bluuebunny/crossref_metadata_2025 huggingface dataset:
SHADOW study: Comparison of conventional clinical follow-up with clinician led video follow-up in newly diagnosed patients with intermediate and high grade glioma receiving adjuvant temozolomide therapy.
Authors: Patil Vijay Maruti , Pande Nikhil , Chandrasekharan Arun , Tonse Raees , MV Chandrakanth , Krishnatry Rahul , Ghanekar Shamika , Bano Nazia , Sastri Jayant , Gupta Tejpal , Jalali Rakesh
Published: September 2018

2024

Background: In patients with gliomas, nurse led telephonic follow-up was associated with high satisfaction rates and was a valid alternative approach to conventional hospital based follow-up. However, other alternative forms of follow-up have not been studied in patients on active treatment. Methods: SHADOW was a prospective, randomized trial (CTRI/2017/01/007626). Adult intermediate to high grade glioma patients on adjuvant temozolomide with facilities for live video call were invited. After their consent, patients underwent a video follow-up (VF) 4 days prior to clinical follow-up (CF). The decisions taken during the VF and CF were noted in 5 domains, relating to temozolomide decisions (primary endpoint), concurrent medications, need for imaging, molecular testing and rehabilitation. Clinicians performing VF or CF were randomly assigned and were blinded for the other arm decisions. Patients satisfaction and costs incurred in each type of follow-up was documented. The planned sample size was 65, assuming an alpha of 0.05, a kappa coefficient of 0.9 with a one sided CI for lower limit of 0.6 and assuming a 20% lost to follow up rate. Agreement analysis was performed for calculation of Cohen's kappa coefficient. Results: 112 patients were screened and 65 were accrued. All patients underwent both VF and CCF. The concurrence in decision of administering temozolomide between VF and CCF was 100% (Cohen kappa = 1.0, 95%CI 1.0-1.0, p < 0.00). In concurrent medication domain (k = 0.66,95% CI 0.04 -1, p < 0.00), imaging domain (k = 1.0, 95%CI 1.0-1.0, p < 0.00), rehabilitation domain (k = 1.0, 95%CI 1.0-1.0, p < 0.00) and molecular testing domain (k = 0.65, 95% CI 0.20-1, p < 0.00), the agreement was substantial. The satisfaction rate was 100% post video follow up and was 98.5 % post clinical follow up. The median cost incurred in VF was 58.15 USD (IQR 43.38-91.69) while that incurred in CCF was 131.23 USD (IQR 68.8-256 (p < 0.00)). Conclusions: The decisions taken regarding administration of adjuvant TMZ were similar between VF and CCF. Hence, it's practical and economical to substitute CCF with VF during adjuvant TMZ administration. Clinical trial information: CTRI/2017/01/007626.
Is less more? Comparing chemotherapy alone to chemotherapy and radiation for high risk, grade II glioma—An analysis of the National Cancer Data Base.
Authors: Jhaveri Jaymin , Liu Yuan , Gillespie Theresa Wicklin , Chowdhary Mudit , Buchwald Zachary , Olson Jeffrey J. , Voloschin Alfredo Daniel , Shu Hui-Kuo George , Crocker Ian R. , Curran Walter John , Patel Kirtesh R.
Published: September 2018

2031

Background: Grade II glioma patients with subtotal resection (STR) or age ≥ 40 are considered high risk. RTOG 9802 demonstrated that for these high-risk patients, chemotherapy and radiation therapy improved overall survival (OS) compared to radiation alone. The purpose of this study is to compare the OS of high risk, grade II glioma patients treated with adjuvant chemotherapy alone (CA) to chemotherapy and radiation therapy (CRT). Methods: Using the National Cancer Data Base (NCDB), high risk (age ≥ 40 or STR) grade II glioma patients with oligodendroglioma, astrocytoma, or mixed tumors were identified. Patients receiving CA were compared to patients receiving CRT. Univariate and multivariable analyses (MVA) were performed. Propensity score (PS) matching was utilized to account for difference in patient characteristics. Kaplan Meier statistics were utilized to compare OS. Results: 1054 high risk, grade II glioma patients were identified, 47.1% receiving CA and 52.9% receiving CRT. Median follow up time was 55.1 months. Patients treated with CA were statistically more likely (all p < 0.05) to be oligodendroglioma histology (65.5% vs. 34.2%), 1p/19 co-deleted (22.8% vs. 7.5%), younger median age (47 vs. 48 years) and treated at an academic program (65.2% vs. 50.3%). MVA demonstrated treatment type was not a significant predictor for OS (p = 0.125), while tumor size > 6cm, astrocytoma histology, and older age were predictors for worse survival (all p < 0.05). Utilizing 1:1 PS matching, with 662 total patients, OS was statistically similar (p = 0.919) for CA and CRT at 5 years (69.1% vs. 68.5%, respectively) and 7 years (55.5% vs. 60.0%, respectively). Conclusions: In this retrospective analysis of the NCDB, long term OS for high-risk, grade II glioma patients treated with CA appears similar to CRT. These findings are hypothesis generating, with the standard of care still remaining CRT as established by RTOG 9802. Prospective clinical trials comparing CA and CRT are warranted.
TERT promoter mutations in progressive treatment-resistant meningiomas.
Authors: Juratli Tareq A. , Thiede Christian , Krex Dietmar , Brastianos Priscilla Kaliopi , Wakimoto Hiroaki , Schackert Gabriele , Kirsch Matthias , Cahill Daniel P.
Published: September 2018

2047

Background: Recurrent meningiomas often undergo a grade-progression to become atypical or malignant upon recurrence. Detailed study of progressive meningioma has been hampered by the lack of available paired specimens. Here, we sequenced the TERT promoter ( TERTp) in a large series of patients with treatment-resistant meningiomas at initial diagnosis as well as their sequential recurrences. Methods: We scored 77 meningiomas from 36 patients for TERTp mutations. All patients in this study developed recurrences during the median follow-up of 13.3 years (range 6.4 - 25.5 years) and underwent three surgeries on average (range 2-8). Additionally, we screened geographically distinct sites of all TERTp-mutant meningiomas to interrogate intratumoral heterogeneity. Results: TERTp mutations were detected in 18 tumor samples (18/77 = 23.3%) from 12 patients, but not in any of the matched blood sample DNAs, excluding germline mutations. Notably, the TERTp mutations were absent in the initial lower-grade tumor and were present in the subsequent recurrent tumors. Moreover, we observe emergent spatial heterogeneity in the form of mixed populations of recurrent tumor cells containing different mutation status of the TERT promoter gene in three cases. Patients with emergence of TERTp -mutant meningiomas had a significantly shorter overall survival than their TERTp wild-type counterparts, when measured from the time of initial diagnosis (2.4 vs 11.1 years, 95% CI 0.25-4.54 vs 9.3- 16.8 years p = 0.007). Conclusions: Our data confirm the high frequency of TERTp mutations and the emergence of TERT promoter mutation in recurrent progressive meningiomas, strongly indicating the presence of ongoing evolution impacting the natural history of these tumors. TERTp mutations are mostly associated with poor outcome. Finally, our study provides important insight into the complexity of tumor heterogeneity and has important implications for targeted therapy in treatment-resistant meningiomas.
Whole exome sequencing and copy-number variation analysis of 20 NF2-associated spinal and cranial meningiomas.
Authors: Dewan Ramita , Pemov Alexander , Hansen Nancy F , Chandrasekharappa Settara C , Mullikin Jim , Boland Joseph F , Asthagiri Ashok R , Stewart Douglas ,   NISC
Published: September 2018

2051

Background: Neurofibromatosis type 2 is a heritable tumor predisposition syndrome characterized by the growth of multiple tumor types in the nervous system, including bilateral vestibular schwannomas, meningiomas and ependymomas. Recent genomic sequencing studies have revealed that NF2 inactivation is the most frequent genetic event in sporadic meningiomas. In line with Knudson’s hypothesis, it is accepted that somatic inactivation of the wildtype NF2 allele initiates tumor growth in NF2 patients, but little is known of what other genes or pathways influence meningioma tumorigenesis. Methods: To investigate this question, we performed whole exome sequencing (WES) (Illumina Hi-Seq 2500 platform, 96 Mb SeqCap EZ Exome + UTR Library, NimbleGen) and SNP-array analysis (HumanOmniExpressExome-8, v1.2 arrays, Illumina) of twenty spinal and cranial meningioma samples from seven NF2 patients. Mutation validation was completed via orthogonal sequencing (IonTorrent, ThermoFisher). Results: We identified NF2 germline mutations in all patients, including five nonsense, one splice site and one likely pathogenic intronic mutation. We found that the predominant mechanism of somatic NF2 inactivation in the tumors was loss of heterozygosity (LOH): we identified large chromosome 22 deletions containing NF2 in nineteen out of twenty meningiomas. The second most frequent chromosomal aberration was a deletion within chromosome 1p, followed by entire chromosome X deletion and rearrangements in chromosome 17q. The remaining samples exhibited normal diploid genomic architecture. Somatic mutations included about twenty point substitutions and small indels. Conclusions: Our study revealed that somatic inactivation of NF2 is the most frequent and only recurrent genetic event in NF2-associated meningiomas. Large LOH events are the most prevalent second hit mechanism and may also represent a common path of meningioma progression. Somatic single nucleotide substitutions and small indels are rare in these tumors. Interestingly, we did not identify mutations in TRAF7, KLF4, AKT1, or SMO, which have been found to be critical for non-NF2 meningioma growth.
Treatment through progression with ofranogene obadenovec (VB-111), an anti-cancer viral therapy, significantly attenuates tumor growth in recurrent GBM: Individual phase 2 patient data.
Authors: Brenner Andrew Jacob , Wen Patrick Y. , Vredenburgh James J. , Peters Katherine B. , Blumenthal Deborah T. , Freedman Laurence S , Oberman Bernice , Lowenton-Spier Noa , Lavi Michal , Harats Dror , Cohen Yael Chava
Published: September 2018

2055

Background: Ofranergene obadenovec (VB-111) is a viral cancer-therapy with a dual mechanism: vascular disruption and induction of a tumor directed immune response. Prolongation of overall survival (OS) has been shown in recurrent glioblastoma (rGBM) patients treated through progression with VB-111 in combination with bevacizumab (BEV) compared to historical controls and to patients with limited exposure (LE) to VB-111. Here we present individual patient tumor growth data. Methods: VB-111 was administered at 1x1013viral particles bimonthly until progression, followed by BEV standard of care (LE cohort). The protocol was amended to allow treatment through progression (TThP) with VB-111 bimonthly, with the addition of BEV 10mg/Kg biweekly, until further progression (TThP cohort). Tumor dimensions were assessed q2 months by MRI locally and by an independent central lab. The slope of the log tumor measurement over time was calculated for each patient, average slopes were compared across therapy groups using the Wilcoxon Rank Sum test. Results: 46 patients received up to 13 doses of VB-111. All started with VB-111 monotherapy. 22 were included in the LE cohort; 24 in the TThP cohort. Cohorts were comparable by measures of age, performance status, prior lines of therapy, baseline tumor dimensions and progression-free-survival. Spider diagrams demonstrate similar rapid tumor growth in both LE and TThP cohorts during the VB-111 monotherapy period (local site data; median % increase (MPI) per 30d: 14.8 vs 14.1, p = 0.98). In the TThP cohort, growth was attenuated after the 1stprogression, compared to the preceding VB-111 monotherapy period (MPI: 0.6 vs 14.1, p = 0.0032); responses were seen, including 2 complete responses (CR), one patient remaining in CR over 3 years. A similar attenuation was seen in central lab tumor measurements. Conclusions: Treatment through progression with VB-111 in combination with BEV induced durable tumor growth attenuation, which was associated with prolonged OS of 15 months in patients with rGBM. The GLOBE phase 3 randomized controlled trial of VB-111 in rGBM is currently underway. Clinical trial information: NCT01260506.
Heterogeneous spectrum of childhood and adult SHH medulloblastoma: Clinical, radiogenomic features, patterns of failure and survival.
Authors: Jalali Rakesh , Dasgupta Archya , Shirsat Neelam , Sridhar Epari , Pungavkar Sona , Chinnaswamy Girish , Sastri Jayant , Krishnatry Rahul , Gupta Tejpal
Published: September 2018

2063

Background: To present SHH pathway driven medulloblastoma (MB) diversities in pediatric and adult patient populations. Methods: 60 patients with SHH-MB seen at our institute during 2009-2015. We assigned 22 predefined radiological features for all MB subgroups including SHH. Outcome data was retrieved from a prospectively maintained database. Results: Median age of entire cohort was 14 years (1-48 years). 29 were adults (a-SHH) and 31 were pediatric SHH (p-SHH). Radiological data available for 39 patients showed a-SHH having lateralised location in 72% cases. Distinct MRI features to predict SHH include mild/moderate contrast enhancement (90%), cystic changes (82%), edema (92%); identical in two age groups. We could predict SHH accurately 95% times. p-SHH were seen to have higher frequency of p53 mutations (70% vs 45%). At median follow-up of 37 months, 25 patients failed [isolated tumor bed (TB) in 10, TB and supratentorially in 2, cranium outside TB in 1, craniospinal in 5 (along with TB), extraneuraxial (ENM) in 5, second primary in 2 (lymphomas)]. 1 and 3 year DFS was 74% (p-SHH) vs 96% (a-SHH) and 58% vs 73% respectively (p-0.19). The failures seen in a-SHH were typically late (10/11 failed > 22 months) as compared to p-SHH (12/14 failing < 24 months). Also location of recurrences was different, with 7 of a-SHH failing at TB and rest 3 developed ENM. Ten of 13 in p-SHH failed beyond TB. Post- recurrence salvage was better in a-SHH compared to p-SHH, 1-year survival of 50% vs 19% (p-0.08). Overall survival at 1 and 3 year 84% and 55% for p-SHH and 100% and 88% for a-SHH respectively (p = 0.04). Histology and tumor location significantly correlated with OS. No significant correlation was seen with CSI dose or chemotherapy. Conclusions: SHH medulloblastoma have unique MRI features and can be predicted up to 95% times pre-operatively. Adult and pediatric SHH MB form extreme diverse groups with different patterns of failure reflecting different tumor kinetics. Adults fail primarily over TB after initial 2 years. Paediatric SHH follow aggressive course with early disseminated recurrences in 1st year. Different treatment modalities may be needed for pediatric and adult SHH MB.
Ceritinib plus nivolumab (NIVO) in patients (pts) with anaplastic lymphoma kinase positive (ALK+) advanced non-small cell lung cancer (NSCLC).
Authors: Felip Enriqueta , De Braud Filippo G. , Maur Michela , Loong Herbert H. F. , Shaw Alice Tsang , Vansteenkiste Johan F. , John Tom , Liu Geoffrey , Lolkema Martijn P. , Scott Jeffrey W. , Yu Richard , Selvaggi Giovanni , Mishra Kaushal , Lau Yi-Yang Yvonne , Tan Daniel Shao-Weng
Published: September 2018

2502

Background: Induction of PD-L1 expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring EML4–ALK rearrangements. Here we explore whether the combination of ALKi (ceritinib) and PD1-inhibitor (NIVO) will provide sustained clinical benefit to pts with ALK+ NSCLC. Methods: This phase 1 dose escalation study enrolled previously treated (ALK inhibitor [ALKi] or chemotherapy) or tx-naive pts with stage IIIB/IV ALK+ NSCLC; who received NIVO 3 mg/kg IV Q2W + ceritinib with low-fat meal, at 450 mg/day (group 1) or 300 mg/day (group 2) until progression/unacceptable toxicity. Primary objective: MTD/recommended dose for expansion. Dose escalation was guided by Bayesian logistic regression model with overdose control. Results: Median follow-up: group 1 (n = 14) 13 mos (10-15); group 2 (n = 22) 6 mos (2-10). As of 9 Sep 2016, 16/36 (44%) pts discontinued tx: disease progression (11 [31%] pts), AE’s (3 [8%] pts), and death (2 [6%] pts). In group 1, 4 pts experienced DLT: pancreatitis (n = 2), lipase and transaminase increase (n = 1), and autoimmune hepatitis (n = 1). In group 2, 2 pts experienced DLT: G3 ALT increase. Both dose levels met Bayesian criteria for dose expansion. Overall most frequent (≥40%) AEs (n = 36), were diarrhea (64%), ALT increase (56%), AST increase (44%) and vomiting (42%). Most frequent ( > 10%) grade ≥3 AEs were increases in ALT (22%), GGT (17%), amylase (11%), and lipase (11%), and maculopapular rash (11%). Incidence of rash (grouped term) was 61%; similar in both groups. Grade 3 rash was reported in 29% pts in group 1 and 14% pts in group 2. Preliminary ceritinib steady state PK (AUC0-24 and Cmax) suggested that 300 mg/day exposure was ~ 70-75% of 450 mg/day. Confirmed (c)/unconfirmed (u) ORR: ALKi-pretreated pts (group 1 [n = 8], group 2 [n = 12]) was 63% (4 cPR,1 uPR; 95% CI: 25%, 92%), and 33% (4 uPR) 95% CI: 10%, 65%) respectively; ALKi-naïve pts, (group 1 [n = 6], group 2 [n = 10]) was 83% (5 cPR; 95% CI: 36%, 100%), and 70% (1 cCR, 3 cPR 3uPR; 95% CI: 35%, 93%) respectively. Conclusions: Ceritinib + NIVO is an active combination in ALK+ NSCLC. However, the protocol will be amended to address observed toxicities. Data will be updated for presentation. Clinical trial information: NCT02393625.
Development of a population pharmacokinetic (PPK) model of intravenous (IV) trastuzumab in patients with a variety of solid tumors to support dosing and treatment recommendations.
Authors: Kirschbrown Whitney Paige , Quartino Angelica Linnea , Li Hanbin , Mangat Ranvir , Wada D Russell , Garg Amit , Jin Jin Y , Lum Bert L.
Published: September 2018

2525

Background: The aim of this analysis was to develop a PPK model for IV trastuzumab (Herceptin), to assess the impact of patient covariates on PK, and perform simulations to support dosing recommendations. Methods: Serum trastuzumab concentration data (26,040 samples) from 1582 patients with metastatic breast cancer (MBC), early breast cancer (EBC), advanced gastric cancer (AGC) or other tumor types, and 6 healthy volunteers in 18 Phase I, II, and III trials were analyzed using nonlinear mixed-effects modeling (NONMEM). Monte Carlo simulations were performed using the NONMEM PK parameter estimates (with variability) to inform dosing recommendations. Results: A two-compartment model with parallel linear and nonlinear elimination best described the data. Significant covariates (P < 0.001) influencing linear CL were baseline weight, SGOT, albumin, primary tumor type, and presence of liver metastases. MBC had similar PK parameters as EBC, with lower distributions of Cmin,ss in MBC explained by covariates. The higher linear CL in AGC patients resulted in a 30.5% lower Cmin,ss. Simulations for drug washout indicated that 95% of patients with breast cancer (BC) reach trastuzumab concentrations < 1 µg/mL (~97% washout) at ≤7 months. Simulations also indicated that a missed dose of trastuzumab in BC or AGC patients of ≤1 week did not result in a long PK under-exposure (i.e. the trastuzumab concentration is within 15% of Cmin,ss by 3 weeks) but a missed dose of > 1 week took approximately 6 weeks to get back within the steady-state exposure range. Conclusions: Trastuzumab PK was well described by a two-compartment model with parallel linear and nonlinear eliminationacross cancer types, disease status, and regimens. No dose adjustment is required based on any of the identified patient covariates (e.g. weight, tumor type). Simulations using the PPK model informed the prescribing information for Herceptin; trastuzumab has a 7-month serum washout period during which patients should avoid an anthracycline-based therapy, pregnancy, or breastfeeding. A re-loading dose is required if a maintenance dose is missed by > 1 week to maintain serum concentrations.
Representation of minorities in oncology clinical trials: Review of the past 14 years.
Authors: Duma Narjust , Vera Aguilera Jesus , Paludo Jonas , Wang Yucai , Leventakos Konstantinos , Mansfield Aaron Scott , Adjei Alex A.
Published: September 2018

2533

Background: Many cancer clinical trials (CT) lack appropriate representation of specific patients populations, limiting the generalizability of the evidence obtained. Therefore, we determined the representation of ethnic minorities in oncology CT. Methods: Enrollment data from all therapeutic trials reported as completed in clinicaltrial.gov from 2003 to 2016 were analyzed. CT in rare cancers (< 1% incidence) or with recruitment outside of the US were excluded. Enrollment fraction (EF) was defined as the number of enrollees divided by the 2013 SEER database cancer prevalence. Chi-square test was used to estimate differences in categorical data. Results: Out of 1,012 CT, 310 (31%) reported ethnicity with a total of 55689 enrollees. Distribution by race and comparison with data from 1996-2002, US cancer prevalence and US census are described in the Table. Participation in CT varied significantly across ethnic groups, non-Hispanic Whites (NHW) were more likely to be enrolled in CT (EF of 1.2%) than African Americans (EF of 0.7%, p < 0.001) and Hispanics (EF of 0.4%, p<0.001). A decrease in African Americans (AA) and Hispanics (H) enrollment was observed when compared with historical data from 1996 to 2002. Hispanics were less represented in breast and prostate cancer CT contributing only to 3% and 1.5% of the study population; African Americans were less represented in lung (5.4%) and renal cell carcinoma (3%) trials. Asians were well represented and their recruitment doubled over the past 14 years (2% vs 5.3%). Conclusions: African Americans and Hispanics were less likely to be enrolled in CT. Comparing with historical data; we observed a decrease in minorities’ recruitment in the past 14 years. This change could be attributed to the increased complexity of CT and mandatory molecular testing as many minorities lack access to institutions with genetic testing capacity. Future trials should take extra measures to recruit participants that adequately represent the U.S. cancer population. [Table: see text]
Food effect studies and drug label recommendations: A review of recently approved oncology products.
Authors: Farha Mark , Masson Eric , Tomkinson Helen , Mugundu Ganesh
Published: September 2018

2535

Background: Evaluation of the effect of food on the pharmacokinetics of orally administered oncology drugs is a critical aspect of drug development, as food can mitigate or exacerbate toxicities and can change and influence variability in systemic exposure. Our aim in this review of approved oncology products is to describe the approaches used by sponsors to assess food effect and decide on the final dosing recommendations. Methods: Data for small molecule oncology drugs approved between 2003-2016 was extracted from the clinical pharmacology review in the sponsor’s FDA submission package. Information on food-effect study design, outcomes, intersubject variability, exposure-response relationships for safety, and the label dosing recommendation regarding food was analyzed. Results: Of the 29 drugs analyzed, 19 food effect studies were conducted in healthy volunteers, and 10 were conducted in cancer patients. The ratio of population geometric means between fed and fasted treatments fell outside the 80-125 percent equivalence limit in 55% of compounds for AUC and in 69% of compounds for Cmax. 6 drugs (21%) are recommended to be given with food, 11 drugs (38%) in the fasted state, and 12 drugs (41%) can be dosed regardless of food. Label recommendations appeared to be driven by the exposure-response analysis. 80% of drugs with a fasted label recommendation despite an increase in bioavailability with food had an exposure-response relationship for safety. Conclusions: Optimizing study design by conducting early food effect studies designed to estimate food effect rather than confirming no food effect, and learning the impact of food early may eliminate unnecessary study arms and save sponsors money and time. Furthermore, understanding the potential of food to mitigate or exacerbate toxicities may improve patients’ experience with treatments and has been shown here to be a major driver of the final dosing recommendation regarding food.
Hormone receptor (AR/ER/PR) expression as a prognostic marker and novel candidate for drug development across multiple tumor types.
Authors: Sen Shiraj , Roszik Jason , Meric-Bernstam Funda , Subbiah Vivek
Published: September 2018

2537

Background: Hormone receptor (HR) [androgen receptor (AR), estrogen receptor (ER), progesterone receptor (PR)] expression is ubiquitous across tumor types and central to breast and prostate cancer treatment. While implicated in tumorigenesis, its role as a prognostic biomarker and therapeutic target in other tumor types has yet to be elucidated. Methods: We performed bioinformatic analyses of HR expression [reported as median transcripts per million (TPM)] using RNAseq from the Cancer Genome Atlas and completed Kaplan-Meier analyses to identify associations between HR expression and median overall survival (OS). Results: 9,743 samples from 9,674 patients across 33 tumor types were analyzed. AR was highly expressed in GBM (2 TPM), low grade glioma (2 TPM), breast (15 TPM), prostate (14 TPM), ovarian (6 TPM), renal clear cell carcinoma (4 TPM) and HCC (2 TPM) . Tumors with the highest quartile of expression had improved OS in renal clear cell [53 months (mo) vs not reached (NR), p = 4x10-11] and adrenocortical carcinoma (45 mo vs NR, p = .03) and worse OS in low grade glioma (119 vs 64 mo, p = 6x10-4). PR was highly expressed in uterine (12 TPM), breast (5 TPM), and renal chromophobe (2 TPM) carcinoma. PR expression was associated with improved OS in sarcoma (49 mo vs NR, p = .03), endometrial (NR, p = .02) and renal clear cell carcinoma (58 mo vs NR, p = .003) and worse OS in low grade glioma (53 vs 97 mo, p = .01), gastric adenocarcinoma (7 vs 17 mo, p = .04), and possibly pancreatic adenocarcinoma (21 vs 44 mo, p = .07). ER was highly expressed in breast (116 TPM), endometrial (87 TPM), ovarian (32 TPM), cervical (4 TPM), thyroid (4 TPM), prostate (3 TPM), and lung adenocarcinoma (2 TPM). ER expression was associated with improved OS in mesothelioma (15 vs 28 mo, p = .03) and endometrial cancer (NR, p = .001) and worse OS in squamous lung cancer (80 vs 48 mo, p = .02). Conclusions: HR expression may represent a novel prognostic marker in multiple tumor types and a candidate for drug development in low grade glioma, gastric adenocarcinomas, squamous cell lung cancer, and pancreatic adenocarcinomas. Protein-based IHC testing and early phase clinical trials targeting HR signaling in these tumor types is warranted.
FDA analysis of MRD data in hematologic malignancy applications.
Authors: Gormley Nicole , Bhatnagar Vishal , Ehrlich Lori A. , Kanapuru Bindu , Lee Hyon-Zu , McKee Amy E. , Farrell Ann , Pazdur Richard
Published: September 2018

2541

Background: There is considerable interest in the use of minimal residual disease (MRD) in clinical trials of hematologic malignancies, especially as a potential surrogate endpoint to expedite drug approval. Although surrogacy has not yet been established in most hematologic malignancies (except CML), MRD data has been submitted in applications to the agency to allow for further characterization of the product’s activity. Here we describe the new drug applications (NDA) or biologics licensing applications (BLA) that included MRD data and provide an analysis of the MRD data and the Agency’s decisions. Methods: The authors reviewed internal databases for all original and supplemental NDA and BLA applications submitted to the Division of Hematology Products (DHP) between 2014 and 2016 that pertained to malignant hematologic conditions. The applications were reviewed for inclusion of MRD data. The clinical reviews and prescribing information (PI) of the identified applications were reviewed for assessment of MRD data and FDA’s findings. Results: There were 34 NDAs or BLAs submitted between 2014-2016. Of these, 13 (38%) included MRD data, in the following diseases: CML, CLL, ALL, and MM. MRD data was added to the PI in 6 cases (46%), not included in 4 (31%), and was not proposed for inclusion in 3 (23%). Among the 6 cases in which MRD data was included in the PI, 5 used PCR testing and 1 used flow cytometry. Among the 4 in which MRD data was not included in the PI, the identified issues included: missing data among those in CR, incomplete test performance characteristics data (e.g.-limit of detection), disparate sample sources (blood, bone marrow), high amount of test failure rates (i.e.-inability to identify a clonal rearrangement), lack of test validation in the proposed disease setting, and inappropriate planned statistical analyses. Conclusions: Nearly 40% of applications submitted to DHP between 2014 and 2016 included MRD data. While the data submitted was deemed adequate for inclusion in the PI in 46% of cases, 31% of applications contained MRD data that the Agency deemed un-interpretable. Data collection and assay performance characteristics should be of significant rigor and completeness to allow for comprehensive review.
Changes in numbers of randomized (RCT) versus non-randomized (NRCT) clinical trials from 2004-2016: Evidence of shifting cancer drug development pathway.
Authors: Vidal Boixader Laura , Curtis Kelly Kevelin , Wahl Jim , Kenny Nicholas , Moss Keren Rachel
Published: September 2018

2543

Background: Trials using randomized designs have been conducted for decades to demonstrate efficacy of novel anti-cancer drugs (NACD). Recently, several NACD have shown high antitumor activity in early phase studies, prompting suggestions that NRCT could expedite drug development. We sought to determine what changes have occurred in numbers of NACD RCT vs NRCT conducted from 2004-2016. Methods: We reviewed a database of NACD clinical trials conducted by INC (excluding phase I and I/II trials) and classified them by RCT vs NRCT, grouped by year (≤ 2010 or > 2010). We queried Citeline Trialtrove database for industry sponsored, phase 2 trials (P2T) initiated from 2006-2016 and examined numbers of RCT vs NRCT by year.A more detailed analysis of non-small cell lung cancer (NSCLC) clinical trials based on drug type category - Immunooncology (IO) vs. all other mechanims of action (NIO) was performed. Results: 190 INC-conducted trials were reviewed. 58 trials (31%) were performed ≤ 2010 and 132 trials (69%) > 2010. Over this period, NRCT (n = 107, 56%) outnumbered RCT (n = 83, 44%). Whereas RCT outnumbered NRCT from 2004-2010 (74% vs 52%), after 2010, NRCT outnumbered RCT (58% vs 42%). Citeline Trialtrove search revealed 4776 industry sponsored P2T initiated from 2006-2016. The total number of P2T started annually was highest in 2007 (n = 621), decreasing to a low of 375 in 2016. The proportion of phase 2 RCT demonstrated an increase from 27% (n = 166) in 2006 to a peak plateau of 37-39% from 2011-2014, followed by a drop to 33% in 2015 and 29% in 2016. Among IO studies, RCT declined in 2015-6 vs. previous years, and a decreased for all NACD in 2016 vs. previous years also was noted. For studies in NSCLC, declines in RCT were evident from 2015-6 vs. previous years ( 45% in 2007-14 vs. 25% in 2015-6). Conclusions: Our data indicate a trend toward fewer trials of NACD using randomized designs and more studies using non-randomized designs, with overall fewer P2T initiated in the past year. This change reflects shifts in NACD development pathways, related to a better understanding of cancer biology, drive to develop personalized treatment and a more flexible regulatory drug approval process.
A study of vistusertib in combination with selumetinib in patients with advanced cancers: TORCMEK phase Ib results.
Authors: Schmid Peter , Forster Martin David , Summers Yvonne J. , Good Jane , Sarker Shah-Jalal , Lim Louise , Mousa Kelly , Middleton Gary William
Published: September 2018

2548

Background: PI3K/mTOR and MAPK pathways are aberrantly activated in many tumours and interact to promote tumour growth and therapeutic resistance. Activity of single pathway inhibition is limited due to compensatory activation of alternative signalling pathways. Dual pathway inhibition has demonstrated synergistic activity in preclinical models, with broad activity across a range of molecular backgrounds. This study was designed to evaluate the optimal doses and schedule of vistusertib (dual mTOR1/2 inhibitor) and selumetinib (MEK1/2 inhibitor) when given in combination. Methods: Thisphase Ib/IIa trial with a dose escalation part (Ib) in treatment refractory advanced solid tumours and expansion cohorts in TNBC, squamous and non-squamous NSCLC (KRASmt & WT) (IIa). Both, continuous daily (CC) (25, 35, 50mg BD) and intermittent (IC) schedules (50, 100, 125mg BD 2ds on, 5 ds off) of vistusertib were investigated. Selumetinib dose was given at a dose of 75mg BD daily. Treatment was given until PD (RECIST 1.1) or intolerable toxicity. The primary endpoint was DLTs. Secondary endpoints included response, clinical benefit, PFS and PK. Results: 23 evaluable patients were enrolled in the PhaseIb part. For the intermittent schedule, no DLTs were reported at any of the dose levels IC1-3. For the continuous schedule, 2 out of 9 patients treated at dose level C2C developed DLTs (G3 mucositis, dizziness and rash). Dose level C3C was not tolerated with DLTs observed in 2 out of 3 patients (G3 mucositis and G3 LFTs). Separate MDTs were determined for intermittent (I3C) and continuous schedules (C2C). Adverse events were in keeping with established single agent safety profiles. Anti-tumour efficacy was demonstrated at various dose levels and across tumour types including uveal melanoma, breast, cervical, uterine, skin or colorectal cancers. There were no objective responses but confirmed stable disease for > 16 weeks were observed in 7 patients with a duration of response ranging up to 55+ weeks. Conclusions: Based on DLTs, dose intensity and cumulative toxicity, the intermittent schedule I3C was selected as RP2D for expansion cohorts. Preliminary anti-tumour activity was observed. Clinical trial information: NCT02583542.
Population pharmacokinetics of durvalumab and fixed dosing regimens in patients with advanced solid tumors.
Authors: Baverel Paul , Dubois Vincent , Jin Chaoyu , Song Xuyang , Jin Xiaoping , Mukhopadhyay Pralay , Gupta Ashok Kumar , Dennis Phillip A. , Ben Yong , Roskos Lorin , Narwal Rajesh
Published: September 2018

2566

Background: Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks its interaction with PD-1 and CD80. The objectives of this analysis were to develop a population pharmacokinetics (PK) model of durvalumab, to quantitate the effect of patient/disease characteristics on PK, and to compare weight (WT)-based versus fixed dosing regimens. Methods: Data were pooled from two studies: Study 1108 (Phase 1/2; various tumor types) and ATLANTIC (Phase 2; NSCLC). A total of 1324 patients provided data following 0.1 to 20 mg/kg IV durvalumab. The population PK was performed using a non-linear mixed effects modeling approach in NONMEM software. The impact of demographics, clinical indices, and biomarkers on PK was explored. Results: Durvalumab PK was best described using a 2-compartment model with both linear and non-linear clearances. The mean (between-patient variability) linear clearance (CL) and central volume of distribution (V1) were 226 mL/day (~29%) and 3.51 L (~21%), respectively. Although population PK analysis identified a few statistically significant covariates (WT, sex, CrCL, post-baseline ADA, ECOG performance status, LDH, sPDL1 levels, tumor type, and albumin), none were found to be clinically relevant (effect on PK parameters < 30%), indicating no need for dose adjustment. Simulations indicated similar overall PK exposures following WT-based (10 mg/kg Q2W) and fixed dosing regimens (1500 mg Q4W or 750 mg Q2W); with all regimens expected to maintain target trough exposure of ~50 µg/mL in ≥95% patients. In a post-hoc analysis, durvalumab clearance was found to decrease slightly over time, with a mean maximal reduction from baseline value of 15.5%. The decrease in CL was associated with tumor shrinkage, decreased LDH, increased albumin and decreased neutrophil to lymphocyte ratio. The small decrease in CL was not considered relevant to PK exposure or dosing. Conclusions: A population PK model of durvalumab was developed and validated. No dose adjustments were needed based on any patient or disease characteristics. The analysis demonstrated the feasibility of switching to a fixed dose regimen. Clinical trial information: NCT02087423 and NCT01693562.
A phase Ia study of CC-90003, a selective extracellular signal-regulated kinase (ERK) inhibitor, in patients with relapsed or refractory BRAF or RAS-mutant tumors.
Authors: Mita Monica M. , LoRusso Patricia , McArthur Grant A. , Kim Edward S. , Bray Gordon L. , Hock Nanette H , Laille Eric J. , Aronchik Ida , Filvaroff Ellen , Wu Xiaoling , Bendell Johanna C.
Published: September 2018

2577

Background: CC-90003 is an irreversible inhibitor of ERK 1/2 with potent anti-proliferative activity in KRAS and BRAF mutant tumor models. We conducted a first-in-human study of CC-90003 in patients with RAS or BRAF mutant tumors. Methods: Patients received escalating doses of oral CC-90003 on a 21/28 day cycle. Standard safety (adverse events, chemistry/hematology, physical findings, ECGs and cardiac ECHO/MUGA scans) and PK parameters were assessed. Response was assessed per RECIST 1.1. A proprietary ELISA-based assay measured ERK levels unbound to CC-90003 in peripheral blood mononuclear cells. Results: Nineteen patients (median age: 60 yrs) harboring KRAS (n = 15), NRAS (n = 1), or BRAF (n = 3) mutant tumors received CC-90003 doses from 20 to 160 mg /day. The MTD was 120 mg based on the occurrence of Grade 3 transaminase elevations (n = 2) and hypertension (n = 1) observed at 160 mg (the NTD). Patients completed a median of 2 cycles (range: 1 to 5). AEs (mostly Grade 1 or 2) reported in ≥ 3 patients included constitutional (asthenia, fatigue), gastrointestinal (anorexia, nausea/vomiting, diarrhea), hepatic (transaminase elevations) and neurologic (dizziness, gait disturbance, paresthesias) toxicities. Grade 1-3 neurotoxicity was observed primarily at doses from 80 to 160 mg/day and resolved with dose reduction/interruption. PK parameters were highly variable, with AUC and Cmax increasing overall, with increasing dose. CC-90003 accumulation was observed after multiple doses. There were no objective responses. Levels of free ERK were reduced by ≥80% compared to baseline by C1D8 at doses ≥ 80 mg/day. Conclusions: ERK inhibition may be an attractive target for the management of mutant RAS or BRAF-driven tumors, however proof-of-concept demonstration for CC-90003 was limited by a lack of objective responses, an unfavorable PK profile and unanticipated neurotoxicity. Clinical trial information: NCT02313012.
SWOG S1221: A phase 1 dose escalation study co-targeting MAPK-dependent and MAPK-independent BRAF inhibitor resistance in BRAF mutant advanced solid tumors with dabrafenib, trametinib, and GSK2141795 (ClinicalTrials.gov NCT01902173).
Authors: Algazi Alain Patrick , Moon James , Chmielowski Bartosz , Lo Roger , Kendra Kari Lynn , Lao Christopher D. , Lewis Karl D. , Gonzalez Rene , Kim Kevin , Godwin John E. , Curti Brendan D. , Othus Megan , Ribas Antoni
Published: September 2018

2578

Background: Aberrant PI3K/AKT signaling in BRAF mutant cancers contributes to resistance to MAPK pathway blockade. We conducted parallel phase 1 dose escalation studies of the doublet of the BRAFi dabrafenib with the AKT inhibitor GSK2141795 and of the triplet of dabrafenib, the MEKi trametinib, and GSK2141795. Methods: Patients (pts) with BRAF-V600E/K mutant advanced solid tumors with adequate end-organ function were eligible regardless of prior BRAFi and MEKi exposure. All pts received dabrafenib at 150 mg twice daily (bid), in the doublet cohorts together with dose escalation (3 + 3 scheme) of GSK2141795 started at 50 mg daily (qd), and in the triplet cohorts with dose escalation of both trametinib starting at 1.5 mg qd and GSK2141795 starting at 25 mg qd. DLTs included significant grade 3 and 4 adverse events (CTCAE v4) within the first 56 days of treatment. Radiographic responses were assessed at 8-week intervals. Results: No DLTs were observed in the doublet cohorts (N = 8) up to dabrafenib 150 mg bid and GSK2141795 75 mg qd. In the triplet cohorts (N = 11), no DLTs were observed at doses of up to trametinib 1.5 mg daily with GSK2141795 75 mg daily. At the highest triplet dose with dabrafenib 150 mg bid, trametinib 2 mg qd with GSK2141795 75 mg qd, 1 of 2 evaluable pts had a DLT of grade 3 febrile neutropenia and grade 3 maculo-papular rash. 2/2 treatment-naïve in the doublet cohorts had PRs (1 melanoma and 1 thyroid) the latter lasting over 1 year. 1/6 BRAF inhibitor-refractory (melanoma) pts also had an objective response. In the triplet cohorts, 3 of 6 treatment-naïve pts had a PR (1 melanoma, 2 lung). One lung pt remains in PR at 2 months and the otherhas an uPR at 1.2 months. Conclusions: Inhibition of both MAPK and PI3K/AKT pathways was well tolerated, leading to durable objective responses in pts with metastatic melanoma, thyroid cancer, and lung cancer. Further study of dual pathway inhibition is warranted. Funding: Supported in part by NIH/NCI grants CA180888, CA180819; and in part by Novartis Pharmaceuticals Corporation and GlaxoSmithKline, LLC. Clinical trial information: NCT01902173.
A phase I dose expansion cohort study of dasatinib in combination with bevacizumab in advanced solid tumors (NCT01445509).
Authors: Osei-Tutu Akosua , Nunes Ana Tablante , Lee Jung-min , Yu Minshu , Hernandez Lidia , Chen Helen X. , Takebe Naoko , Houston Nicole D. , Ekwede Irene , Steinberg Seth M. , Chen Jin-Qiu , Cao Liang , Figg W. Douglas , Butcher Donna , Annunziata Christina M. , Kohn Elise C.
Published: September 2018

2585

Background: Dasatinib is a known inhibitor of the SRC family kinases and is approved for use in chronic myelogenous leukemia. Bevacizumab inhibits angiogenesis, binding to human vascular endothelial growth factor (VEGF, or VEGF-A) with high affinity. VEGF receptor signals intracellularly via a cascade regulated by SRC. Given the presence of this signaling pathway in both tumor cells and endothelial cells, we hypothesized that attenuation of both SRC and VEGF simultaneously would have synergistic antitumor activity. We previously reported the maximum tolerated dose (MTD) of dasatinib 100mg daily with bevacizumab 10mg/kg q2wk in patients with advanced solid tumors. We now report clinical activity of the combination, and translational endpoints of an expansion cohort. Methods: This is a phase 1 dose escalation with non-randomized expansion cohort. We monitored safety, and response was assessed every 8 weeks using RECIST criteria. Correlative endpoints include blood flow by dynamic MR imaging, endothelial cell density by CD31 immunohistochemistry, functional angiogenic potential by plasma cytokines and rat aortic ring assay, and tumor cell activation state by phosphoprotein analysis. Results: We enrolled 39 patients at the MTD for a total of 50 patients on study, including both the dose escalation and dose expansion phases. No patient experienced dose limiting toxicities during dose escalation. The most common adverse events were grade 2 hypertension and proteinuria. By RECIST, 5 (10%) patients had a partial response, and stable disease was seen in 29 (58%) of patients with a range from 12-145+ weeks on study. We had two exceptional responders with endometrial carcinoma who continue on study to date (112 weeks and 145 weeks). Translational endpoints were correlated with clinical outcome. Conclusions: Bevacizumab and dasatinib are safe in combination, with potential clinical activity. This combination warrants further investigation in solid tumors. Ongoing translational research using specimens from exceptional responders will suggest potential biomarkers of clinical benefit, to be tested in future prospective clinical trials. Clinical trial information: NCT01445509.
SWI/SNF complex subunit aberrations in diverse cancers: Next-generation sequencing of 539 patients.
Authors: Groisberg Roman , Hong David S. , Janku Filip , Jiang Yunfang , Wei ChongJuan , Karp Daniel D. , Tsimberidou Apostolia Maria , Naing Aung , Bhalla Kapil N. , Meric-Bernstam Funda , Subbiah Vivek
Published: September 2018

2588

Background: The SWI/SNF complex is an ATP-dependent chromatin remodeler that is enriched at promoters and enhancers of active genes. It has been implicated as both an oncogene and tumor suppressor. Specific subunit mutations have even been associated with specific cancers with increased PRC2 component EZH2 activity. EZH2/ EED inhibitors are in early stage development to target SWI/SNF complex. Methods: We analyzed 539 consecutive patients with diverse malignancies who were referred for Phase 1 clinical trials and had CLIA certified targeted next-generation sequencing (Foundation one) for presence of aberrations in SWI/SNF complex genes (ARID1A, ARID2, PBRM1, SMARCA4, SMARCB1). Patient charts were reviewed for general demographics (sex, age at diagnosis and death, performance status), tumor histology, stage, metastatic sites, treatment history, outcomes and co-occurring alterations. Results: Fifty patients had mutations in SWI/SNF subunits. Median age at diagnosis was 56 (14-79 years) and M:F ratio 21:29. Kidney, colorectal, ovary and breast were the most common among 15 different cancers. Most were stage IV at diagnosis (68%), had a strong family history of cancer (80%) & were smokers (42%). The most common mutated subunit was ARID1A (50%) followed by PBRM1 (16%), ARID2 (12%), SMARCA4 (12%), and SMARCB1 (10%). All mutations were predicted to be inactivating. Actionable co-occurring pathway alterations were found in 58% of patients, most commonly PI3K (26%), FGFR(16%), and NOTCH1/2 (10%). The majority of patients (62%) were enrolled on a clinical trial. Best responses on other targeted agents included 1 CR (BRAFV600E colon), 4 PR (transformed teratoma, skin SCC, ovarian, NSCLC), 12 SD. Exceptional responders included BRAFV600E colon cancer on BRAFi based therapy for 66 cycles, NSCLC on Nivolumab for 34 cycles, and MSI-H colon cancer on regorafenib/cetuximab for 27 cycles. Conclusions: The role of SWI/SNF in patients with extended clinical benefit from other targeted agents should be explored. Co-occurring genetic alterations are observed in PI3K, FGFR, and NOTCH pathways. Future pre-clinical and/or clinical studies could target these pathways in combination with EZH2/EED inhibitors.