Explore the vast range of titles available.

The TROG 96.01 trial assessed whether 3-month and 6-month short-term neoadjuvant androgen deprivation therapy (NADT) decreases clinical progression and mortality after radiotherapy for locally advanced prostate cancer. Here we report the 10-year results. Between June, 1996, and February, 2000, 818 men with T2b, T2c, T3, and T4 N0 M0 prostate cancers were randomly assigned to receive radiotherapy alone, 3 months of NADT plus radiotherapy, or 6 months of NADT plus radiotherapy. The radiotherapy dose for all groups was 66 Gy, delivered to the prostate and seminal vesicles (excluding pelvic nodes) in 33 fractions of 2 Gy per day (excluding weekends) over 6·5–7·0 weeks. NADT consisted of 3·6 mg goserelin given subcutaneously every month and 250 mg flutamide given orally three times a day. NADT began 2 months before radiotherapy for the 3-month NADT group and 5 months before radiotherapy for the 6-month NADT group. Primary endpoints were prostate-cancer-specific mortality and all-cause mortality. Treatment allocation was open label and randomisation was done with a minimisation technique according to age, clinical stage, tumour grade, and initial prostate-specific antigen concentration (PSA). Analysis was by intention-to-treat. The trial has been closed to follow-up and all main endpoint analyses are completed. The trial is registered with the Australian New Zealand Clinical Trials Registry, number ACTRN12607000237482. 802 men were eligible for analysis (270 in the radiotherapy alone group, 265 in the 3-month NADT group, and 267 in the 6-month NADT group) after a median follow-up of 10·6 years (IQR 6·9–11·6). Compared with radiotherapy alone, 3 months of NADT decreased the cumulative incidence of PSA progression (adjusted hazard ratio 0·72, 95% CI 0·57–0·90; p=0·003) and local progression (0·49, 0·33–0·73; p=0·0005), and improved event-free survival (0·63, 0·52–0·77; p<0·0001). 6 months of NADT further reduced PSA progression (0·57, 0·46–0·72; p<0·0001) and local progression (0·45, 0·30–0·66; p=0·0001), and led to a greater improvement in event-free survival (0·51, 0·42–0·61, p<0·0001), compared with radiotherapy alone. 3-month NADT had no effect on distant progression (0·89, 0·60–1·31; p=0·550), prostate cancer-specific mortality (0·86, 0·60–1·23; p=0·398), or all-cause mortality (0·84, 0·65–1·08; p=0·180), compared with radiotherapy alone. By contrast, 6-month NADT decreased distant progression (0·49, 0·31–0·76; p=0·001), prostate cancer-specific mortality (0·49, 0·32–0·74; p=0·0008), and all-cause mortality (0·63, 0·48–0·83; p=0·0008), compared with radiotherapy alone. Treatment-related morbidity was not increased with NADT within the first 5 years after randomisation. 6 months of neoadjuvant androgen deprivation combined radiotherapy is an effective treatment option for locally advanced prostate cancer, particularly in men without nodal metastases or pre-existing metabolic comorbidities that could be exacerbated by prolonged androgen deprivation. Australian Government National Health and Medical Research Council, Hunter Medical Research Institute, AstraZeneca, and Schering-Plough.

Evolutionary pressures to protect against food scarcity likely resulted in highly-conserved pathways designed to minimize energy expenditure, one of which involves the minimization of muscle mass; these mechanisms may be counter-productive in a modern world suffering from obesity and sarcopenia. Growth differentiation factor 8 (GDF8)/myostatin, acting via ActRIIA/B receptors, is the best-characterized negative regulator of muscle mass, leading to therapeutic efforts to augment muscle growth by blocking GDF8 or ActRIIA/B. ActRIIA/B blockade approximately doubles the muscle increase of GDF8 blockade, and as ActRIIA/B responds to multiple other TGFβ-family members, this implies other ligands might also regulate muscle mass. Previously, we suggested that activin A (ActA) is the key second negative regulator acting via ActRIIA/B, as blockade of both GDF8 and ActA in mice/monkeys matches the muscle growth of ActRIIA/B blockade. Here, we extend these observations to humans in a two-part, randomized, placebo-controlled Phase 1 trial ( www.clinicaltrials.gov , NCT02943239) conducted at two sites in New Zealand. Eligible subjects included healthy postmenopausal females aged 45–70 years and males aged 35–60 years not intending to father children, with a body mass index of 18–32 kg/m 2 . Part I tested single-dose administration of anti-GDF8 alone, anti-ActA alone, several dose combinations of anti-GDF8 + anti-ActA, or placebo in healthy postmenopausal females; part II tested multiple-dose administration of anti-ActA alone or placebo in healthy postmenopausal females, combination anti-GDF8 + anti-ActA or placebo in healthy postmenopausal females, and anti-ActA alone or placebo in healthy males. The primary outcome measure was the incidence and severity of treatment-emergent adverse events through week 16 for the single-dose part of the study and through week 40 for the multiple-dose part of the study. Secondary endpoints included percent and absolute change in thigh muscle volume, percent and absolute change in total and regional body composition, pharmacokinetic profiles of the GDF8 and ActA mAbs in serum over time, changes in serum total GDF8 and total ActA levels over time, and the presence of anti-drug antibodies against the GDF8 mAb or the ActA mAb. Magnetic resonance imaging was used to quantitate changes in thigh muscle volume and dual x-ray absorptiometry was used to quantitate changes in regional body composition (total lean mass, appendicular lean body mass, android fat mass, and total fat mass). A total of 82 subjects were enrolled (48 in the single-dose part and 34 in the multiple-dose part of the study). Baseline demographic and clinical characteristics were generally balanced across the single- and multiple-dose parts of the study. Combining GDF8 and ActA blocking antibodies led to greater muscle growth than either antibody alone; increases in muscle were accompanied by reductions in fat. The observed clinical effects on muscle and fat paralleled mAb exposure in serum. The combination was generally well tolerated, and no subjects tested positive for anti-drug antibodies post-treatment. These results suggest that GDF8 and ActA are the dominant negative regulators of muscle mass in humans, and that combined blockade may be a promising therapeutic approach in muscle atrophy and obesity settings. GDF8 and activin A are the dominant negative regulators of muscle mass in animal models. This two-part, randomized, placebo-controlled Phase 1 trial suggests that GDF8 and activin A are also the dominant negative regulators of muscle mass in humans.

Purpose This randomized, open-label, two-arm, parallel-group, single dose, multi-center phase I study (ClinicalTrials.gov ID, NCT05275010) investigated the comparability of the pharmacokinetics of a new formulation combining pertuzumab (P) and trastuzumab (H) in one fixed-dose combination for subcutaneous injection (FDC SC) using a proprietary on-body injector (OBI) or a handheld syringe with hypodermic needle in healthy male subjects. Methods Healthy male subjects were randomized 1:1 to either PH FDC SC using a handheld syringe (Arm 1) or an OBI device (Arm 2). Co-primary endpoints were: (i) area under the time–concentration curve (AUC) from the start of dosing to day 63 (AUC 0–62 ) of serum P, (ii) maximum serum concentration (C max ) from start of dosing to 63 days of serum P, (iii) AUC from the start of dosing to day 63 (AUC 0–62 ) of serum H, and (iv) C max from start of dosing to 63 days of serum H. Safety was a key secondary endpoint. Liquid chromatography coupled to tandem mass spectrometry was used to measure pertuzumab and trastuzumab simultaneously in serum samples. Results The obtained geometric mean ratios for C max and AUC 0–62 were within the pre-specified bioequivalence margins (0.80, 1.25) for both P and H, therefore meeting the criteria for bioequivalence. No discontinuations due to safety reasons were reported. Overall, the final safety analysis with longer follow-up was consistent with the primary analysis; there were no new or unexpected safety findings. Conclusion This study demonstrated the feasibility of a hands-free device approach to deliver pertuzumab and trastuzumab in one fixed-dose combination for subcutaneous injection without compromising pharmacokinetics and safety.

Inappropriate and chronic activation of the cytosolic NOD‐, LRR‐, and pyrin domain‐containing 3 (NLRP3) inflammasome, a key component of innate immunity, likely underlies several inflammatory diseases, including coronary artery disease. This first‐in‐human phase I trial evaluated safety, pharmacokinetics (PKs), and pharmacodynamics (PDs) of oral, single (150–1800 mg) and multiple (300 or 900 mg twice daily for 7 days) ascending doses (SADs and MADs) of GDC‐2394, a small‐molecule inhibitor of NLRP3, versus placebo in healthy volunteers. The study also assessed the food effect on GDC‐2394 and its CYP3A4 induction potential in food‐effect (FE) and drug–drug interaction (DDI) stages, respectively. Although GDC‐2394 was adequately tolerated in the SAD, MAD, and FE cohorts, two participants in the DDI stage experienced grade 4 drug‐induced liver injury (DILI) deemed related to treatment, but unrelated to a PK drug interaction, leading to halting of the trial. Both participants experiencing severe DILI recovered within 3 months. Oral GDC‐2394 was rapidly absorbed; exposure increased in an approximately dose‐proportional manner with low‐to‐moderate intersubject variability. The mean terminal half‐life ranged from 4.1 to 8.6 h. Minimal accumulation was observed with multiple dosing. A high‐fat meal led to delays in time to maximum concentration and minor decreases in total exposure and maximum plasma concentration. GDC‐2394 had minimal CYP3A4 induction potential with the sensitive CYP3A4 substrate, midazolam. Exploratory ex vivo whole‐blood stimulation assays showed rapid, reversible, and near‐complete inhibition of the selected PD biomarkers, IL‐1β and IL‐18, across all tested doses. Despite favorable PK and target engagement PD, the GDC‐2394 safety profile precludes its further development.

Purpose This first-in-human study was designed to evaluate the pharmacokinetic (PK) equivalence between HD204 and the European Union (EU)-sourced bevacizumab, between HD204 and the United States of America (US)-sourced bevacizumab, and between EU-sourced and US-sourced bevacizumab (NCT 03390673). Methods In this randomized, double-blind, 3-way parallel group, single-dose comparative PK study, healthy male subjects were randomized to receive a single 1 mg/kg intravenous dose of HD204, EU-sourced bevacizumab or US-sourced bevacizumab. PK parameters were calculated using non-compartmental methods. PK equivalence was determined using the pre-defined equivalence margin of 0.8-1.25 in terms of AUC.sub.(0-[infinity]) for the pairwise comparisons. Findings Baseline demographics for the 119 randomized subjects were similar across the three groups. The 90% CIs for the ratio of the geometric means of HD204 to US-sourced bevacizumab, HD204 to EU-sourced bevacizumab, and EU-sourced to US-sourced bevacizumab were all within the interval of 80% to 125% for AUC.sub.0-inf, thus demonstrating equivalency in the PK properties for all three treatment groups. Similarly, the ratio of the geometric means for AUC.sub.0-last and C.sub.max were all within the 80% and 125% margins, supporting the robustness of the primary findings. All other PK parameters, including the half-life (t1/2) clearance (CL), volume of distribution (Vd) and time of maximum concentration (t.sub.max ), were comparable. There was no difference between the 3 treatment arms in terms of vital signs, laboratory tests and adverse events. None of the subjects treated with HD204 had positive ADA results. Implications HD204 demonstrates equivalent pharmacokinetic profiles compared to those of both US-sourced and EU-sourced bevacizumab. (NCT 03390673).

Several inflammatory cytokines that promote inflammation and pathogenesis in asthma signal through the Janus kinase 1 (JAK1) pathway. This phase I, randomized, placebo‐controlled trial assessed the pharmacokinetics and safety of single and multiple ascending doses up to 15 mg twice daily for 14 days of a JAK1 inhibitor, GDC‐0214, in healthy volunteers (HVs; n = 66). Doses were administered with a dry powder, capsule‐based inhaler. An accompanying open‐label gamma scintigraphy study in HVs examined the lung deposition of a single dose of inhaled Technetium‐99m (99mTc)‐radiolabeled GDC‐0214. GDC‐0214 plasma concentrations were linear and approximately dose‐proportional after both single and multiple doses. Peak plasma concentrations occurred at 15–30 min after dosing. The mean apparent elimination half‐life ranged from 32 to 56 h across all single and multiple dose cohorts. After single and multiple doses, all adverse events were mild or moderate, and none led to treatment withdrawal. There was no clear evidence of systemic toxicity due to JAK1 inhibition, and systemic exposure was low, with plasma concentrations at least 15‐fold less than the plasma protein binding‐corrected IC50 of JAK1 at the highest dose. Scintigraphy showed that approximately 50% of the emitted dose of radiolabeled GDC‐0214 was deposited in the lungs and was distributed well to the peripheral airways. 99mTc‐radiolabeled GDC‐0214 (1 mg) exhibited a mean plasma Cmax similar to that observed in phase I at the same dose level. Overall, inhaled GDC‐0214 exhibited pharmacokinetic properties favorable for inhaled administration.

Introduction ReCOV is a recombinant protein vaccine that aims to induce cross-neutralization against SARS-CoV-2 variants. The phase I and phase II studies were conducted in New Zealand and the Philippines, respectively, for ReCOV primary series. Methods Both studies were randomized, double-blind, placebo-controlled designed among COVID-19 vaccine-naïve healthy adults who received two doses of study vaccination with a 21-day interval. In phase I, 100 younger (15–55 years) and older (56–80 years) subjects were 4:1 randomized to receive ReCOV (20 µg or 40 µg) or placebo. In the phase II study, 347 subjects (≥ 18 years) were 2:1 randomized to receive 40 µg ReCOV or placebo. Subjects that received ReCOV were followed up for 6 months after the second dosing. The safety outcomes included solicited and unsolicited AEs, SAEs, and AESIs. The immunogenicity outcomes were live-virus neutralizing antibody (NAb) against prototype, while pseudovirus NAbs against several SARS-CoV-2 variants were included in phase II as well. Results No related SAE, AESI, or AE leading to early discontinuation were reported. The AE incidences were higher in ReCOV groups than placebo group in phase I while they were similar between study groups in phase II. The majority of solicited AEs were mild or moderate with median duration of 1.0–4.0 days. The common (≥ 10%) solicited AEs in phase I were injection site reactions, headache, pyrexia, fatigue, and myalgia, and common reported (≥ 5%) ones in phase II included injection site pain, headache, and pyrexia. Robust neutralizing activities against the prototype were observed in ReCOV groups, peaking at 14 days post the second dosing: in phase I, the GMTs for 20 μg and 40 μg ReCOV groups were 1643.2 IU/mL (95% CI 1188.5, 2271.9) and 1289.2 IU/mL (95% CI 868.3, 1914.1) in younger adults, and 1122.3 IU/mL (95% CI 722.6, 1743.1) and 680.3 IU/mL (95% CI 440.2, 1051.4) in older adults, respectively, while in the ReCOV group of phase II, the GMTs for subjects with seronegative and seropositive status at baseline were 3741.0 IU/mL (95% CI 3113.4, 4495.0) and 6138.3 IU/mL (95% CI 5255.1, 7169.9), respectively. In phase II, substantial levels of pseudovirus NAbs against SARS-CoV-2 variants were demonstrated; the peak GMTs for prototype, Omicron BA.2, and BA.4/5 were 8857, 4441, and 2644, and 15,667.3, 7334.3, and 4478.8 among seronegative and seropositive subjects, respectively. The neutralization persisted till 6 months post the second dosing, with only 2.5- to 5.2-fold declines for Omicron variants. Conclusions Two doses of 20 µg and 40 µg ReCOV are safe and immunogenic against SARS-CoV-2 prototype. The cross-neutralizing activities against Omicron variants support ReCOV advance to late-stage clinical trials. Trial Registration Phase I study, clinicaltrials.gov NCT04818801; phase II study, clinicaltrials.gov NCT05084989.

Purpose To demonstrate pharmacokinetic (PK) comparability for a single dose of 600 mg subcutaneous (SC) trastuzumab, administered via a novel single-use injection device (SID) or handheld syringe in 119 randomized healthy male subjects. Methods The co-primary PK endpoints area under the time–concentration curve from the start of dosing to day 22 (AUC 0–21 days ) and maximum observed trastuzumab serum concentration ( C max ) were dose-normalized and body-weight-adjusted, and compared using geometric mean ratios (GMRs). SID performance, injection site pain, adverse events, and antidrug antibodies (ADAs) were assessed. Results GMRs and 90 % confidence intervals (CIs) were 1.01 (0.96–1.07) for AUC 0–21 days and 1.02 (0.96–1.10) for C max , which fell within the prespecified bioequivalence range (0.80–1.25). No SID quality issues or failures occurred. Adverse events were mostly mild, with no deaths, adverse event-related withdrawals, or life-threatening, cardiac, or serious events reported. The ADA rate was low, and no neutralizing antibodies were detected. Conclusions Trastuzumab SC via SID demonstrated comparable PK and safety to handheld syringe administration. SID performance was very satisfactory.

MSB11455 is a proposed biosimilar to the currently licensed reference pegfilgrastim (Neulasta®). This study was designed primarily to compare the immunogenicity of MSB11455 and Neulasta®. As secondary objectives, the safety and tolerability of MSB11455 and Neulasta® were also compared. Healthy adult subjects were randomized to either MSB11455 or Neulasta®, stratified by antipolyethylene glycol (PEG) antibody status at screening and study site. Subjects received a single subcutaneous dose of MSB11455 or Neulasta® (both 6 mg/0.6 mL) on day 1 of each of two study periods (same product in both periods), separated by a washout of 28‐35 days. Immunogenicity samples were taken predose and up to day 84 post–first dose. Noninferiority was confirmed if the upper limit of the exact one‐sided adjusted 95% confidence interval (CI) for the difference in antidrug antibody (ADA)‐positive rates was < 10%. Safety was assessed throughout the study. Overall, 336 subjects were randomized and treated (N = 168 in each group). Noninferiority of MSB11455 over Neulasta® was demonstrated for immunogenicity; the difference in confirmed treatment‐induced ADA‐positive rate between MSB11455 and Neulasta® was −0.6% (upper limit of the exact one‐sided adjusted 95% CI: 6.25%). ADAs were mostly directed against the PEG moiety of pegfilgrastim. No filgrastim‐specific neutralizing antibodies were detected in either treatment group. Safety and tolerability were as expected for pegfilgrastim, and comparable between treatments. This study supports and strengthens the available evidence for the biosimilarity of MSB11455 to Neulasta®.