Safety and efficacy of the tumor-selective adenovirus enadenotucirev with or without paclitaxel in platinum-resistant ovarian cancer: a phase 1 clinical trial

BackgroundTreatment outcomes remain poor in recurrent platinum-resistant ovarian cancer. Enadenotucirev, a tumor-selective and blood stable adenoviral vector, has demonstrated a manageable safety profile in phase 1 studies in epithelial solid tumors.MethodsWe conducted a multicenter, open-label, phase 1 dose-escalation and dose-expansion study (OCTAVE) to assess enadenotucirev plus paclitaxel in patients with platinum-resistant epithelial ovarian cancer. During phase 1a, the maximum tolerated dose of intraperitoneally administered enadenotucirev monotherapy (three doses; days 1, 8 and 15) was assessed using a 3+3 dose-escalation model. Phase 1b included a dose-escalation and an intravenous dosing dose-expansion phase assessing enadenotucirev plus paclitaxel. For phase 1a/b, the primary objective was to determine the maximum tolerated dose of enadenotucirev (with paclitaxel in phase 1b). In the dose-expansion phase, the primary endpoint was progression-free survival (PFS). Additional endpoints included response rate and T-cell infiltration.ResultsOverall, 38 heavily pretreated patients were enrolled and treated. No dose-limiting toxicities were observed at any doses. However, frequent catheter complications led to the discontinuation of intraperitoneal dosing during phase 1b. Intravenous enadenotucirev (1×1012 viral particles; days 1, 3 and 5 every 28-days for two cycles) plus paclitaxel (80 mg/m2; days 9, 16 and 23 of each cycle) was thus selected for dose-expansion. Overall, 24/38 (63%) patients experienced at least 1 Grade ≥3 treatment-emergent adverse event (TEAE); most frequently neutropenia (21%). Six patients discontinued treatment due to TEAEs, including one patient due to a grade 2 treatment-emergent serious AE of catheter site infection (intraperitoneal enadenotucirev monotherapy). Among the 20 patients who received intravenous enadenotucirev plus paclitaxel, 4-month PFS rate was 64% (median 6.2 months), objective response rate was 10%, 35% of patients achieved stable disease and 65% of patients had a reduction in target lesion burden at ≥1 time point. Five out of six patients with matched pre-treatment and post-treatment biopsies treated with intravenous enadenotucirev plus paclitaxel had increased (mean 3.1-fold) infiltration of CD8 +T cells in post-treatment biopsies.ConclusionsIntravenously dosed enadenotucirev plus paclitaxel demonstrated manageable tolerability, an encouraging median PFS and increased tumor immune-cell infiltration in platinum-resistant ovarian cancer.Trial registration numberNCT02028117.

The X-ray plateau phase of gamma-ray burst originating from an expanding shell with a Lorentz factor of a few tens

Gamma-ray bursts (GRBs) are one of the most energetic explosions known in the Universe and are also known to have the most relativistic jets, with initial expansion Lorentz factors of $100< \Gamma_i <1000$ \cite{KP91, Fenimore+93, WL95, LS01, ZLB11, Zou+11, Racusin+11}. Many of these objects have a plateau in their early X-ray light curves (up to thousands of seconds) \cite{Nousek+06, OBrien+06, Zhang+06, Liang+07, Srinivasaragavan+20}. In this phase, the X-ray flux decreases much slower than theoretically expected \cite{MR93} which has puzzled the community for many years. Here, we show that the observed signal during this phase in both the X-ray and the optical bands is naturally obtained within the classical GRB “fireball” model, provided that (i) the initial Lorentz factor of the relativistically expanding jet is of the order of a few tens, rather than a few hundreds, as is often cited in the literature, and (ii) the expansion occurs into a medium-low density “wind” with density typically 3-4 orders of magnitude below the expectation from a Wolf-Rayet star \cite{CL99}. Within this framework, the end of the “plateau” phase (the beginning of the regular afterglow) marks the transition from the coasting phase to the self-similar expansion phase, which follows the scaling laws first derived by Blandford \& McKee.\cite{BM76}. This result therefore implies that the long GRB progenitors are either (i) not Wolf-Rayet stars, or (ii) the properties of the wind ejected by these stars prior to their final explosion are very different than the properties of the wind ejected at earlier times. This result shows that the range of Lorentz factors in GRB jets is much wider than previously thought, and bridges an observational ‘gap’ between mildly relativistic jets\cite{Ghisellini1993} inferred in active galactic nuclei, $\Gamma_i\lesssim 20$, to the much higher Lorentz factors, $\Gamma_i\lesssim 1000$ inferred in a few extreme GRBs\cite{Racusin+11}.

The Sharma–Mittal Model’s Implications on FRW Universe in Chern–Simons Gravity

The Sharma–Mittal holographic dark energy model is investigated in this paper using the Chern–Simons modified gravity theory. We investigate several cosmic parameters, including the deceleration, equation of state, square of sound speed, and energy density. According to the deceleration parameter, the universe is in an decelerating and expanding phase known as de Sitter expansion. The Sharma–Mittal HDE model supports a deceleration to acceleration transition that is compatible with the observational data. The EoS depicts the universe’s dominance era through a number of components, such as ω=0, 13, 1, which indicate that the universe is influenced by dust, radiation, and stiff fluid, while −1<ω<13, ω=−1, and ω<−1 are conditions for quintessence DE, ΛCDM, and Phantom era dominance. Our findings indicate that the universe is in an accelerated expansion phase, and this is similar to the observational data.

Safety and Efficacy of Vibostolimab and Pembrolizumab in Patients with Relapsed or Refractory Hematologic Malignancies: A Multicohort, Open-Label, Phase 2 Study

Background: The T-cell immunoglobulin and ITIM domain (TIGIT) is highly coexpressed with programmed cell death 1 (PD-1) on both CD4 and CD8 T cells in cancers. Blockade of TIGIT with vibostolimab (MK-7684) has demonstrated antitumor activity in multiple preclinical tumor models. Inhibition of the PD-1 pathway with pembrolizumab has demonstrated efficacy and safety in several hematologic malignancies. Enhanced antitumor activity with anti-TIGIT and anti-PD-L1 combination therapy has been seen in a preclinical model. A multicohort, open-label, phase 2 study will evaluate the safety and efficacy of MK-7684A, a coformulation of vibostolimab and pembrolizumab, in patients with relapsed or refractory (r/r) hematologic malignancies. Study Design and Methods: This two-part phase 2 study includes a signal-finding phase (part 1) with the option for a dose-expansion phase (part 2), depending on the observed risk-benefit profile from part 1. Patients must have confirmed diagnosis of r/r disease, including classical Hodgkin lymphoma (cHL; cohort A or B), primary mediastinal B-cell lymphoma (PMBCL; cohort A or B), follicular lymphoma (FL; cohort C), diffuse large B-cell lymphoma (DLBCL; cohort D), multiple myeloma (MM; cohort E), or non-Hodgkin lymphoma (NHL; cohort F) (Table 1). Three hundred thirty participants are expected to enroll in part 1 (signal finding) and part 2 (cohort expansion). In part 1, patients in cohorts A-F will receive MK-7684A (vibostolimab 200 mg + pembrolizumab 200 mg) by IV infusion every 3 weeks (Q3W) for up to 35 cycles. Patients will continue treatment until investigator-determined PD, start of new anticancer treatment, documented complete response, or completion of maximum 35 cycles of treatment. Safety data from the first 12 treated patients from any cohort will be collected. Dose-limiting toxicities (DLTs) will be monitored for the first 6 weeks of continuous treatment. If ≥5 of the 12 patients experience DLTs during this period, enrollment may be discontinued. After the DLT review period, safety data will be collected every 6 months for all enrolled patients. Efficacy assessments will be performed Q3W, with the initial tumor imaging performed ≤28 days after enrollment and repeated at 12 weeks (cohorts A-D, F) or 4 weeks (cohort E) after enrollment. Adverse events (AEs) will be monitored throughout the study, and severity will be graded according to the guidelines outlined in NCI CTCAE version 5.0. Each patient will be monitored for AEs and serious AEs for 30 day and 90 days, respectively, after discontinuation of study intervention. The primary end point for part 1 is the number and proportion of patients with DLTs, AEs, and discontinuations from study treatment due to AEs. Safety and tolerability will be assessed by clinical review. Secondary end points include investigator-assessed objective response rate, investigator-assessed duration of response, disease control rate, and pharmacokinetic end points. Overall survival, progress-free survival, health-related quality of life assessments, and molecular assessments will be exploratory. In the part 2 dose-expansion phase, the plan is to enroll approximately 120 patients from cohorts B-E to receive up to 35 cycles of MK-7684A Q3W; 30 additional patients may be enrolled in a cohort expansion (cohort G) to receive vibostolimab monotherapy Q3W for up to 35 cycles. Cohort G will include patients with cHL or PMBCL with PD after ≥2 or ≥3 prior therapies, FL after ≥2 prior therapies, DLBCL after ≥2 prior therapies, and/or MM after ≥3 prior therapies. Figure 1 Figure 1. Disclosures Yusuf: Merck & Co., Inc.: Current Employment. Jemielita: Merck & Co., Inc.: Current Employment, Other: Current Stockholder. Marinello: Merck & Co., Inc.: Current Employment, Other: Current Stockholder.

Duvelisib in Patients with Relapsed/Refractory Peripheral T-Cell Lymphoma from the Phase 2 Primo Trial: Results of an Interim Analysis

Relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) is a family of aggressive lymphomas, with a median overall survival (OS) of less than 6 months. Current FDA approved therapies for R/R PTCL have modest overall response rates (ORR) of &lt; 30%. Duvelisib (DUV), a dual PI3K-δ,γ inhibitor, is FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia and R/R follicular lymphoma. On 10/3/2019, DUV received orphan designation for treatment of patients with R/R T-cell lymphomas. In the Phase 2, open-label, multi-center, parallel cohort PRIMO trial of DUV in R/R PTCL, the initial results of the dose-optimization phase (N=33) demonstrated a 54% ORR in the 75 mg BID (N=13) and 35% in the 25 mg BID (N=20) cohorts, respectively, by investigator assessment (INV). (NCT03372057; supported by Secura Bio). The expansion phase of PRIMO has a targeted enrollment of ~125 pts. Expansion phase eligibility criteria included histologically confirmed R/R PTCL after &gt;1 cycle of a prior standard regimen, a CD4 lymphocyte count of ≥ 50/mm 3 and required PJP prophylaxis. HSV/VZV prophylaxis was strongly recommended. Based on the dose optimization results, pts in the expansion phase receive DUV at 75 mg BID for 2 cycles to maximize rapid tumor control, followed by 25 mg BID to maintain long-term disease control and mitigate late toxicities, until progressive disease (PD) or unacceptable toxicity. The primary endpoint is ORR by IRC assessment, and secondary endpoints include ORR by INV assessment, duration of response (DOR), PFS, OS, disease control rate, and safety; all analyses consisted of pts that received at least 1 dose of DUV. This analysis is from an interim data cutoff as of May 21, 2021 that includes the first 6 months of data for the 78 patients included in the analysis. Pts had a median age of 66.5 years (range, 21-92 years) and a median of 3 prior lines of therapy (range, 1-7). The ORR by IRC assessment was 50% (39/78 patients) and the CR rate was 32.1% (25/78 patients), see Table 1. 14 patients (18%) remained on treatment; 37 pts discontinued due to PD (47.4%), 15 discontinued to due adverse events (19.2%) , 4 died (5.1%), and 1 each discontinued for secondary malignancy, lack of response, and withdrawal of consent. 5 patients (6.4%) discontinued therapy to undergo stem cell transplant, which suggests that DUV may be used as a bridge to transplant for appropriate patients. There were 3 deaths related or possibly related to duvelisib: pneumonitis, Epstein-Barr associated lymphoproliferative disorder, and sepsis. The most frequent &gt; Grade 3 adverse events seen were neutropenia (38.5%), ALT/AST increased (24.4%/ 21.8%), rash (7.7%), lymphocyte count decreased (7.7%), and sepsis (6.4%), see Table 2. ALT and/or AST elevations were the most common AEs leading to treatment discontinuations (N=12, 15.4%). The interim results of the first 78 patients in the PRIMO expansion phase show an ORR of 50% and a CR rate of 32%, which suggests this therapy is superior to currently available SOC therapeutic options. Duvelisib was well tolerated in this population and remained consistent with the known safety profile of DUV. These data, from a large diverse population of T cell lymphoma patients, build upon prior reports demonstrating DUV as an active oral treatment for pts with RR PTCL. Data from this interim analysis may be updated prior to the abstract presentation. Figure 1 Figure 1. Disclosures Brammer: Celgene: Research Funding; Kymera Therapeutics: Consultancy; Seattle Genetics: Speakers Bureau. Zinzani: BMS: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; SANDOZ: Other: Advisory board; ADC Therap.: Other; SERVIER: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; Incyte: Other, Speakers Bureau; Beigene: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Zain: Secura Bio, Ono , Legend, Kiyowa Kirin, Myeloid Therapeutics Verastem Daichi Sankyo: Consultancy; Secura Bio, DaichiSankyo, Abbvie: Research Funding; Kiyoaw Kirin, Secura Bio, Seattle Genetics: Honoraria. Casulo: BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Jacobsen: Takeda: Consultancy; Syros: Consultancy; Janssen: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Gritti: Takeda: Consultancy; Roche: Consultancy; Kite Gilead: Consultancy; IQvia: Consultancy; Italfarmaco: Consultancy; Clinigen: Consultancy. Litwak: Secura Bio: Current Employment. Cohan: Secura Bio: Current Employment. Katz: Secura Bio: Current Employment. Mehta-Shah: C4 Therapeutics: Consultancy; Roche/Genentech: Research Funding; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Innate Pharmaceuticals: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; AstraZeneca: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Secura Bio: Consultancy, Research Funding; Ono Pharmaceuticals: Consultancy; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding. OffLabel Disclosure: Duvelisib is approved in relapsed/refraction CLL/SLL and FL. This study evaluates duvelisib in PTCL

CTNI-22. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA

BACKGROUND mTOR activation is a mechanism of resistance in CDK4/6 targeting. We evaluated tumor pharmacokinetics (PK) and tumor pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent high-grade glioma (HGG) patients. METHODS Recurrent HGG patients with (1) intact RB, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations receive five days of presurgical ribociclib plus everolimus prior to resection at 2, 8 or 24 hours after the final dose. Beginning at 400mg QD ribociclib plus 2.5mg QD everolimus, six dose-escalations summit at 600mg QD plus 60mg QW. Gadolinium [Gd]-enhancing and nonenhancing tumor regions, CSF, and plasma are collected. Total and unbound drug concentrations are determined using validated LC-MS/MS methods. RB and S6 phosphorylation are compared to matched archival tissue. To select patients for a therapeutic expansion phase of combined drug therapy, the protocol includes a PK ‘trigger’ (i.e., for each drug, unbound concentration in Gd-nonenhancing tumor &gt; 5-fold biochemical IC50) and a PD ‘trigger’ (i.e., for each tumor, &gt; 30% decrease in pRB and pS6). RESULTS 21 patients with WHO Grade III (n=2) and IV (n=19) gliomas were enrolled into the Phase 0 component of the study. No dose-limiting toxicities were observed. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 719 nM, whereas unbound everolimus tumor concentrations were undetectable. Across all dose-levels, 62% (13/21) and 22% (5/21) of tumors demonstrated decreased tumor RB and S6 phosphorylation, respectively. Tumor proliferation (MIB-1) was decreased in 67% (14/21) of all patients. No patients qualified for the therapeutic expansion phase. CONCLUSION In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor whereas everolimus exhibits no meaningful tumor penetration. These findings support further clinical development of ribociclib, but not everolimus, for the treatment of high-grade glioma patients.

Scalar and tensor perturbations in DHOST bounce cosmology

We investigate the bounce realization in the framework of DHOST cosmology, focusing on the relation with observables. We perform a detailed analysis of the scalar and tensor perturbations during the Ekpyrotic contraction phase, the bounce phase, and the fast-roll expansion phase, calculating the power spectra, the spectral indices and the tensor-to-scalar ratio. Furthermore, we study the initial conditions, incorporating perturbations generated by Ekpyrotic vacuum fluctuations, by matter vacuum fluctuations, and by thermal fluctuations. The scale invariance of the scalar power spectrum can be acquired introducing a matter contraction phase before the Ekpyrotic phase, or invoking a thermal gas as the source. The DHOST bounce scenario with cosmological perturbations generated by thermal fluctuations proves to be the most efficient one, and the corresponding predictions are in perfect agreement with observational bounds. Especially the tensor-to-scalar ratio is many orders of magnitude within the allowed region, since it is suppressed by the Hubble parameter at the beginning of the bounce phase.

Selumetinib in combination with dexamethasone for the treatment of relapsed/refractory RAS-pathway mutated paediatric and adult acute lymphoblastic leukaemia (SeluDex): study protocol for an international, parallel-group, dose-finding with expansion phase I/II trial

Introduction Event free survival rates at 15 years for paediatric patients with relapsed/refractory acute lymphoblastic leukaemia (ALL) are 30-50%, with 5-year survival for adult patients only 20%. A large proportion of patients with newly diagnosed and relapsed ALL harbour somatic mutations that activate the RAS-signalling cascade. Steroids are a backbone of all induction blocks of ALL therapy, with preclinical data suggesting the combination of dexamethasone with the MEK1/2 inhibitor, selumetinib (ARRY-142886), results in a potent synergistic anti-cancer effect. Methods and analysis The SeluDex trial is an international, parallel-group, dose-finding with expansion, phase I/II trial to assess the selumetinib/dexamethasone combination in adult and paediatric patients with relapsed/refractory, RAS pathway mutant ALL. The Cancer Research UK Clinical Trials Unit at University of Birmingham is the UK Coordinating Centre, with national hubs in Copenhagen, Denmark; Monza, Italy; Munster, Germany; Paris, France; and Utrecht, Netherlands. Paediatric centres are all part of the Innovative Therapies for Children with Cancer consortium. Patients with morphologically proven relapsed/refractory or progressive B-cell precursor or T-ALL, with demonstrated RAS pathway activating mutations are eligible. Adult patients are >18 years old, ECOG <2 and paediatric <18 years old, Lansky play scale ≥60% or Karnofsky score ≥60%. The primary objective in phase I is to determine the recommended phase II dose of selumetinib as defined by occurrence/non-occurrence of dose limiting toxicities using the continual reassessment method, and phase II will evaluate preliminary anti-leukaemic activity of the selumetinib/dexamethasone combination, as defined by morphological response 28 days post treatment using a Bayesian approach. Target recruitment is between 26 and 42 patients (minimum of 13 and maximum of 21 in each group), depending on how many phase I patients are included also in phase II. Ethics and dissemination Medical ethical committees of all the participating countries will approve the study protocol. The results of this trial will be disseminated through national and international presentations and peer-reviewed publications. Trial registration number The trial was registered on EudraCT 2016-003904-29 on 21st September 2016, ISRCTN 92323261, ClinicalTrials.Gov NCT03705507, and ITCC-063 study.

Estimating Precipitating Energy Flux, Average Energy, and Hall Auroral Conductance From THEMIS All-Sky-Imagers With Focus on Mesoscales

Recent attention has been given to mesoscale phenomena across geospace (∼10 s km to 500 km in the ionosphere or ∼0.5 RE to several RE in the magnetosphere), as their contributions to the system global response are important yet remain uncharacterized mostly due to limitations in data resolution and coverage as well as in computational power. As data and models improve, it becomes increasingly valuable to advance understanding of the role of mesoscale phenomena contributions—specifically, in magnetosphere-ionosphere coupling. This paper describes a new method that utilizes the 2D array of Time History of Events and Macroscale Interactions during Substorms (THEMIS) white-light all-sky-imagers (ASI), in conjunction with meridian scanning photometers, to estimate the auroral scale sizes of intense precipitating energy fluxes and the associated Hall conductances. As an example of the technique, we investigated the role of precipitated energy flux and average energy on mesoscales as contrasted to large-scales for two back-to-back substorms, finding that mesoscale aurora contributes up to ∼80% (∼60%) of the total energy flux immediately after onset during the early expansion phase of the first (second) substorm, and continues to contribute ∼30–55% throughout the remainder of the substorm. The average energy estimated from the ASI mosaic field of view also peaked during the initial expansion phase. Using the measured energy flux and tables produced from the Boltzmann Three Constituent (B3C) auroral transport code (Strickland et al., 1976; 1993), we also estimated the 2D Hall conductance and compared it to Poker Flat Incoherent Scatter Radar conductance values, finding good agreement for both discrete and diffuse aurora.