT) in pts with TP53WT MCM. Methods: Using 3+3 dose escalation design, pts with advanced TP53WT (using a CLIA-approved assay) MCM received AMG 232 PO QD for seven days of each 3-week cycle (7/21) at 120, 240, or 480 mg plus either T 2 mg PO QD and D 150 mg PO BID (Arm 1; BRAFV600-mutant) or T 2 mg QD (Arm 2; BRAFnonV600-mutant). Results: At the time of this analysis, 21 pts (median age, 58 y [range 24–76]; male, n = 11; at least 2 systemic treatments, n = 15) were treated. Arm 2 enrolled first: AMG 232 120 mg (n = 6), then 240 mg (n = 6). Due to chronic grade (G) 2 gastrointestinal toxicity, an intermediate dose (180 mg; n = 3) was determined as the preliminary MTD. Arm 1 enrolled at AMG 232 120 mg (n = 4), then 180 mg (n = 2). The most common reasons for AMG 232 withdrawal were disease progression (n = 8) and AEs (n = 4); 6 pts remain on AMG 232. All 21 pts had treatment-related AEs (TRAEs); the most common TRAEs were nausea (n = 18), fatigue (n = 17), diarrhea (n = 14), and vomiting (n = 13). The only DLT (Arm 2; 240 mg) was G 3 pulmonary embolism. Preliminary PK analysis suggests that AMG 232 exposure (area under the curve) is similar to that as monotherapy at the same dose, with no apparent drug-drug interaction between AMG 232 and T; analysis of D and T PK is ongoing. Of 21 pts, 6 had partial response (Arm 1/2, n = 4 [67%]/2 [13%]), 13 had stable disease (Arm 1/2, n = 2 [33%]/11 [73%]), and 2 progressed (Arm 1/2, n = 0/2 [13%]) as best response; 17 had tumor reduction (Arm 1/2, n = 6 [100%]/11 [73%]). Conclusions: In this population of pts with MCM, AMG 232 combined with D and/or T during DE was tolerable up to 180 mg QD 7/21 days, showing an acceptable PK profile and early antitumor activity. Clinical trial information: NCT02110355.
Phase 1 dose escalation study of the folate receptor-targeted small molecule drug conjugate EC1456.
Authors: Harb Wael A. , Edelman Martin J. , Chambers Setsuko K. , Garland Linda L. , Armour Alison , Wang Ding , Goss Glenwood D. , Sachdev Jasgit
Published: September 2018

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Background: The folate receptor (FR) is highly expressed in a variety of cancers including adenocarcinoma of the lung, but is expressed at low levels in most normal tissues, making it a potential target for therapeutic intervention. EC1456 is an FR-targeted small molecule drug conjugate (SMDC) consisting of folic acid chemically attached through a bio-releasable linker system to a potent microtubule inhibitor, tubulysin B hydrazide (TubBH). EC1456 binds to, and is endocytosed by the FR-expressing cancer cell to deliver TubBH. Following endocytosis, the FR recycles back to the membrane surface every 18-24 hours. Therefore alternative EC1456 schedules will be evaluated for safety, pharmacokinetics, and therapeutic benefit. Methods: Part A (dose escalation) is being evaluated in unselected patients (pts) with advanced solid tumors. 4 schedules (3-week cycle) are being evaluated: BIW (twice weekly); QW (once weekly); CWD (continuously weekly); QIW (four times a week). The primary objective of Part A is to determine the RP2 dose and schedule of EC1456. Part B (expansion) will confirm the MTD and RP2 dose and evaluate efficacy of EC1456 in 99mTc-etarfolatide-selected NSCLC patients in up to three schedules. Results: 74 Part A pts are evaluable for toxicity. Median age is 68 (range: 26-88); 53 pts are female. Toxicities are primarily Grade (Gr) 1 and 2. Common treatment-related adverse events (TRAE) are gastrointestinal, fatigue, metabolic changes, alopecia, and headache. 5 Gr 3 DLTs have been observed: infusion reaction (4.5 mg/m2 QW), headache (10.0 mg/m2 QW), and abdominal pain (7.5 mg/m2 BIW, 12.5 mg/m2 QW and 10.0 mg/m2CWD). TRAEs are summarized in the table for each schedule. Durable stable disease of 12 wks or longer has been observed in 12 pts (6 BIW and 6 QW). Conclusions: All Part A EC1456 schedules have been well tolerated. RP2 dose for BIW is 6.0 mg/m2 and QW is 12.5 mg/m2; dose escalation is ongoing for CWD and QIW. Early signs of efficacy in an unselected pt population may be suggested by durable stable disease. Safety and efficacy evaluation in the 99mTc-etarfolatide-selected NSCLC population (Part B) is ongoing. Clinical trial information: NCT01999738. [Table: see text]
A phase 1/2 study of intermittent, high dose sunitinib in patients with advanced solid tumors.
Authors: Rovithi Maria , Labots Mariette , Honeywell Richard , Ten Tije Albert J. , Ruijter Rita , Skardhamar Mikkjal , Peters Godefridus J. , Voortman Jens , Verheul Henk M.W.
Published: September 2018

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Background: Despite widespread clinical integration, refinement of treatment with sunitinib is actively pursued. Sub-therapeutic blood levels rather than true resistance and tumor adaptation through drug accumulation have been accounted as reasons for treatment failure. Based on our preclinical data with high dose sunitinib and prospective analyses supporting the concept of intermittent dosing, we designed a phase 1 trial to investigate the feasibility and tolerability of high dose, once weekly (1w) or once every two weeks (2w) sunitinib (NCT02058901). Methods: Eligible were patients (pts) with advanced solid tumors, refractory to standard treatment, measurable disease, WHO ≤ 1. Sunitinib was administered orally 1w or 2w. Starting dose was 200 mg, with cohorts escalating in 100 mg steps until maximum tolerated dose (MTD). Response was evaluated by RECIST 1.1. Treatment continued until progression or unacceptable toxicity. Dedicated PK sampling was performed. Sunitinib plasma concentration was measured by LC-MS. Results: 34 (w) and 24 (2w) pts were included, predominantly with mCRC [56% (1w) and 55% (2w)]. MTD was set at 300 mg (1w) and 700 mg (2w). Most common adverse events were fatigue (79%, one pt with G3), nausea (71%, all G1-2), anorexia (29%, all G1-2). Median PFS of evaluable pts was 2.7 mo (1w) and 2.6 mo (2w), while 39% pts (1w) and 25% pts (2w) had PFS > 5 mo. CT scans in pts with treatment benefit showed extensive tumor necrosis. Mean sunitinib plasma Cmax was 190 [300 mg (1w), range: 185-295] and 476 ng/mL [(700 mg (2w), range: 323-580]. Accumulation was minimal. Conclusions: Once weekly or once every two weeks, high dose sunitinib is feasible and clinically efficacious in heavily pretreated pts with advanced solid tumors, while toxicity remains well manageable. Importantly, no accumulation was recorded and sunitinib exposure was significantly increased, compared to the universal, flat dose. Since increased sunitinib exposure has been correlated to improved outcome, we consider this alternative scheduling as promising strategy to produce enduring clinical benefit in a wider patient population. Expansion cohorts are ongoing. Clinical trial information: NCT02058901.