A phase I open-label, dose-escalation study of NUC-3373, a targeted thymidylate synthase inhibitor, in patients with advanced cancer (NuTide:301).

PURPOSE: 5-fluorouracil (5-FU) is inefficiently converted to the active anti-cancer metabolite, fluorodeoxyuridine-monophosphate (FUDR-MP), is associated with dose-limiting toxicities and challenging administration schedules. NUC-3373 is a phosphoramidate nucleotide analog of fluorodeoxyuridine (FUDR) designed to overcome these limitations and replace fluoropyrimidines such as 5-FU. PATIENTS AND METHODS: NUC-3373 was administered as monotherapy to patients with advanced solid tumors refractory to standard therapy via intravenous infusion either on Days 1, 8, 15 and 22 (Part 1) or on Days 1 and 15 (Part 2) of 28-day cycles until disease progression or unacceptable toxicity. Primary objectives were maximum tolerated dose (MTD) and recommended Phase II dose (RP2D) and schedule of NUC-3373. Secondary objectives included pharmacokinetics (PK), and anti-tumor activity. RESULTS: Fifty-nine patients received weekly NUC-3373 in 9 cohorts in Part 1 (n = 43) and 3 alternate-weekly dosing cohorts in Part 2 (n = 16). They had received a median of 3 prior lines of treatment (range: 0-11) and 74% were exposed to prior fluoropyrimidines. Four experienced dose-limiting toxicities: two Grade (G) 3 transaminitis; one G2 headache; and one G3 transient hypotension. Commonest treatment-related G3 adverse event of raised transaminases occurred in < 10% of patients. NUC-3373 showed a favorable PK profile, with dose-proportionality and a prolonged half-life compared to 5-FU. A best overall response of stable disease was observed, with prolonged progression-free survival. CONCLUSION: NUC-3373 was well-tolerated in a heavily pre-treated solid tumor patient population, including those who had relapsed on prior 5-FU. The MTD and RP2D was defined as 2500 mg/m2 NUC-3373 weekly. NUC-3373 is currently in combination treatment studies. TRIAL REGISTRATION: Clinicaltrials.gov registry number NCT02723240. Trial registered on 8th December 2015. https://clinicaltrials.gov/study/NCT02723240 .

The Novel Nucleoside Analogue ProTide NUC-7738 Overcomes Cancer Resistance Mechanisms In Vitro and in a First-In-Human Phase I Clinical Trial.

PURPOSE: Nucleoside analogues form the backbone of many therapeutic regimens in oncology and require the presence of intracellular enzymes for their activation. A ProTide is comprised of a nucleoside fused to a protective phosphoramidate cap. ProTides are easily incorporated into cells whereupon the cap is cleaved and a preactivated nucleoside released. 3'-Deoxyadenosine (3'-dA) is a naturally occurring adenosine analogue with established anticancer activity in vitro but limited bioavailability due to its rapid in vivo deamination by the circulating enzyme adenosine deaminase, poor uptake into cells, and reliance on adenosine kinase for its activation. In order to overcome these limitations, 3'-dA was chemically modified to create the novel ProTide NUC-7738. EXPERIMENTAL DESIGN: We describe the synthesis of NUC-7738. We determine the IC50 of NUC-7738 using pharmacokinetics (PK) and conduct genome-wide analyses to identify its mechanism of action using different cancer model systems. We validate these findings in patients with cancer. RESULTS: We show that NUC-7738 overcomes the cancer resistance mechanisms that limit the activity of 3'-dA and that its activation is dependent on ProTide cleavage by the enzyme histidine triad nucleotide-binding protein 1. PK and tumor samples obtained from the ongoing first-in-human phase I clinical trial of NUC-7738 further validate our in vitro findings and show NUC-7738 is an effective proapoptotic agent in cancer cells with effects on the NF-κB pathway. CONCLUSIONS: Our study provides proof that NUC-7738 overcomes cellular resistance mechanisms and supports its further clinical evaluation as a novel cancer treatment within the growing pantheon of anticancer ProTides.

A Phase 2a cohort expansion study to assess the safety, tolerability, and preliminary efficacy of CXD101 in patients with advanced solid-organ cancer expressing HR23B or lymphoma.

BACKGROUND: This Phase 2a dose expansion study was performed to assess the safety, tolerability and preliminary efficacy of the maximum tolerated dose of the oral histone de-acetylase (HDAC) inhibitor CXD101 in patients with relapsed / refractory lymphoma or advanced solid organ cancers and to assess HR23B protein expression by immunohistochemistry as a biomarker of HDAC inhibitor sensitivity. METHODS: Patients with advanced solid-organ cancers with high HR23B expression or lymphomas received CXD101 at the recommended phase 2 dose (RP2D). Key exclusions: corrected QT > 450 ms, neutrophils < 1.5 × 109/L, platelets < 75 × 109/L, ECOG > 1. Baseline HR23B expression was assessed by immunohistochemistry. RESULTS: Fifty-one patients enrolled between March 2014 and September 2019, 47 received CXD101 (19 solid-organ cancer, 28 lymphoma). Thirty-four patients received ≥80% RP2D. Baseline characteristics: median age 57.4 years, median prior lines 3, male sex 57%. The most common grade 3-4 adverse events were neutropenia (32%), thrombocytopenia (17%), anaemia (13%), and fatigue (9%) with no deaths on CXD101. No responses were seen in solid-organ cancers, with disease stabilisation in 36% or patients; the overall response rate in lymphoma was 17% with disease stabilisation in 52% of patients. Median progression-free survival was 1.2 months (95% confidence interval (CI) 1.2-5.4) in solid-organ cancers and 2.6 months (95%CI 1.2-5.6) in lymphomas. HR23B status did not predict response. CONCLUSIONS: CXD101 showed acceptable tolerability with efficacy seen in Hodgkin lymphoma, T-cell lymphoma and follicular lymphoma. Further studies assessing combination approaches are warranted. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01977638 . Registered 07 November 2013.

A Phase Ib Open-Label, Dose-Escalation Study of NUC-1031 in Combination with Carboplatin for Recurrent Ovarian Cancer.

PURPOSE: NUC-1031 is a first-in-class ProTide modification of gemcitabine. In PRO-002, NUC-1031 was combined with carboplatin in recurrent ovarian cancer. PATIENTS AND METHODS: NUC-1031 was administered on days 1 and 8 with carboplatin on day 1 every 3 weeks for up to six cycles. Four dose cohorts of NUC-1031 (500, 625, and 750 mg/m2) with carboplatin (AUC4 or 5) were investigated. Primary endpoint was recommended phase II combination dose (RP2CD). Secondary endpoints included safety, investigator-assessed objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), and pharmacokinetics. RESULTS: A total of 25 women with recurrent ovarian cancer, a mean of 3.8 prior lines of chemotherapy, and a median platinum-free interval of 5 months (range: 7-451 days) were enrolled; 15 of 25 (60%) were platinum resistant, 9 (36%) were partially platinum sensitive, and 1 (4%) was platinum sensitive. Of the 23 who were response evaluable, there was 1 confirmed complete response (4%), 5 partial responses (17%), and 8 (35%) stable disease. The ORR was 26% and CBR was 74% across all doses and 100% in the RP2CD cohort. Median PFS was 27.1 weeks. NUC-1031 was stable in the plasma and rapidly generated high intracellular dFdCTP levels that were unaffected by carboplatin. CONCLUSIONS: NUC-1031 combined with carboplatin is well tolerated in recurrent ovarian cancer. Highest efficacy was observed at the RP2CD of 500 mg/m2 NUC-1031 on days 1 and 8 with AUC5 carboplatin day 1, every 3 weeks for six cycles. The ability to deliver carboplatin at AUC5 and the efficacy of this schedule even in patients with platinum-resistant disease makes this an attractive therapeutic combination.

Megavoltage Radiosensitization of Gold Nanoparticles on a Glioblastoma Cancer Cell Line Using a Clinical Platform.

Gold nanoparticles (GNPs) have demonstrated significant dose enhancement with kilovoltage (kV) X-rays; however, recent studies have shown inconsistent findings with megavoltage (MV) X-rays. We propose to evaluate the radiosensitization effect on U87 glioblastoma (GBM) cells in the presence of 42 nm GNPs and irradiated with a clinical 6 MV photon beam. Cytotoxicity and radiosensitization were measured using MTS and clonogenic cellular radiation sensitivity assays, respectively. The sensitization enhancement ratio was calculated for 2 Gy (SER2Gy) with GNP (100 µg/mL). Dark field and MTS assays revealed high co-localization and good biocompatibility of the GNPs with GBM cells. A significant sensitization enhancement of 1.45 (p = 0.001) was observed with GNP 100 µg/mL. Similarly, at 6 Gy, there was significant difference in the survival fraction between the GBM alone group (mean (M) = 0.26, standard deviation (SD) = 0.008) and the GBM plus GNP group (M = 0.07, SD = 0.05, p = 0.03). GNPs enabled radiosensitization in U87 GBM cells at 2 Gy when irradiated using a clinical platform. In addition to the potential clinical utility of GNPs, these studies demonstrate the effectiveness of a robust and easy to standardize an in-vitro model that can be employed for future studies involving metal nanoparticle plus irradiation.

Re-irradiation for recurrent glioblastoma (GBM): a systematic review and meta-analysis.

PURPOSE: To determine the efficacy and toxicity of re-irradiation for patients with recurrent GBM. MATERIALS AND METHODS: We searched various biomedical databases from 1998 to 2018, for eligible studies where patients were treated with re-irradiation for recurrent GBM. Outcomes of interest were 6 and 12-month overall survival (OS-6, OS-12), 6 and 12-month progression free survival (PFS-6, PFS-12) and serious (Grade 3 +) adverse events (AE). We used the random effects model to pool outcomes across studies and compared pre-defined subgroups using interaction test. Methodological quality of each study was assessed using the Newcastle-Ottawa scoring system. RESULTS: We found 50 eligible non-comparative studies including 2095 patients. Of these, 42% were of good or fair quality. The pooled results were as follows: OS-6 rate 73% (95% confidence interval (CI) 69-77%), OS-12 rate 36% (95% CI 32-40%), PFS-6 rate 43% (95% CI 35-50%), PFS-12 rate 17% (95% CI 13-20%), and Grade 3 + AE rate 7% (95% CI 4-10%). Subgroup analysis showed that prospective studies reported higher toxicity rates, and studies which utilized brachytherapy to have a longer OS-12. Within the external beam radiotherapy group, there was no dose-response [above or below 36 Gy in 2 Gy equivalent doses (EQD2)]. However, a short fractionation regimen (≤ 5 fractions) seemed to provide superior PFS-6. CONCLUSION: The available evidence, albeit mostly level III, suggests that re-irradiation provides encouraging disease control and survival rates. Toxicity was not uniformly reported, but seemed to be low from the included studies. Randomized controlled trials (RCT) are needed to establish the optimal management strategy for recurrent GBM.

Intensity-modulated radiotherapy for paranasal sinuses and base of skull tumors.

Paranasal sinus and skull base tumors are rare aggressive head and neck cancers, and typically present in the locally advanced stages. As a result, achieving wide surgical resection with clear margins is a challenge for these tumors, and radiotherapy is thus usually indicated as an adjuvant modality following surgery to optimize local control. Given the integral role of radiotherapy in the management of this subgroup of head and neck tumors, the advent of intensity-modulated radiotherapy (IMRT) has led to substantial improvement of clinical outcomes for these patients. This is primarily driven by the improvement in radiation dosimetry with IMRT compared to conventional two dimensional (2D)- and 3D-techniques, in terms of ensuring dose intensity to the tumor target coupled with minimizing dose exposure to critical organs. Consequently, the evident clinical benefits of IMRT have been in reduction of normal tissue toxicities, ranging from critical neurological symptoms to less debilitating but bothersome symptoms of eye infections and radiation-induced skin changes. Another domain where IMRT has potential clinical utility is in the management of a subset of non-resectable T4 paranasal sinus and skull base tumors. For these inoperable lesions, the steep dose-gradient between tumor and normal tissue is even more advantageous, given the crucial need to maintain dose intensity to the tumor. Innovative strategies in this space also include the use of induction chemotherapy for patient selection. In this review, we summarized the data for the aforementioned topics, including specific discussions on the different histologic subtypes of paranasal sinus and skull base tumors.

Early Decompressive Hemicraniectomy for Malignant Middle Cerebral Artery Infarction in Asian Patients: A Single-Center Study.

INTRODUCTION: Early decompression craniectomy (within 48 hours of stroke onset) in acute and malignant middle cerebral artery (MCA) ischemic stroke (IS) reduces mortality and increases the proportion of patients with favorable functional outcome. Various cultural and social issues among Asians lead to some differences in clinical practice, especially when surgical interventions are involved. Accordingly, decompressive craniectomy in Asian patients with stroke is often delayed. MATERIALS AND METHODS: Data for all patients with acute IS hospitalized in our center were entered into a prospectively maintained registry. In this retrospective analysis, data for all patients with malignant MCA IS who underwent decompressive craniectomy were extracted. Various demographic, clinical, and neuroimaging factors were analyzed for identifying independent predictors of favorable functional outcome at 6 months, which was defined as modified Rankin Scale score of 0-3 points. RESULTS: From January 2005 to December 2014, a total of 75 patients with acute MCA IS underwent decompressive craniectomy. Median age was 55 years (interquartile range 44-64) with male preponderance (66%) and median National Institute of Health Stroke Scale score 21 points (interquartile range 18-24). A considerable proportion of these patients (38.7%) received intravenous thrombolysis. The majority (70%) of patients suffered right MCA IS, and decompressive surgery was performed within 48 hours of symptom onset in 50 (67%) of the patients. Favorable functional outcome was achieved in 25 (33.3%) patients at 6 months. Right MCA stroke (odds ratio 9.158; 95% confidence interval 1.881-44.596, P = 0.006) and early decompression surgery (odds ratio 4.011; 95% confidence interval 1.058-15.208, P = 0.041) were independent predictors of favorable functional outcome at 6 months. CONCLUSIONS: Early decompression craniectomy, especially in right MCA ischemic stroke, is associated with better favorable functional outcome.