Common Drug-related Adverse Events Research Articles

Bimekizumab in psoriasis: a monocentric study evaluating short- and mid-term effectiveness and safety profile in a real-world setting.

Bimekizumab is a humanized monoclonal IgG1 antibody with a unique mechanism of action, as it inhibits both IL17A and IL17F molecules. This dual inhibition is thought to be responsible for its high efficacy in treating chronic plaque psoriasis with rapid onset of action in Randomized Controlled Trials (RCTs). Concerning safety, oral candidiasis was one of the most common drug-related adverse events, commonly mild-to-moderate in severity. Although data from RCTs supporting this efficacy and safety profile of bimekizumab is numerous, results from the real-world setting concerning short- and mid-term treatment effectiveness and safety profile are limited. An observational, retrospective, monocentric study was conducted at the Psoriasis Outpatient Unit of "A. Sygros" Hospital for Skin and Venereal Diseases, in Athens, Greece, which included 61 adult patients with moderate-to-severe skin psoriasis, who received at least one dosage of bimekizumab. At week 4, 65.7% achieved PASI75, 45.7% PASI90, and 32.4% PASI100. After 16 weeks of treatment, 92.3/76.9/66.7% of the patients achieved PASI75/90/100, respectively. Increased BMI, previous treatment with another IL-17 inhibitor, or previous exposure to another biologic did not seem to influence the possibility of achieving PASI90 and PASI100 at week 16 of bimekizumab treatment in this cohort. Six (9.8%) cases of possibly drug-related AEs were reported, from which four incidences of oral candidiasis. Our results confirm that this IL17A/F inhibitor is highly effective, with a tolerability profile similar to the one expected from RCTs.

Real-life efficacy and safety of cemiplimab in advanced cervical cancer from a nominal use program in Italy: The MITO 44 study

Backgroundcemiplimab is an immunoglobulin G4 monoclonal antibody targeting the programmed cell death-1 receptor. A nominal use program is available in Italy in advanced cervical cancer (CC) patients treated with platinum based chemotherapy based on the results of EMPOWER-Cervical 1/GOG-3016/ENGOTcx9 trial. This real-world, retrospective cohort, multicenter study aimed at describing clinical outcomes of patients with advanced CC treated with cemiplimab in Italy. MethodsThe primary objective of the study was to assess the feasibility and the replicability of the initial results in a real world setting of cemiplimab nominal use. The primary endpoint of our analysis was progression free survival (PFS). Secondary endpoints included overall response rate (ORR), overall survival (OS) and safety data. ResultsFrom March 2022 to December 2023, 135 patients were treated in 12 Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies (MITO) Centers. Forty-two percent of patients had one or more comorbidities, hypertension being the most common (23.4%). Median PFS was 4.0 months (range 3.0–6.0) and median OS was 12.0 months (12.0- NR) with no differences according to PD-L1 status. Complete response (CR) or no evidence of disease (NED) were observed in 8.6%; partial response (PR) in 21.1%, stable disease (SD) in 14.8% and progression was recorded in 44.5% of patients. Most common drug related adverse events (AEs) were anemia (39.1%) and fatigue (27.8%). Immune related AEs occurred in 18.0%. ConclusionsThis study confirms the feasibility and the replicability of the cemiplimab nominal use in advanced CC, in a real-world practice in Italy.

A Phase 1 Study of Intravenous EGFR-ErbituxEDVsMIT in Children with Solid or CNS Tumours Expressing Epidermal Growth Factor Receptor.

Recurrent or refractory solid and central nervous system (CNS) tumours in paediatric patients have limited treatment options and carry a poor prognosis. The EnGeneIC Dream Vector (EDV) is a novel nanocell designed to deliver cytotoxic medication directly to the tumour. The epidermal growth factor receptor is expressed in several CNS and solid tumours and is the target for bispecific antibodies attached to the EDV. To assess the safety and tolerability of EGFR-Erbitux receptor EnGeneIC Dream Vector with mitoxantrone (EEDVsMit) in children with recurrent / refractory solid or CNS tumours expressing EGFR. Patients aged 2-21 years with relapsed or refractory CNS and solid tumours, or radiologically diagnosed diffuse intrinsic pontine glioma (DIPG), were treated in this phase I open-label study of single agent EEDVsMit. Thirty-seven patients' tumours were screened for EGFR expression. EEDVsMit was administered twice weekly in the first cycle and weekly thereafter. Standard dose escalation with a rolling 6 design was employed. Dosing commenced at 5 × 108 EEDVsMit per dose and escalated to 5×109 EEDVsMit per dose. EGFR expression was detected in 12 (32%) of the paediatric tumours tested. Nine patients were enrolled and treated on the trial, including three patients with diffuse midline glioma. Overall, EEDVsMit was well tolerated, with no dose-limiting toxicities observed. The most common drug-related adverse events were grade 1-2 fever, nausea and vomiting, rash, lymphopaenia, and mildly deranged liver function tests. All patients had disease progression, including one patient who achieved a mixed response as the best response. EGFR-Erbitux receptor targeted EnGeneIC Dream Vector with mitoxantrone can be safely delivered in paediatric patients aged 2-21 years with solid or CNS tumours harbouring EGFR expression. The discovery of EGFR expression in a high proportion of paediatric gliomas means that EGFR may be useful as a target for other treatment strategies. Targeted therapeutic-loaded EDVs may be worth exploring further for their role in stimulating an anti-tumour immune response. NCT02687386.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8±0.4/-6.6±0.3mmHg at W4 and -12.7±0.5/-7.6±0.3mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p<.001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p<.001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Phase II of desynchronized irinotecan plus bevacizumab, oxaliplatin, 5-fluorouracil, and folinic acid (bFOLFIRINOX-3) administration in chemorefractory metastatic colorectal cancer patients.

e15563 Background: In chemorefractory metastatic colorectal cancer (mCRC), targeted therapy such as TAS-102 and regorafenib have shown a modest survival benefit with a median progression free survival (PFS) of only about 2 months. A phase I of FOLFIRINOX3-bevacizumab (bFOLFIRINOX 3) defined the RP2D for irinotecan and showed promising activity. The aim of this phase II trial was to evaluate the safety and efficacy of bFOLFIRINOX-3 in chemorefractory mCRC. Methods: The phase I trial defined the combination of bFOLFIRINOX-3 at the irinotecan’s RP2D of 70mg/m² day 1 and day 3. In phase II, patients &gt; 18years and ECOG 0 or 1, with a pathological confirmed mCRC and experienced treatment failure after standard chemotherapies that include at least 5-fluorouracil, oxaliplatin and irinotecan were enrolled. Absence of residual neuropathy and previous grade 3 irinotecan related toxicity was manditory. Regimen tested consisted of bevacizumab (5mg/kg), folinic acid (400mg/m2), 5-fluorouracil (2400mg/m2 for 46h), oxaliplatin (85mg/m2) and irinotecan (70mg/m² administered before and after infusional 5-fluorouracil). CT scan were performed every 2 months. Primary endpoint was the 2-months PFS. Secondary endpoints included objective response rate (ORR), median PFS, overall survival (OS) and toxicity. Results: Twenty-free patients were enrolled (October 2018 to December 2022). Median age was 62 y (range: 50-70y). These patients have been treated with several previous lines of chemotherapy (median = 3, range [1-6]). Median follow up was 11 months (range [3-31.3]). The 2-months PFS was 100%. Overall response rate was 17,4%. Median PFS was 7.8 months (IC95%[5.9;9.5]) and median OS was 31.3 months (IC95% [12.4;NR]). Grade 3 adverse events occured in 43.5% with mostly diarrhea (39.1%) and neutropenia (21.7%). Grade 3 diarrhea was consistently resolving after a dose reduction of chemotherapy. The most common drug-related adverse events (all grades) were fatigue (60.9%), diarrhea (73.9%), nausea (39.1%), peripheral neuropathy (47.8%), thrombopenia (82.6%) and anemia (56.5%). Conclusions: The combination of bFOLFIRINOX-3 yielded better ORR, median PFS and OS than standard of care. The regimen was well tolerated. The study met its primary endpoint and support for future randomized phase III compared to standard of care. Clinical trial information: NCT03795311 .

Targeting B Cell Maturation Antigen in Patients with Multiple Myeloma: Current Perspectives.

Relapsed/refractory multiple myeloma remains a challenging disease necessitating the development of more effective treatment options. In the past decade, myeloma therapies have made significant advancements with the introduction of new treatment modalities. One of the new major targets for these novel therapeutics has been B-cell maturation antigen (BCMA), which is expressed on mature B-lymphocytes and plasma cells. There are three main categories of BCMA-targeted therapies currently available, including bispecific antibodies (BsAbs), antibody drug conjugates (ADCs), and chimeric antigen receptor (CAR) T-cell therapies. In this review, we discuss the existing BCMA-targeted therapies and provide insights into currently available treatment and future developments, with a particular focus on clinical efficacy and common drug-related adverse events.

Safety, pharmacokinetics, and pharmacodynamics of intravenous ferric carboxymaltose in children with iron deficiency anemia

BackgroundIron deficiency is the primary cause of anemia in children. Intravenous (IV) iron formulations circumvent malabsorption and rapidly restore hemoglobin.MethodsThis Phase 2, non-randomized, multicenter study characterized the safety profile and determined appropriate dosing of ferric carboxymaltose (FCM) in children with iron deficiency anemia. Patients aged 1–17 years with hemoglobin <11 g/dL and transferrin saturation <20% received single IV doses of undiluted FCM 7.5 mg/kg (n = 16) or 15 mg/kg (n = 19).ResultsThe most common drug-related treatment-emergent adverse event was urticaria (in three recipients of FCM 15 mg/kg). Systemic exposure to iron increased in a dose-proportional manner with approximate doubling of mean baseline-corrected maximum serum iron concentration (157 µg/mL with FCM 7.5 mg/kg; and 310 µg/mL with FCM 15 mg/kg) and area under the serum concentration–time curve (1901 and 4851 h·µg/mL, respectively). Baseline hemoglobin was 9.2 and 9.5 g/dL in the FCM 7.5 and 15 mg/kg groups, respectively, with mean maximum changes in hemoglobin of 2.2 and 3.0 g/dL, respectively.ConclusionsIn conclusion, FCM was well tolerated by pediatric patients. Improvements in hemoglobin were greater with the higher dose, supporting use of the FCM 15 mg/kg dose in pediatric patients (Clinicaltrials.gov NCT02410213).ImpactThis study provided information on the pharmacokinetics and safety of intravenous ferric carboxymaltose for treatment of iron deficiency anemia in children and adolescents.In children aged 1–17 years with iron deficiency anemia, single intravenous doses of ferric carboxymaltose 7.5 or 15 mg/kg increased systemic exposure to iron in a dose-proportional manner, with clinically meaningful increases in hemoglobin.The most common drug-related treatment-emergent adverse event was urticaria.The findings suggest that iron deficiency anemia in children can be corrected with a single intravenous dose of ferric carboxymaltose and support use of a 15 mg/kg dose.

Safety, Tolerability and Pharmacokinetics of Single-Dose Oral SYHA1402 in Healthy Chinese Subjects.

To assess the safety, tolerability and pharmacokinetics of a single dose of SYHA1402 in healthy Chinese subjects. This was a randomized, double-blind, placebo-controlled, single-ascending dose study in healthy subjects. Subjects received a single dose of SYHA1402 25mg, 50mg, 100mg, 200mg, 400mg or 800mg, or matching placebo. Safety and tolerability were assessed throughout the study. The pharmacokinetic (PK) parameters of SYHA1402 were estimated using non-compartmental analysis. In all, 54 subjects were enrolled and completed the study. Specifically, there were no deaths, serious adverse events or withdrawals from study due to adverse events. All treatment-emergent adverse events were mild. The most common drug-related adverse event was sinus bradycardia. The time to maximum concentration ranged from 1.13 to 2.25h, and the terminal elimination half-life range was 1.51-4.70h. SYHA1402 exhibited nonlinear PK parameters with less than dose-proportional increases in exposure after single oral doses of 25 to 800mg. SYHA1402 administered as a single dose was well tolerated and safe over the dose range of 25-800mg. More than 50% of the unchanged SYHA1402 was excreted in urine within the dose range of 25-100mg. NCT03988413 ( https://www. gov/ ; registration date: 17 June 2019).

Potent antitumor activity of ensartinib in MET exon 14 skipping-mutated non-small cell lung cancer

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of ensartinib were 67% and 94% in cohort 1, and 73% and 91% in cohort 2. The median DoR was 6.8 months and median PFS was 6.1 months in the total population. Rash was the most common drug-related adverse event, and peripheral edema of any grade was reported in only 9% patients. Molecular simulations indicated favorable binding of ensartinib to c-MET. The kinase assay demonstrated an IC50 of 7.9 nM of ensartinib against METex14 protein. In vitro, Hs746T (METex14 mutation) and EBC-1 (MET amplification) cells were sensitive to ensartinib, with IC50 values of 31 and 44 nM, respectively. Ensartinib exhibited comparable inhibitory effects on cell migration as crizotinib and tepotinib in both cell types. In vivo, ensartinib suppressed the growth of Hs746T cells. Ensartinib also potently inhibited the viability of PDOs. Overall, Ensartinib exhibited substantial antitumor effects against METex14 mutant NSCLCs in preclinical and clinical trials, with relatively low peripheral edema rates.

Effect of Induction Therapy With Olamkicept vs Placebo on Clinical Response in Patients With Active Ulcerative Colitis

Olamkicept, a soluble gp130-Fc-fusion-protein, selectively inhibits interleukin 6 (IL-6) trans-signaling by binding the soluble IL-6 receptor/IL-6 complex. It has anti-inflammatory activities in inflammatory murine models without immune suppression. To assess the effect of olamkicept as induction therapy in patients with active ulcerative colitis. Randomized, double-blind, placebo-controlled phase 2 trial of olamkicept in 91 adults with active ulcerative colitis (full Mayo score ≥5, rectal bleeding score ≥1, endoscopy score ≥2) and an inadequate response to conventional therapy. The study was conducted at 22 clinical study sites in East Asia. Patients were recruited beginning in February 2018. Final follow-up occurred in December 2020. Eligible patients were randomized 1:1:1 to receive a biweekly intravenous infusion of olamkicept 600 mg (n = 30) or 300 mg (n = 31) or placebo (n = 30) for 12 weeks. The primary end point was clinical response at week 12 (defined as ≥3 and ≥30% decrease from baseline total Mayo score; range, 0-12 [worst] with ≥1 decrease and ≤1 in rectal bleeding [range, 0-3 {worst}]). There were 25 secondary efficacy outcomes, including clinical remission and mucosal healing at week 12. Ninety-one patients (mean age, 41 years; 25 women [27.5%]) were randomized; 79 (86.8%) completed the trial. At week 12, more patients receiving olamkicept 600 mg (17/29 [58.6%]) or 300 mg (13/30 [43.3%]) achieved clinical response than placebo (10/29 [34.5%]), with adjusted difference vs placebo of 26.6% (90% CI, 6.2% to 47.1%; P = .03) for 600 mg and 8.3% (90% CI, -12.6% to 29.1%; P = .52) for 300 mg. Among patients randomized to receive 600 mg olamkicept, 16 of 25 secondary outcomes were statistically significant compared with placebo. Among patients randomized to receive 300 mg, 6 of 25 secondary outcomes were statistically significant compared with placebo. Treatment-related adverse events occurred in 53.3% (16/30) of patients receiving 600 mg olamkicept, 58.1% (18/31) receiving 300 mg olamkicept, and 50% (15/30) receiving placebo. The most common drug-related adverse events were bilirubin presence in the urine, hyperuricemia, and increased aspartate aminotransferase levels, and all were more common in the olamkicept groups compared with placebo. Among patients with active ulcerative colitis, biweekly infusion of olamkicept 600 mg, but not 300 mg, resulted in a greater likelihood of clinical response at 12 weeks compared with placebo. Further research is needed for replication and to assess longer-term efficacy and safety. ClinicalTrials.gov Identifier: NCT03235752.

Efficacy, safety, and palatability of arpraziquantel (L-praziquantel) orodispersible tablets in children aged 3 months to 6 years infected with Schistosoma in Côte d'Ivoire and Kenya: an open-label, partly randomised, phase 3 trial

WHO has underlined the need for a child-friendly treatment for schistosomiasis, a prevalent parasitic disease in low-income and middle-income countries. After successful phase 1 and 2 trials, we aimed to evaluate the efficacy, safety, palatability, and pharmacokinetics of arpraziquantel (L-praziquantel) orodispersible tablets for preschool-aged children. This open-label, partly randomised, phase 3 study was conducted at two hospitals in Côte d'Ivoire and Kenya. Children with a minimum bodyweight of 5 kg in those aged 3 months to 2 years and 8 kg in those aged 2-6 years were eligible. In cohort 1, participants aged 4-6 years infected with Schistosoma mansoni were randomly assigned (2:1) to receive a single dose of oral arpraziquantel 50 mg/kg (cohort 1a) or oral praziquantel 40 mg/kg (cohort 1b) using a computer-generated randomisation list. Cohorts 2 (aged 2-3 years) and 3 (aged 3 months to 2 years) infected with S mansoni, and the first 30 participants in cohort 4a (aged 3 months to 6 years) infected with Schistosoma haematobium, received a single dose of oral arpraziquantel 50 mg/kg. After follow-up assessments, arpraziquantel was increased to 60 mg/kg (cohort 4b). Laboratory personnel were masked to the treatment group, screening, and baseline values. S mansoni was detected using a point-of-care circulating cathodic antigen urine cassette test and confirmed using the Kato-Katz method. The primary efficacy endpoint was clinical cure rate at 17-21 days after treatment in cohorts 1a and 1b, measured in the modified intention-to-treat population and calculated using the Clopper-Pearson method. This study is registered with ClinicalTrials.gov, NCT03845140. Between Sept 2, 2019, and Aug 7, 2021, 2663 participants were prescreened and 326 were diagnosed with S mansoni or S haematobium. 288 were enrolled (n=100 in cohort 1a, n=50 in cohort 1b, n=30 in cohort 2, n=18 in cohort 3, n=30 in cohort 4a, and n=60 in cohort 4b), but eight participants received antimalarial drugs and were excluded from the efficacy analyses. The median age was 5·1 years (IQR 4·1-6·0) and 132 (47%) of 280 participants were female and 148 (53%) were male. Cure rates with arpraziquantel were similar to those with praziquantel (87·8% [95% CI 79·6-93·5] in cohort 1a vs 81·3% [67·4-91·1] in cohort 1b). No safety concerns were identified during the study. The most common drug-related treatment-emergent adverse events were abdominal pain (41 [14%] of 288 participants), diarrhoea (27 [9%]), vomiting (16 [6%]), and somnolence (21 [7%]). Arpraziquantel, a first-line orodispersible tablet, showed high efficacy and favourable safety in preschool-aged children with schistosomiasis. The Global Health Innovative Technology Fund, the European and Developing Countries Clinical Trials Partnership, and the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: 10.13039/100009945).

Retrospective review of safety and efficacy of anlotinib in advanced osteosarcoma with metastases after failure of standard multimodal therapy.

To study the safety and efficacy of anlotinib, a multitargeted tyrosine kinase inhibitor, in the treatment of advanced osteosarcoma (OSS) with metastases. We retrospectively studied patients with advanced OSS and metastases who received anlotinib treatment in our hospital from June 2018 to April 2020. All patients had received standard multimodal therapies, before taking anlotinib. Therapeutic doses of anlotinib were 12mg for adults and 10mg for children and adolescents once a day for 2 consecutive weeks, followed by a week of withdrawal. This 3-week cycle of treatment was continued until the tumor progressed rapidly or the patients failed to tolerate the side effects. Adverse drug reactions were recorded, and therapeutic efficacy was evaluated based on progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and objective response rate (ORR). The median PFS was 9.8±.9 months, and the 6- and 10-month PFS rates were 73% and 33%, respectively. The median OS was 11.4±.6 months. No patients achieved complete response. After 6 months of treatment, the DCR and ORR were 80% and 13%, respectively. No drug-related deaths or Grade 4 adverse events occurred in the patients. Five patients (33%) had Grade 3 adverse events. The most common drug-related adverse events were hand-food syndrome, fatigue, high blood pressure, anorexia, and pneumothorax. Anlotinib had a modest therapeutic effect in patients with advanced OSS after the failure of standard treatment. The adverse events were mostly tolerable or relieved after treatment.

First-in-human phase I dose-escalation and dose-expansion trial of the selective MEK inhibitor HL-085 in patients with advanced melanoma harboring NRAS mutations

BackgroundHL-085 is a selective, orally administered MEK1/2 inhibitor. We aimed to evaluate the safety and efficacy of HL-085 in patients with advanced melanoma harboring NRAS mutations.MethodsThis was a multicenter phase 1 study. HL-085 was administered twice daily in a standard 3 + 3 dose-escalation design (10 dose cohorts; 0.5–18 mg twice daily), followed by dose expansion at the recommended phase II dose (RP2D). The primary endpoints included tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and RP2D.ResultsBetween September 13, 2017, and January 18, 2021, 42 patients were enrolled (dose escalation phase: n = 30; dose expansion phase: n = 12). No DLT was reported during dose escalation and MTD was not reached with HL-085 doses up to 18 mg twice daily. The RP2D was 12 mg twice daily. The most common all-grade drug-related adverse events (AEs) across all dose levels were rash (61.9%), increased creatine phosphokinase (CK, 59.5%), face edema (50.0%), increased aspartate aminotransferase (47.6%), peripheral edema (40.5%), diarrhea (33.3%), alanine aminotransferase (33.3%), and paronychia (19.0%), most of which were grade 1 and 2. Most frequency of grade ≥ 3 AEs were CK (14.2%), asthenia (7.1%), peripheral edema (4.8%), and acneiform dermatitis (4.8%). In the cohort of 12 mg twice daily dose (15 patients), confirmed objective response rate was 26.7%; disease control rate was 86.7%; median duration of response was 2.9 months; median progression-free survival was 3.6 months.ConclusionsThe HL-085 showed acceptable tolerability and substantial clinical activity in patients with advanced melanoma harboring NRAS mutations.Trial registrationTrial registration ClinicalTrials.gov number: NCT03973151.

1251. 5-year outcomes of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) as initial treatment of HIV-1 in adults with high baseline HIV-1 RNA and/or low CD4 count in two Phase 3 randomized clinical trials

Abstract Background People with HIV (PWH) who are initiated on guidelines-recommended first-line INSTI-based antiretroviral therapy routinely achieve rapid virologic suppression; however, those with a high baseline (BL) HIV-1 RNA and/or low CD4 count may be more challenging to manage in the short- and long-term. To further characterize long-term outcomes over 5 years in select subgroups, we analyzed results from two studies examining B/F/TAF as initial treatment stratified by BL HIV-1 RNA and/or CD4 count. Methods Adults with HIV were randomized to receive blinded initial treatment with B/F/TAF versus dolutegravir [DTG]/abacavir/lamivudine (Study 1489) or DTG+F/TAF (1490) for 144 weeks (W) of blinded treatment followed by an optional switch to open-label B/F/TAF for 96W. We present virologic response (HIV-1 RNA &amp;lt; 50 c/mL, missing=excluded and missing=failure) and study drug-related adverse events (DRAE) from a pooled analysis of participants originally randomized to B/F/TAF who had BL HIV-1 RNA 100,00-400,000 copies(c)/mL, HIV-1 RNA &amp;gt;400,000 c/mL and/or CD4 count &amp;lt; 200 cells/µL through W240. Results 634 adults (median age 32 years, 89% men, 33% Black/African descent, 24% Hispanic/LatinX) originally randomized to B/F/TAF were included for analysis. At BL, 80 participants had a BL CD4 count &amp;lt; 200 cells/µL and 119 participants had HIV-1 RNA &amp;gt;100,000 c/mL, of whom, 20 had HIV-1 RNA &amp;gt;400,000 c/mL. At W240, virologic suppression was high for the low CD4 count and/or high HIV-1 RNA subgroups (Table). No participant in the final resistance analysis developed virologic resistance to any component of B/F/TAF. Across the subgroups, the most common DRAEs were nausea, headache and diarrhea and there were no serious DRAEs. There was only one discontinuation due to a DRAE in the low CD4 count subgroup, and none in the high HIV-1 RNA subgroup. Conclusion Initial treatment with B/F/TAF was safe and efficacious over 5 years of follow-up in people with a high BL HIV-1 RNA and/or low CD4 count. These outcomes provide additional evidence that B/F/TAF is an effective and durable regimen for a broad range of PWH, including those with advanced disease. Disclosures Moti Ramgopal, MD, FACP, FIDSA, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Speakers Bureau|Janssen: Advisor/Consultant|Janssen: Speakers Bureau|Merck: Advisor/Consultant|Merck: Speakers Bureau|ViiV: Advisor/Consultant|ViiV: Speakers Bureau Axel Baumgarten, MD, AbbVie: Honoraria|Gilead Sciences: Honoraria|Janssen: Honoraria|MSD: Honoraria|ViiV: Honoraria Anton Pozniak, MD, FRCP, Gilead: Grant/Research Support|Gilead: Honoraria|Janssen: Grant/Research Support|Janssen: Honoraria|Merck: Honoraria|theratec: Honoraria|ViiV: Grant/Research Support|ViiV: Honoraria Chloe Orkin, MBChB, FRCP, MD, Gilead Sciences: Honoraria|GSK: Honoraria|Janssen: Honoraria|MSD: Honoraria Juan Manuel Tiraboschi, PhD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Grant/Research Support|MSD: Advisor/Consultant|MSD: Grant/Research Support|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Grant/Research Support Debbie P. Hagins, MD, FAPCR, AAHIVS, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Speakers Bureau|Janssen: Grant/Research Support|Merck: Advisor/Consultant|Merck: Grant/Research Support|ViiV: Advisor/Consultant|ViiV: Grant/Research Support Hailin Huang, PhD, Gilead Sciences, Inc.: Employer|Gilead Sciences, Inc.: Stocks/Bonds Kristin Andreatta, MSc, Gilead Sciences, Inc: Employee of Gilead Sciences|Gilead Sciences, Inc: Stocks/Bonds Nathan Unger, PharmD, AAHIVP, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Jason Hindman, PharmD, MBA, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Hal Martin, MD, Gilead Sciences: employee|Gilead Sciences: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Olayemi Osiyemi, MD, Gilead: Advisor/Consultant|gsk: Advisor/Consultant|viiv: Advisor/Consultant.

Prospective Observational Study of Sorafenib in Hepatocellular Carcinoma Patients With Very High Risk of Recurrence After Surgery

Surgical resection remains the mainstay of treatment for hepatocellular carcinoma (HCC). However, reducing the risk of postoperative recurrence is urgently needed. We planned a prospective observational study to investigate the efficacy and safety of adding sorafenib in a maintenance setting after surgery in HCC patients with high risk of recurrence. Patients with HCC (invasion of the hepatic vein or inferior vena cava or tumor size >7 cm or tumor to nontumor standardized uptake value ratio >2 by fluorodeoxyglucose positron emission tomography) who underwent macroscopically curative resection were eligible. Dose and schedule of sorafenib were set at 800 mg/day for six months after hepatic resection. The primary endpoint was progression-free survival, and the secondary endpoints were overall survival and safety. This study was registered with the UMIN Clinical Trials Registry (UMIN000013089). Ten patients were evaluated. Six patients completed the pre-planned treatment. Three patients discontinued treatment because of disease progression (lung metastasis in two patients and liver metastasis in one), and one patient discontinued because of pneumonia. The most common drug-related adverse event was increased γ-glutamyl transpeptidase (γGTP). None of the patients suffered grade 4 adverse events. The median progression-free survival was 380 (range=38-1,555) days. The median overall survival was 1000 (range=850-1,705) days. Four patients survived without disease progression for more than 800 days. Although the sample size was limited, this is the first study to demonstrate the safety and efficacy of sorafenib in a maintenance setting after surgery for HCC patients with high risk of recurrence.

First in Human (FIH) Study of GFH009, a Highly Selective Cyclin-Dependent Kinase 9 (CDK9) Inhibitor, in Patients with Relapsed/Refractory (r/r) Hematologic Malignancies

Background: The key roles of cyclin-dependent kinases in cell proliferation and various aspects of transcription have led to efforts to develop CDK inhibitors as cancer therapeutics. Positive transcription elongation factor b (PTEFb) consisting of Cyclin T and CDK9 is a key regulator of transcription in cancer cells. It is vital for transcription of short-lived gene products, such as MYC and MCL-1, that maintain cancer cell survival. GFH009 is a potent and highly selective CDK9 inhibitor. Here we report preliminary safety and efficacy data from the FIH study of GFH009 in patients with r/r hematologic malignancies (NCT04588922). Methods: This is a phase I, multicenter, dose-escalation trial of GFH009 enrolling patients with relapsed/refractory acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL) or lymphoma. The Bayesian optimal interval (BOIN) design is employed in the dose escalation cohorts of 3-6 patients. In the first part of the trial, GFH009 was administered intravenously over 30-60 minutes twice per week. The primary endpoint was to evaluate the safety of GFH009 measured by adverse events using common terminology criteria for adverse event (CTCAE) v5.0 and dose limiting toxicities (DLTs). Disease responses were evaluated using Lugano (2014) for lymphoma, IWG criteria (2003) for AML, and iwCLL (2018) for CLL/SLL. Blood samples were collected and analyzed for pharmacokinetics (PK) and pharmacodynamics (PD). Results: As of 15 July 2022, a total of 46 patients were screened, and 30 received at least one dose of GFH009 as monotherapy, including 16 lymphoma patients in 2.5, 4.5, 9 and 15 mg dose cohorts and 14 AML patients in 9, 15, 22.5 and 30 mg dose cohorts. The median age was 52 (range 18-73), and 53% were male. Nine patients (30%) discontinued treatment due to disease progression, eight (27%) due to subjects’ decision and six (20%) due to lack of efficacy. No DLTs were observed to date. The most common drug related AEs were white blood cell decreased [20.0% (6/30), 6.7% (2/30) of which was ≥ G3], neutrophil count decreased [16.7% (5/30), 6.7% (2/30) ≥ G3] and anemia [13.3% (4/30), 3.3% (1/30) ≥ G3]. G3/G4 treatment emergent AEs recorded in >10% of patients included anemia, white blood cell decreased, platelet count decreased, neutrophil count decreased and pneumonia. The total of 12 serious adverse events (SAEs) occurred in 11 subjects, three of which were drug related. All the drug related SAEs were G3 pneumonia. One death was recorded due to disease progression of AML. Four lymphoma patients (3 in 4.5 mg and 1 in 9 mg) achieved stable disease (SD) including one peripheral T cell lymphoma (PTCL), one diffuse large B-cell lymphoma, one Hodgkin lymphoma and one mucosa-associated lymphoid tissue (MALT) lymphoma. The patient with PTCL at 9 mg dose had 62% decrease in sum of the product of the perpendicular diameters for multiple lesions (SPD) based on computed tomography (CT). The duration of treatment of the PTCL patient and MALT lymphoma patient was 12 weeks and 41 weeks respectively and they continue treatment at the cut-off date. No objective response was observed in AML patients, but two patients, one at 9 mg dose level and one at 15 mg dose level, had decrease of bone marrow blasts ≥ 50%. PK exposure increased in a dose-proportional manner as increasing dose from 2.5 mg to 22.5 mg. The mean half-life ranged from 14.9 h to 17.7 h. Pharmacodynamic assessment of MYC and MCL1 mRNA in whole blood showed post-dose reduction of short half-life mRNA transcripts at higher dose levels. Conclusion: GFH009 as monotherapy is well tolerated at the tested doses and has shown clinical activity in patients with r/r lymphoma. The dose escalation in patients with AML and lymphoma is ongoing. Different dosing regimens are currently being explored for potentially better inhibition on the target. GFH009 add-back in patients refractory to or relapsed while on venetoclax and hypomethylating agents is planned in AML patients. Key words: cyclin-dependent kinases, CDK9 inhibitor, MYC, MCL-1, AML, lymphoma, CLL, SLL, PTCL, MALT lymphoma

LB1148: An Enteral Protease Inhibitor Significantly Accelerated the Return of Bowel Function after Bowel Resection

Introduction: Return of bowel function is a clinically accepted determinant of recovery after gastrointestinal (GI) surgery. Postoperative ileus presents significant clinical challenges that may prolong hospital stay, contribute to readmission, and increase morbidity and expense. The aim of this study was to determine if a novel enteral formulation of tranexamic acid, LB1148, could accelerate return of GI function in patients undergoing bowel resection surgery. Methods: We conducted a phase II multicenter, randomized, double-blind, placebo-controlled study of LB1148 for the restoration of postoperative bowel function in patients undergoing elective bowel resection. The study included both open and laparoscopic surgical approaches with anastomosis and or stoma creation. Primary outcome was recovery of bowel function as measured by time from end of surgery to oral food tolerance and passage of stool. Results: A total of 120 patients completed the study. Treatment groups were well balanced for patient demographics and included a broad range of baseline surgery characteristics, approaches, and methodologies. Median time to return of bowel function was 2.77 days vs 3.83 days in patients receiving LB1148 and placebo, respectively (hazard ratio=1.8; p = 0.0008). Key GI functional data will be presented based on laparoscopy and laparotomy with surgical characteristics including, right hemicolectomy, left hemicolectomy, and rectosigmoid surgery. The most common drug-related adverse events were GI disorders (LB1148 4.7% vs placebo 3.2%). No drug-related serious adverse events occurred in the trial. Conclusion: For patients undergoing elective bowel resection surgery, LB1148 was safe and well-tolerated and significantly accelerated the return of bowel function.

First-in-human study to evaluate the safety, tolerability and pharmacokinetics of a novel analgesic and antipyretic drug with structural similarity to acetaminophen

JNJ-10450232 (NTM-006) is a new molecular entity that comprises structural similarities to acetaminophen and provides comparable analgesia in animals and humans without causing the hepatotoxicity associated with acetaminophen overdose in preclinical models. This double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of JNJ-10450232 (NTM-006) following single (50–6000 mg) and multiple (250–2500 mg twice daily for 8 days) doses in healthy male volunteers. JNJ-10450232 (NTM-006) was absorbed within 1–3 h, except at high doses at which Cmax was delayed and bimodal, while increases in AUC were more than dose proportional. CL/F and Vd/F decreased approximately 3-fold with increasing single doses up to 6000 mg and multiple doses up to 1000 mg, resulting in similar t½ values that ranged from 8 to 10 h across doses. JNJ-10450232 (NTM-006) was generally safe and well tolerated, and no dose-limiting toxicities were observed. Transient increases in indirect bilirubin were noted at post-baseline timepoints due to UGT1A1 inhibition, without any evidence of adverse hepatic effects. Macular rash and generalized erythema were the most common drug-related adverse events after multiple doses.

A novel combo of niraparib and anlotinib in platinum-resistant ovarian cancer, the final efficacy and safety report of ANNIE study, a phase II, multi-center trial (LBA 2)

<b>Objectives:</b> Patients with platinum-resistant ovarian cancer have a poor prognosis. Effective treatment options for these patients are limited. In this study (ANNIE), we evaluated the efficacy and safety of niraparib combined with anlotinib in patients with platinum-resistant recurrent (PRR) epithelial ovarian, fallopian tubal, or primary peritoneal cancer. <b>Methods:</b> The ANNIE trial (ClinicalTrials.gov identifier NCT04376073) was a multicentre, single-arm, phase 2 study. The patients with PRR and the measurable disease were given oral niraparib 300mg/200mg once daily continuously and anlotinib 12mg/10mg/8mg on day 1-14 of each 21-day cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR) according to RECIST version 1.1. An exploratory analysis of archival peripheral blood was conducted in an attempt to analysis the correlation between circulating tumor markers and prognosis. <b>Results:</b> Between May 22, 2020, and April 22, 2021, 40 patients were finally enrolled. The subjects had previously received a median 4 lines (range, 1-9) of chemotherapy. Only 5 subjects had a deleterious germline <i>BRCA</i>1/2 mutation. At the cutoff date of analysis on December 31, 2021, 7 subjects were still on treatment. Thirty-six subjects underwent imaging evaluation. The confirmed best overall response showed 1 case with complete responses, 19 with partial responses, yielding the ORR of 55.6% (95% CI, 38.1%~ 72.1%). The median progression-free survival was 8.3 (95% CI, 5.86~ 10.81) months. The median overall survival was not reached. The most common drug-related adverse events were hypertension (55.0%), leucopenia (45.0%) and hand-foot syndrome (42.5%), and the most common Grade 3/4 events were neutropenia (17.5%), hypertension (12.5%) and anemia (12.5%). No treatment-related death was recorded. Preliminary analysis showed that patients with wild-type <i>PPM1D</i> had more significant changes in tumor size than those with <i>PPM1D</i> mutation (<i>P</i> =0.048). Further analysis of biomarkers and treatment prognostic results is ongoing and released soon. <b>Conclusions:</b> Niraparib in combination with anlotinib showed promising antitumor activity and tolerable toxicity in patients with platinum-resistant recurrent ovarian cancer.Fig. 1

Safety, tolerability and pharmacokinetics of a Class I natural medicine with therapeutic potential for vascular dementia: Naoqingzhiming tablet

Naoqingzhiming, whose active ingredient is echinacoside, is the first new Class I natural medicine approved for clinical trials for the therapeutic potential of vascular dementia in China. We report randomized, double-blind, placebo-controlled trials to evaluate the safety, tolerability and pharmacokinetics of single ascending doses of Naoqingzhiming tablet after oral administration in healthy Chinese subjects. The single ascending dose of Naoqingzhiming tablet (180–2160 mg) were well tolerated in all enrolled subjects, without serious adverse events and adverse events leading to withdrawal from the study. The most common drug-related treatment-emergent adverse events were elevated blood bilirubin and serum uric acid. No clinically significant findings were found in the physical examinations, vital signs or electrocardiograms. After single-dose administration of Naoqingzhiming tablet, echinacoside was absorbed with a Tmax at 1.25–1.75 h and declined with a t1/2 of 2.42–3.33 h. However, the proportionality coefficients for Cmax, AUC0−t and AUC0-∞ of echinacoside were not fully contained in the pre-defined 90 % CI criterion (0.91–1.09). As a result, the dose proportionality could not be concluded statistically within the dosage range of this study. Overall, the safety profile and PK properties support further development and use of Naoqingzhiming in vascular dementia.