In this letter, a resource allocation scheme for 5G new radio (NR) based vehicle-to-vehicle (V2V) sidelink mode 1 unicast communication is proposed. First, a M/G/1 queueing model-based end-to-end ...(E2E) latency analysis on the communication methodology is performed considering packet retransmissions. Based on the latency requirements of NR-V2V unicast traffic, a Sidelink Unicast V2V Real-time (SUVR) scheme is proposed to minimize the required number of resource blocks (RBs). Simulation results show that the proposed SUVR scheme provides more efficient resource management at the gNodeB, while satisfying the packet latency quality of service (QoS) requirements for vehicular user equipment compared to the benchmarked VRSAP scheme.
Abstract
BACKGROUND
Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed ...glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients with O6-methylguanine methyltransferase (MGMT) unmethylated tumors into a therapeutic regimen of niraparib plus fractionated radiotherapy when PK threshold is met.
METHODS
Presumed newly-diagnosed GBM patients received 4 days of niraparib (300/200 mg QD) prior to planned resection 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and non-enhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. PARP inhibition was assessed by quantification of PAR induction after ex vivo irradiation of surgical vs non-irradiated tissue. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound niraparib > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. Patients with MGMT unmethylated tumors and positive PK were eligible for phase 2 dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib.
RESULTS
All phase 0 patients (n = 44) met the PK threshold. In non-enhancing tumor regions, the mean unbound concentration of niraparib was 226.7 nM (n = 38). PAR suppression after ex vivo radiation was observed in 71% of the patients (20/28). Eighteen out of 26 patients with unmethylated tumors enrolled in phase 2. Five of the 18 initial patients in phase 2 experienced grade 4 thrombocytopenia related to niraparib. All adverse events were resolved without sequelae. For patients who completed at least 6 months of follow-up, PFS6 was 64% (n = 11) with 9.2-month median follow-up. Median follow-up for all patients (n = 18) was 4.2 months with 8 patients remaining on treatment and 2 patients ongoing PFS6 follow-up.
CONCLUSIONS
Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.
Abstract
BACKGROUND
ATM inhibition has been hypothesized to potentiate the effects of radiation by preventing acute phase DNA damage repair, and a Phase 1 trial of this combination in patients with ...GBM is ongoing (NCT03423628). To test this hypothesis, this phase 0/1b study aimed to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of AZD1390, an ATM inhibitor with BBB penetration, in combination with ex vivo radiation in patients with GBM (NCT05182905).
METHODS
Recurrent GBM patients received 3 days of AZD1390 prior to planned resection at 2-4, 4-6 or 23-25 hours following the final dose. Tumor tissue, cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase. ATM inhibition was assessed via ex vivo radiation and quantification of pRAD50 levels compared to non-radiated control. Patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen.
RESULTS
In 17 patients treated to date, AZD1390 was consistently measured in the Gd-non-enhancing tumor region. All patients (n = 17) exceeded the PK threshold to qualify for the expansion phase of the study. With 5Gy ex-vivo radiation of surgical specimen, pRAD50 expression was significantly suppressed in AZD1390 treated patients compared to untreated controls (geomean 1.8% vs 29.1%, average 94% reduction, p < 0.01). Median 6-month progression-free survival has not been reached at a median clinical follow-up of 4.3 months.
CONCLUSION
AZD1390 is well-tolerated in recurrent GBM patients, achieving pharmacologically relevant concentrations in non-enhancing tumor tissue, and substantially suppressing induction of pRAD50 levels ex vivo post-radiation. This is the first pharmacodynamic evidence that AZD1390 may be a potent radio-potentiator in patients with GBM.
Emerging evidence suggests that "adaptive" induction of autophagy (the cellular process responsible for the degradation and recycling of proteins and organelles) may confer a cardioprotective ...phenotype and represent a novel strategy to limit ischemia-reperfusion injury. Our aim was to test this paradigm in a clinically relevant, large animal model of acute myocardial infarction.
Anesthetized pigs underwent 45 minutes of coronary artery occlusion and 3 hours of reperfusion. In the first component of the study, pigs received chloramphenicol succinate (CAPS) (an agent that purportedly upregulates autophagy; 20 mg/kg) or saline at 10 minutes before ischemia. Infarct size was delineated by tetrazolium staining and expressed as a % of the at-risk myocardium. In separate animals, myocardial samples were harvested at baseline and 10 minutes following CAPS treatment and assayed (by immunoblotting) for 2 proteins involved in autophagosome formation: Beclin-1 and microtubule-associated protein light chain 3-II. To investigate whether the efficacy of CAPS was maintained with "delayed" treatment, additional pigs received CAPS (20 mg/kg) at 30 minutes after occlusion. Expression of Beclin-1 and microtubule-associated protein light chain 3-II, as well as infarct size, were assessed at end-reperfusion. CAPS was cardioprotective: infarct size was 25±5 and 41±4%, respectively, in the CAPS-pretreated and CAPS-delayed treatment groups versus 56±5% in saline controls (P<0.01 and P<0.05 versus control). Moreover, administration of CAPS was associated with increased expression of both proteins.
Our results demonstrate attenuation of ischemia-reperfusion injury with CAPS and are consistent with the concept that induction of autophagy may provide a novel strategy to confer cardioprotection.
A growing body of evidence suggests that breast cancer recurrence risk is linked to lifestyle behaviors. This study examined correlations between breast cancer recurrence, risk reduction beliefs, and ...related behaviors among African American breast cancer survivors (AA BCSs). Study participants included 191 AA BCSs, mean age = 56.3 years, who completed a lifestyle assessment tool. Most respondents believed that being overweight (52.7%), lack of physical activity (48.7%), and a high fat diet (63.2%) are associated with breast cancer recurrence. Over 65% considered themselves overweight; one third (33.5%) agreed that losing weight could prevent recurrence, 33.0% disagreed, while the remaining 33.5% did not know; and nearly half (47.9%) believed that recurrence could be prevented by increasing physical activity. Almost 90% survivors with BMI < 25 Kg/M² reported no recurrence compared to 75.7% with BMI ≥ 25 Kg/M² (p = 0.06); nearly all of the women (99.2%) answered "yes" to seeking professional help to lose weight, 79.7% of which were recurrence-free (p = 0.05). These results provide information about AA BCSs' beliefs and behaviors protective against breast cancer recurrence. Additional research is warranted to determine the effectiveness of educational interventions for AA BCSs that promote consumption of a healthy diet and engaging in regular physical activity.
Abstract
BACKGROUND
This dual-drug Phase 0 study (NCT04391595) evaluates the tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of abemaciclib, a selective CDK4/6-inhibitor, plus LY3214996, ...a selective ERK1/2 inhibitor, in recurrent GBM patients.
METHODS
Adult recurrent GBM patients (n=10) with intact RB expression, > 30% pERK expression, and CDKN2A/B deletion or CDK4/6 amplification received six days of abemaciclib (150mg BID) plus LY3214996 (200mg QD) prior to a planned resection at 3-5 or 7-9 hour time interval after the final drug dose in a Time-Escalation Arm. Tumor tissue (gadolinium Gd-enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. Tumor PD effects, including RB and RSK phosphorylation, were compared to matched archival or pre-treatment biopsied tissue. A PK ‘trigger’ (i.e., unbound concentration > 5x biochemical IC50) was set for each drug. Gd-nonenhancing tumor tissue exhibiting abemaciclib and LY3214996 concentrations in excess of their trigger threshold qualified patients for postoperative dual-drug therapy.
RESULTS
No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, median unbound concentrations of abemaciclib were 31.2 nM (3-5 hour cohort) and 25.1 nM (7-9 hour cohort) while median unbound concentrations of LY3214996 were 52.0 nM (3-5 hour cohort) and 10.2 nM (7-9 hour cohort). Tumor RB and RSK phosphorylation decreased in 6/10 and 2/10 patients, respectively. Tumor proliferation (MIB-1) was decreased in 8/10 patients. 5/10 patients exceeded PK thresholds for both abemaciclib (12 nM) and LY3214996 (25 nM), thereby entering the study’s therapeutic expansion phase.
CONCLUSION
Abemaciclib and LY3214996 achieve pharmacologically-relevant concentrations in Gd-non-enhancing GBM tissue and are associated with suppression of RB pathway and tumor proliferation. The Optimal Time Interval (OTI) for tissue sampling was 3-5 hours after the final drug dose. Based on this interim analysis, the trial will accrue an additional 25 patients at this OTI.
Abstract
BACKGROUND
5-ALA SDT is not a blood-brain barrier disruption technique, but rather a first-in-class drug-device therapy exploiting the heme synthesis pathway in recurrent glioblastoma ...(rGBM). Following IV 5-ALA administration, aberrant tumor metabolism results in protoporphyrin-IX (PpIX) accumulation. Activation of PpIX by non-invasive, non-ablative magnetic resonance-guided focused ultrasound (MRgFUS) induces reactive oxygen species and tumor cell death. This first-in-human Phase 0/1 study investigates the feasibility, safety, and biological effects of 5-ALA SDT in rGBM patients.
METHODS
Six hours prior to SDT, adult patients with rGBM were administered 10mg/kg of an IV formulation of 5-ALA (SONALA-001). Patients were assigned to one of three ascending acoustic energy levels of MRgFUS (200J/400J/800J, measured at transducer surface), followed by a four-day interval prior to planned tumor resection. In each patient, 50% of the enhancing and nonenhancing tumor volume was targeted with MRgFUS with the untreated tumor serving as an internal control. The Optimal Biological Dose (OBD) associated with 5-ALA SDT is the energy level associated with greatest tumor cell death.
RESULTS
8 patients were accrued across all energy levels, and none demonstrated drug- or device-related adverse events. Compared to internal control tissue, the apoptosis biomarker, cleaved caspase-3, was elevated in all patients, but most prominently at the 200J energy level. The oxidative stress biomarkers 4-hydroxynonenal, glutathione, cysteine, and thiol were elevated in treated vs. control tissues at all energy levels. The mean Cmax for 5-ALA and PpIX in plasma were 305 µM and 65 nM, respectively. No off-target histological or radiographic alterations were detected in any patient.
CONCLUSIONS
This first-in-human Phase 0/1 study of a new therapeutic modality for rGBM patients demonstrates that 5-ALA SDT is safe at 200 to 800J and likely induces targeted cell death in rGBM patients via oxidative stress. At 10mg/kg of 5-ALA, the OBD is at or lower than 200J.
Abstract
This study evaluates glioblastoma (GBM) pharmacokinetics (PK) and pharmacodynamics (PD) of pamiparib, a PARP1/2-selective inhibitor, graduating patients to a therapeutic expansion phase of ...drug plus radiotherapy. Newly-diagnosed (Arm A) and recurrent GBM (Arm B) patients received 4 days of pamiparib (60 mg BID) prior to planned resection at 2-4 or 8-12 hours following the final dose. Arm C included recurrent GBM patients who received 4 days of olaparib (200 mg BID). Tumor tissue cerebrospinal fluid (CSF), and plasma were collected. Total and unbound drug concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’, defined as unbound drug > 5-fold biochemical IC50 in nonenhancing tumor determined eligibility for the therapeutic expansion phase. PARP inhibition was assessed via ex vivo radiation and quantification of PAR levels compared to non-radiated control. All patients exceeding the PK threshold were eligible for an expansion phase of study drug plus radiotherapy followed by maintenance regimen. In Arms A (n = 20) and B (n = 15), the mean unbound concentrations of pamiparib in Gd-nonenhancing tumor region were 171.5 nM and 102.9 nM, respectively and in Arm C (n = 4) the mean unbound concentration of olaparib was 11.0 nM. All patients in Arms A and B, but only one in Arm C, exceeded the PK threshold to qualify for the expansion phase of the study. 12/20 (60%), 7/14 (50%), and 1/4 (25%) patients in Arms A, B, and C, respectively progressed to expansion phase. Radiation-induced PAR expression was 2.44 fold in untreated control vs 1.16 in Arm A, 0.82 in Arm B and 1.11 in Arm C patients, respectively. The median progression-free survival was 5.4 (Arm A) (n = 7), 5.0 months (Arm B) (n = 6), and 2.7 months (Arm C) (n = 1), respectively. Pamiparib was generally well-tolerated, achieved pharmacologically-relevant concentrations in nonenhancing GBM tissue and suppressed induction of PAR levels ex vivo post-radiation.
Abstract
BACKGROUND
Poly (ADP-ribose) polymerase (PARP) mediates DNA damage response; niraparib is an investigational PARP1/2-selective inhibitor. This Phase 0 study evaluates newly-diagnosed ...glioblastoma (GBM) tumor pharmacokinetics (PK) and pharmacodynamics (PD), graduating patients to a therapeutic regimen of niraparib plus fractionated radiotherapy when high unbound drug concentrations are present in gadolinium-nonenhancing tumor.
METHODS
Presumed newly-diagnosed GBM patients received 4 days of niraparib (300 mg QD) prior to planned resection at 3-5 or 8-12 hours following the last dose. Tumor tissue (enhancing and nonenhancing regions), cerebrospinal fluid (CSF), and plasma were collected. Total and unbound niraparib concentrations were measured using validated LC-MS/MS methods. A PK ‘trigger’ determined eligibility for the therapeutic expansion phase and was defined as unbound niraparib > 5-fold biochemical IC50 (i.e., 19 nM) in non-enhancing tumor. PARP inhibition was assessed by quantification of PAR induction after 10 Gy ex vivo irradiation in surgical tissue compared to non-irradiated control tissue. Patients with unmethylated MGMT tumors exceeding the PK threshold were eligible for expansion phase dosing of niraparib plus radiotherapy followed by a maintenance phase of niraparib.
RESULTS
Nineteen patients were enrolled into the Phase 0 study; all tumors met the study’s PK threshold and five unmethylated patients continued onto the expansion phase. One expansion phase patient experienced treatment-related Grade 3 serious adverse event (ALT and AST elevation) and four remain on treatment (median 4.2 months). In nonenhancing regions, the mean unbound concentrations of niraparib were 353.4 nM and 331.9 nM in the 3-5 hr cohort (n= 17) and the 8-12 hr (n = 3) cohort, respectively. The suppression of PAR levels after ex vivo radiation was observed in 69% of the patients (11/16).
CONCLUSIONS
Niraparib achieves pharmacologically-relevant concentrations in non-enhancing, newly-diagnosed GBM tissue in excess of any other studied PARP inhibitor.
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